Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus

Emil Ørskov Ipsen; Kasper S Madsen; Yuan Chi; Ulrik Pedersen-Bjergaard; Bernd Richter; Maria-Inti Metzendorf; Bianca Hemmingsen

doi:10.1002/14651858.CD013516.pub2

. 2020 Nov 19;2020(11):CD013516. doi: 10.1002/14651858.CD013516.pub2

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus

Emil Ørskov Ipsen ¹, Kasper S Madsen ¹, Yuan Chi ², Ulrik Pedersen-Bjergaard ³, Bernd Richter ⁴, Maria-Inti Metzendorf ⁴, Bianca Hemmingsen ^4,^✉

Editor: Cochrane Metabolic and Endocrine Disorders Group

PMCID: PMC8092670 PMID: 33210751

Abstract

Background

The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM.

Objectives

To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM.

Search methods

We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases).

Selection criteria

We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose‐lowering drugs, behaviour‐changing interventions, placebo or no intervention.

Data collection and analysis

Two review authors independently screened abstracts, read full‐text articles and records, assessed risk of bias and extracted data. We performed meta‐analyses with a random‐effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE.

Main results

We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both.

Our main outcome measures were all‐cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health‐related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set.

Three studies compared pioglitazone with metformin. They did not report all‐cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low‐certainty evidence). No SAEs were reported in two studies (201 participants; low‐certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low‐certainty evidence). No participant experienced a SAE (very low‐certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low‐certainty evidence). No participant experienced a SAE (low‐certainty evidence).

One study compared pioglitazone with a personalised diet and exercise consultation. All‐cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low‐certainty evidence). No participant experienced a SAE (low‐certainty evidence).

Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All‐cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low‐certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups versus 131/695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low‐certainty evidence). There were 3/93 participants with SAEs in the pioglitazone groups versus 1/94 participants in the placebo groups (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low‐certainty evidence). However, the largest study for this comparison did not distinguish between serious and non‐serious adverse events. This study reported that 121/303 (39.9%) participants in the pioglitazone group versus 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03). One study observed cardiovascular mortality in 2/181 participants in the pioglitazone group versus 0/186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low‐certainty evidence). One study observed NMI in 2/303 participants in the pioglitazone group versus 1/299 participants in the placebo group (RR 1.97: 95% CI 0.18 to 21.65; P = 0.58; very low‐certainty evidence).

Twenty‐one studies compared pioglitazone with no intervention. No study reported on cardiovascular mortality, NMI/S, QoL or socioeconomic effects. All‐cause mortality was 11/441 participants in the pioglitazone groups versus 12/425 participants in the no‐intervention groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low‐certainty evidence). Incidence of T2DM was 60/1034 participants in the pioglitazone groups versus 197/1019 participants in the no‐intervention groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate‐certainty evidence). Studies reported SAEs in 16/610 participants in the pioglitazone groups versus 21/601 participants in the no‐intervention groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low‐certainty evidence).

We identified two ongoing studies, comparing pioglitazone with placebo and with other glucose‐lowering drugs. These studies, with 2694 participants. may contribute evidence to future updates of this review.

Authors' conclusions

Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low‐certainty evidence) and compared with no intervention (moderate‐certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low‐certainty evidence).

The data and reporting of all‐cause mortality, SAEs, micro‐ and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Plain language summary

Does pioglitazone prevent or delay type 2 diabetes and its complications in people at risk of developing type 2 diabetes mellitus?

What is type 2 diabetes?

Type 2 diabetes, also known as adult‐onset diabetes, is the most common type of diabetes. It prevents the body from using insulin properly ‐ insulin is a hormone that helps the body to regulate blood sugar levels. People with type 2 diabetes may suffer long‐term effects (diabetic complications), such as eye or kidney disease, or develop foot ulcers. People with moderately elevated blood sugar levels (often referred to as 'prediabetes') are said to have an increased risk of developing diabetes. Pioglitazone is a blood sugar‐lowering medicine, which is used to treat people with type 2 diabetes.

What did we want to find out?

We wanted to know whether pioglitazone can also be used to prevent or delay type 2 diabetes in people at increased risk of developing the condition. We examined the effects of pioglitazone on important outcomes for patients, such as complications of diabetes, death from any cause, health‐related quality of life and unwanted effects of the treatment.

What did we do?

We searched for studies that investigated pioglitazone used to prevent or delay the onset of type 2 diabetes. Participants had to have elevated blood sugar levels, but lower than diagnostic levels for diabetes, and they needed to be free from other diseases. Studies had to apply the intervention (pioglitazone) for at least 24 weeks.

What we found

We found 27 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) with a total of 4186 participants. The studies compared pioglitazone with other antidiabetic drugs, diet and exercise, placebo (a 'sham' treatment), or no intervention. Twenty‐three out of 27 studies were conducted in China. The studies lasted between 24 weeks and three years.

This evidence is up to date as of November 2019.

Key results

Five studies compared pioglitazone with other antidiabetic drugs (metformin, acarbose or repaglinide) and one study compared pioglitazone with diet and exercise. There were no clear beneficial or harmful effects on the risk of developing diabetes comparing the drugs.

Six studies compared pioglitazone with placebo. There was a reduction or delay in the development of type 2 diabetes: 188 out of 1000 people treated with placebo developed type 2 diabetes compared with 75 per 1000 people treated with pioglitazone (possible spread: 32 per 1000 to 179 per 1000).

Twenty‐three studies compared pioglitazone with no intervention. There was a reduction or delay in the development of type 2 diabetes: 193 out of 1000 people with no intervention developed type 2 diabetes compared with 60 per 1000 treated with pioglitazone (possible spread: 44 per 1000 to 77 per 1000).

Only a few studies reported death from any cause, serious unwanted effects, non‐fatal heart‐attacks or strokes. We were not able to detect any clear benefits or harms of pioglitazone for these outcomes. None of the included studies reported health‐related quality of life or socioeconomic effects (such as costs of the intervention, absence from work, medication consumption).

We found two ongoing studies that we could potentially include in this review. These studies may contribute data from around 2694 participants to future updates of our review.

Future research should focus on whether the effect of pioglitazone is sustained after people stop taking it. Furthermore, research should focus on patient‐important outcomes such as unwanted effects and complications of diabetes.

Quality of the evidence

All studies had problems in their methods or the way they reported results. Moreover, many outcomes were reported by no or just a few studies. We are therefore uncertain whether pioglitazone prevents or delays type 2 diabetes in people at risk of developing the condition.

Summary of findings

Background

Description of the condition

'Prediabetes', 'borderline diabetes', the 'prediabetic stage', 'high risk of diabetes' or 'intermediate hyperglycaemia' (WHO/IDF 2006), are often characterised by various measurements of elevated blood glucose concentrations (such as isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), isolated elevated glycosylated haemoglobin A1c (HbA1c) or combinations thereof). These elevated blood glucose levels indicating hyperglycaemia are considered too high to be normal but below the diagnostic threshold for type 2 diabetes mellitus (T2DM). Therefore, because of the continuous spectrum from the normal to the diabetic stage, a sound evidence base is needed to define thresholds for conditions of 'sub‐diabetes'. It is obvious that the different terms used to describe various stages of hyperglycaemia might induce different emotional reactions. For example, the term 'prediabetes' may imply (at least for the lay person) that diabetes is unavoidable whereas (high) risk of diabetes has the positive connotation that the disease may be avoided altogether. We will use all of the above‐mentioned terms throughout this systematic review, however we will focus on 'prediabetes' because many people associate this label with dire consequences ‐ despite the disputable construct of intermediate health states termed prediseases (Viera 2011). On the other hand, any diagnosis of 'prediabetes' might be an opportunity to review, for example, eating habits and physical activity levels, thus enabling affected individuals to actively change their way of life.

The most commonly used criteria to define people with a high risk of developing T2DM were established by the American Diabetes Association (ADA) and the World Health Organization (WHO). The first glycaemic measurement used to define the prediabetic stage by the US National Diabetes Data Group was IGT (NDDG 1979). IGT is based on the measurement of plasma glucose two hours after ingestion of 75 g glucose. The prediabetic range is defined as a plasma glucose level between 7.8 mmol/L and 11.1 mmol/L (140 mg/dL to 200 mg/dL) two hours after the glucose load. Studies have indicated that IGT is caused by insulin resistance and defective insulin secretion (Abdul‐Ghani 2006). In 1997 the ADA and later on the WHO introduced the IFG concept to define 'prediabetes' (ADA 1997; WHO 1999). The initial definition of IFG was a fasting plasma glucose level of 6.1 mmol/L to 6.9 mmol/L (110 mg/dL to 125 mg/dL). Later on, the ADA reduced the lower threshold for defining IFG to 5.6 mmol/L (100 mg/dL) (ADA 2003). However, this lower cut‐off point for IFG to define 'prediabetes' was not endorsed by the WHO (WHO/IDF 2006). IFG seems to be associated with ß‐cell dysfunction (impaired insulin secretion) and an increase of the hepatic glucose output (DeFronzo 1989). More recently, HbA1c has been introduced for identifying people with a high risk of developing T2DM. In 2009, the International Expert Committee (IEC) suggested the HbA1c to identify people with a high risk of T2DM. People with HbA1c measurements between 6.0% and 6.4% fulfilled this criterion (IEC 2009). Shortly after, the ADA redefined this HbA1c level as 5.7% to 6.4% to identify people with a high risk of developing T2DM (ADA 2010). Unlike IFG and IGT, HbA1c reflects longer‐term glycaemic control, that is, how the blood glucose levels have been during the previous two to three months (Inzucchi 2012).

In 2010, the International Diabetes Federation (IDF) estimated the prevalence of IGT to be 343 million, and this number is predicted to increase to 471 million by 2035 (IDF 2013). Studies have shown poor correlations between HbA1c and IFG/IGT (Gosmanov 2014; Selvin 2011). Moreover, the various glycaemic tests do not seem to identify the same people (Gosmanov 2014; Selvin 2011). The risk of progression from 'prediabetes' to T2DM depends on the diagnostic criteria used to identify 'prediabetes' (Richter 2018). Some people diagnosed with 'prediabetes' will never develop T2DM, and some will return to normoglycaemia (Richter 2018). IFG and HbA1c are both thought to predict a different risk spectrum for developing T2DM (Cheng 2006; Morris 2013). Most importantly, dysglycaemia is commonly an asymptomatic condition, and naturally often remains 'undiagnosed' (CDC 2015).

Currently, ADA recommends reduced calorie intake and increased physical activity for people with increased risk of T2DM (ADA 2017). It is still not clarified if any particular intervention, especially glucose‐lowering drugs, should be recommended for people with 'prediabetes' (Yudkin 2014). Studies have indicated that the progression from 'prediabetes' to T2DM is reduced, or maybe just delayed with 'lifestyle' interventions (usually increased physical activity, dietary changes or both) (Diabetes Prevention Program 2002; Diabetes Prevention Program FU 2009; Finnish Diabetes Prevention Study Group 2001). A recent meta‐analysis of 22 studies with behaviour‐changing interventions in people at high risk of T2DM concluded that the effect of behaviour‐changing interventions on longer‐term diabetes prevention had not been clarified (Dunkley 2014).

The prescription of pharmacological glucose‐lowering interventions for the prevention of T2DM is not generally accepted among international diabetes associations and clinicians. Several groups of pharmacological glucose‐lowering interventions have been investigated in people with 'prediabetes'. Some findings indicate that the progression from 'prediabetes' to T2DM is reduced or maybe just delayed (Diabetes Prevention Program 2002; Diabetes Prevention Program FU 2009). However, the ADA recommends metformin for people with 'prediabetes' and a body mass index (BMI) more than 35 kg/m², aged less than 60 years, and for women with prior gestational diabetes mellitus (ADA 2015). Several Cochrane Reviews have not shown prevention of T2DM after use of insulin secretagogues, sodium‐glucose cotransporter (SGLT) 2 inhibitors, dipeptidyl‐peptidase (DDP) 4 inhibitors, and glucagon‐like peptide (GLP) 1 (Hemmingsen 2016a; Hemmingsen 2016b; Hemmingsen 2017).

Description of the intervention

Glucose‐lowering drugs are most often used to treat T2DM in its initial stages if behaviour‐changing modifications have failed. Pioglitazone affects many tissues and parts of the body. For people with T2DM, pioglitazone can be prescribed as monotherapy or in combination with existing glucose‐lowering interventions (Davies 2019). Currently, pioglitazone is not recommended for people with intermediate hyperglycaemia. The cost of pioglitazone is low in most countries (Davies 2019).

Pioglitazone is a member of the thiazolidinedione group, which also encompasses troglitazone (withdrawn due to hepatic toxicity) and rosiglitazone (withdrawn from several markets due to suspected cardiovascular risk) (Babai 2018; Cohen 2010).

Adverse effects of the intervention

The most common adverse effects of pioglitazone are heart failure, bone fracture, oedema and weight gain (Liao 2017; Richter 2006).

How the intervention might work

Pioglitazone is known to improve insulin sensitivity, glycaemic control, hypertension and dyslipidaemia in people with T2DM (Schernthaner 2013). Pioglitazone decreases fasting and postprandial plasma glucose levels by improving the sensitivity of hepatic and peripheral (muscle) tissue to insulin (Schernthaner 2013). By improving insulin sensitivity, thiazolidinediones may exert beneficial effects on cardiovascular risk factors (Schernthaner 2013).

Pioglitazone exerts its action through a selective and potent inhibition of peroxisome proliferator‐activated receptor (PPAR)‐gamma (Ninomiya 2016). PPARs are transcription factors that reside in the nucleus and become activated by ligands such as thiazolidinediones. Thiazolidinediones enter the cell, bind to the nuclear receptors, and alter the expression of genes. There are several PPARs including PPAR‐alpha, PPAR‐beta/delta, and PPAR‐gamma. PPAR‐gamma receptors are present in adipose, hepatic and skeletal muscle tissue and control insulin‐responsive genes, which have a wide‐ranging influence (Ninomiya 2016).

Why it is important to do this review

There has been an increased focus on the prevention or delay of T2DM with non‐pharmacological interventions and glucose‐lowering medications. Currently, several studies are being conducted to clarify whether the progression from an at‐risk status to T2DM can be stopped or postponed with glucose‐lowering agents (ClinicalTrials.gov). However, a more important issue for people with dysglycaemia is whether the intervention reduces the risk of death or complications ‐ especially cardiovascular disease ‐ related to T2DM.

One systematic review evaluated the effects of pioglitazone in people with T2DM, insulin resistance and intermediate hyperglycaemia. However, the investigators did not search for unpublished data nor apply rigorous Cochrane methodology (Liao 2017). This review concluded that pioglitazone was associated with a reduced risk of macrovascular complications (all types of participants combined). However, the risks of heart failure, bone fracture, oedema and weight gain were increased (Liao 2017).

Objectives

To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs).

Types of participants

We included nondiabetic individuals at risk of developing T2DM, that is, diagnosed with intermediate hyperglycaemia or 'prediabetes'.

Diagnostic criteria for 'prediabetes'

To be consistent with changes in the classification of and diagnostic criteria for 'prediabetes' (IFG, IGT and elevated HbA1c) over the years, the diagnosis should have been established using the standard criteria valid at the time the study started (for example ADA 1997; ADA 2010; NDDG 1979; WHO 1999). Ideally, the diagnostic criteria should be described. If necessary, we used the study authors' definition of 'prediabetes'. Differences of glycaemic measurements used to define 'prediabetes' may introduce substantial heterogeneity. We therefore subjected diagnostic criteria to a subgroup analysis.

Types of interventions

We planned to investigate the following comparisons of intervention versus control/comparator intervention.

Intervention

Pioglitazone as monotherapy
Pioglitazone as a part of a dual combination therapy

Comparisons

Any pharmacological glucose‐lowering monotherapy intervention (e.g. acarbose, metformin, sulphonylurea) compared with pioglitazone as monotherapy
Behaviour‐changing interventions (e.g. diet, exercise, diet and exercise) compared with pioglitazone as monotherapy
Placebo compared with pioglitazone as monotherapy
No intervention compared with pioglitazone as monotherapy
Any pharmacological glucose‐lowering agent (e.g. acarbose, metformin, sulphonylurea) compared with pioglitazone as a part of a dual combination therapy. This glucose‐lowering agent had to be identical in both the intervention and comparator groups (e.g. pioglitazone plus metformin versus metformin or pioglitazone plus acarbose versus acarbose plus metformin).

Concomitant interventions (e.g. educational programmes or additional pharmacotherapy) had to be identical in both the intervention and comparator groups to establish fair comparisons.

For studies including multiple arms, we included any arms that met the review inclusion criteria.

Minimum duration of intervention

We included studies with a duration of the intervention of 24 weeks or more.

Minimum duration of follow‐up

The minimum duration of follow‐up was 24 weeks (end of the intervention period).

We defined any follow‐up period going beyond the original time frame for the primary outcome measure as specified in the power calculation of the study's protocol as an extended follow‐up period, also called 'open‐label extension study' (Buch 2011; Megan 2012).

Summary of specific exclusion criteria

We excluded studies of people exclusively diagnosed with 'metabolic syndrome' because this is a special population that is not representative of people with only intermediate hyperglycaemia. Also, the composite of risk indicators such as elevated blood lipids, insulin resistance, obesity and hypertension, which is termed 'metabolic syndrome' is of doubtful clinical usefulness and uncertain distinct disease entity.
We excluded studies evaluating participants with intermediate hyperglycaemia in combination with another condition (e.g. cystic fibrosis) except for hypertension.
We excluded studies evaluating participants with intermediate hyperglycaemia because of other medical interventions (e.g. glucocorticoids).

We included studies in obese people and participants with previous gestational diabetes, if study investigators described that the participants had intermediate hyperglycaemia. We planned to include studies that did not report one or more of our primary or secondary outcome measures in the publication. If a study had been included this way, we planned to contact the corresponding study author for supplementary data.

Types of outcome measures

Primary outcomes

All‐cause mortality
Incidence of T2DM
Serious adverse events

Secondary outcomes

Cardiovascular mortality
Non‐fatal myocardial infarction
Non‐fatal stroke
Congestive heart failure
Amputation of lower extremity
Blindness or severe vision loss
End‐stage renal disease
Non‐serious adverse events
Hypoglycaemia
Health‐related quality of life
Time to progression to T2DM
Measures of blood glucose control
Socioeconomic effects

Method of outcome measurement

All‐cause mortality: defined as death from any cause
Incidence of T2DM and time to progression to T2DM: defined according to diagnostic criteria valid at the time the diagnosis was established, using the standard criteria valid at the time the study started (e.g. ADA 2008; WHO 1998). If necessary, we used the study authors' definition of T2DM.
Serious adverse events: defined according to the International Conference on Harmonisation Guidelines as any event that led to death, that was life‐threatening, required in‐patient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability, and any important medical event that may have had jeopardised the participant or required intervention to prevent it, or as reported in studies (ICH 1997).
Cardiovascular mortality, non‐fatal myocardial infarction, non‐fatal stroke, congestive heart failure, amputation of lower extremity, blindness or severe vision loss, hypoglycaemia (mild, moderate, severe/serious): defined as reported in studies
End‐stage renal disease: defined as dialysis, renal transplantation or death due to renal disease
Non‐serious adverse events: defined as number of participants with any untoward medical occurrence not necessarily having a causal relationship with the intervention
Health‐related quality of life: defined as mental and physical health‐related quality of life, separate and combined, evaluated by a validated instrument such as Short‐Form 36 (SF‐36)
Measures of blood glucose control: fasting blood glucose, blood glucose two hours after ingestion of 75 g glucose and HbA1c measurements
Socioeconomic effects: for example, costs of the intervention, absence from work, medication consumption

Timing of outcome measurement

Measured at the end of the intervention and the end of follow‐up: all‐cause mortality, cardiovascular mortality, non‐fatal myocardial infarction, non‐fatal stroke, congestive heart failure, amputation of lower extremity, blindness or severe vision loss, hypoglycaemia (mild, moderate, severe/serious), health‐related quality of life, measures of blood glucose control, socioeconomic effects
Measured at the end of the intervention and the longest reported end of follow‐up: incidence of T2DM
Measured at any time of the intervention and during follow‐up: serious adverse events, non‐serious adverse events, hypoglycaemia (mild, moderate, severe/serious)

Search methods for identification of studies

Electronic searches

We searched the following sources from the inception of each database to the date of search and placed no restrictions on the language of publication:

Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11) via the Cochrane Register of Studies Online (CRSO), searched 12 November 2019;
MEDLINE (Ovid MEDLINE ALL 1946 to Daily Update) searched 12 November 2019;
ClinicalTrials.gov (www.clinicaltrials.gov) searched 12 November 2019;
World Health Organization International Clinical Trials Registry Platform (ICTRP; www.who.int/trialsearch/) searched 12 November 2019;
China Network Knowledge Infrastructure (CNKI; cnki.net) searched 4 March 2020;
Chinese Scientific Journals Database (VIP; cqvip.com) searched 4 March 2020;
Wan Fang data (wanfangdata.com.cn/index.html) searched 4 March 2020;
SinoMed (sinomed.ac.cn) searched 4 March 2020.

For detailed search strategies, see Appendix 7.

We did not include Embase in our search, as RCTs indexed in Embase are now prospectively added to CENTRAL via a highly sensitive screening process (Cochrane 2018).

Searching other resources

We tried to identify other potentially eligible studies or ancillary publications by searching the reference lists of included studies, systematic reviews, meta‐analyses, and health technology assessment reports. In addition, we contacted the authors of included studies to obtain additional information on the retrieved studies and establish whether we may have missed further studies.

We also searched databases from regulatory agencies (European Medicines Agency (EMA) and US Food and Drugs Administration (FDA); (Hart 2012; Schroll 2015)).

We did not use abstracts or conference proceedings for data extraction unless full data were available from study authors because this information source does not fulfil the CONSORT requirements, which consists of, "an evidence‐based, minimum set of recommendations for reporting randomized trials" (CONSORT 2018). We defined grey literature as records detected in ClinicalTrials.gov, WHO ICTRP or databases from regulatory agencies.

Data collection and analysis

Selection of studies

Two review authors (EI, BH) independently screened the abstract, title, or both, of every record retrieved by the literature searches, to determine which studies should be further assessed. We obtained the full text of all potentially relevant records. We resolved disagreements through consensus or by recourse to a third review author (KM). If we could not resolve a disagreement, we planned to categorise the study as a 'Study awaiting classification' and contacted the study authors for clarification. We made an adapted PRISMA flow diagram to show the process of study selection (Liberati 2009). All articles excluded after full‐text assessment are listed with reason for exclusion in Characteristics of excluded studies.

Data extraction and management

For English language studies that fulfilled our inclusion criteria, two review authors (EI, KM) independently extracted key participant and intervention characteristics. For Chinese language studies that fulfilled our inclusion criteria, two review authors (EI, YC) independently extracted key participant and intervention characteristics. We described interventions according to the 'template for intervention description and replication' (TIDieR) checklist (Hoffmann 2014; Hoffmann 2017).

We reported data on efficacy outcomes and adverse events using standardised data extraction sheets from Cochrane Metabolic and Endocrine Disorders (CMED). We resolved disagreements by discussion or, if required, by consultation with a third review author (BH) (for details see Characteristics of included studies; Table 5; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14; Appendix 15; Appendix 16; Appendix 17; Appendix 18; Appendix 19; Appendix 20; Appendix 21; Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6.

1. Overview of study populations.

Study ID (study design)	Intervention(s) and comparator(s)	Description of power and sample size calculation	Screened/eligible (N)	Randomised (N)	Analysed (primary outcome) (N)	Finishing study (N)	Randomised finishing study (%)	Follow‐up (extended follow‐up)^a
ACT NOW (parallel RCT)	I: pioglitazone 45 mg/day titrated up from 30 mg/day after 1 month if no adverse effects plus BCI	"Based upon this information (see assumptions below), it can be calculated that approximately 600 subjects with IGT will be required to achieve 90% statistical power that pioglitazone decreases the conversion rate of IGT to type 2 diabetes by 50%. This power calculation assumes that randomized individuals drop out prior to the confirmed diagnosis of diabetes with an exponential hazard rate of 0.10 (or less) per year. The following assumptions were used to calculate the sample size: (i) The primary endpoint is the development of diabetes, (ii) Participants are randomized over a 21 month period and followed for a total of 3.75 years, starting from the time that the first IGT subject is recruited, (iii) Type I error rate (alpha) is 0.05, (iv) The desired power is 90%, (v) The development of diabetes in the placebo‐treated group is 11% per year,(vi) The hazard rate for the development of diabetes in the pioglitazone‐treated group is reduced by 50%. (vii) The drop out rate is 10% per year"	1827/602	303	303	213	70.3	24‐48 months (extended follow‐up with median of 11.4 months)
	C: placebo once daily, placebo dose titrated up after 1 month if no adverse effects plus BCI		1827/602	299	299	228	76.3
	Total:			602	602	441	73.3
Attallah 2007 (2 x 2 factorial RCT)	I: pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks plus GH placebo from 4‐40 weeks	"Sample size was determined using data from Johannsson et al. [19], in which nine months of GH resulted in a 17.9% ± 3.5% reduction in visceral fat along with an improvement in insulin sensitivity in abdominally obese men. Using this information, we determined that 12 participants were needed per group to have an 80% chance of detecting a change in visceral fat of at least 17.9%. However, since women were also included in the study and are known to respond less effectively to GH than men, we increased the sample size to 15."	185/81	22	15	15	68.1	43‐44 weeks
	C: pioglitazone placebo plus GH placebo from 4‐40 weeks		185/81	19	16	16	84.2
	Total:			41	31	31	75.6
Bone 2013 (parallel RCT)	I: pioglitazone 45 mg/day titrated up from 30 mg/day plus vitamin D and calcium	"The a priori sample size calculation projected that 75 women per treatment group would be required for the two‐sided 95% CI of the estimated between‐group treatment difference to be within the target precision limits of ± 2.3%, assuming a SD of 6.5% and dropout rate of 18%. In a post hoc power calculation using the observed SD of 3% and 60 women per group, it was determined that the study had greater than 90% power to detect a between group difference in percentage change in BMD from baseline to month 12 if the true difference were 1.7%	386/156	78	78	57	73.1	18 months
	C: matching placebo once daily plus vitamin D and calcium		386/156	78	78	61	76.9
	Total:			156	156	117	75
Che 2014 (parallel RCT)	I: L‐amlodipine 5 mg/day plus pioglitazone 30 mg/day	—	—	38	38	38^b	100^c	6 months
	C: L‐amlodipine 5 mg/day	—	—	35	35	35^b	100^c
	Total:			73	73	73^b	100^c
Chen 2007a (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	50	50	50	100	12 months
	C1: acarbose 150 mg/day plus BCI			50	46	46	92
	C2: metformin 750 mg/day plus BCI			50	46	46	92
	C3: BCI			50	50	50	100
	C4: no intervention			50	50	50	100
	Total:			250	242	242	96.8
Chen 2007b (parallel RCT)	I: pioglitazone 15 mg/day plus captopril 50 mg/day and Betaloc 50 mg/day	—	—	88	83	83	94.3	24 months
	C: captopril 50 mg/day and Betaloc 50 mg/day	—	—	80	73	73	91.3
	Total:			168	156	156	94.0
Deng 2013 (parallel RCT)	I: pioglitazone 30 mg/day plus BCI	—	—	303	303^b	303^b	100^b	Mean of 2.2 years
	C: BCI	—	—	302	302^b	302^b	100^b
	Total:			605	605^c	605^c	100^c
Fang 2013 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	60	60	55	91.7	12 months
	C: BCI	—	—	60	60	56	93.3
	Total:			120	120	111	92.5
Gao 2011 (parallel RCT)	I: pioglitazone 30 mg/day, captopril and other antihypertensive drug(s) plus BCI	—	—	50	50	48	96	18 months
	C: captopril and other antihypertensive drug(s) plus BCI	—	—	50	50	46	92
	Total:			100	100	94	94
Guo 2009 (parallel RCT)	I: pioglitazone 30 mg/day plus BCI	—	—	30	30	30^b	100^b	6 months
	C: BCI	—	—	30	30	30^b	100^b
	Total:			60	60	60^c	100^c
Guo 2010 (parallel RCT)	I: pioglitazone 30 mg/day plus BCI	—	—	32	32	32	100	12 months
	C: BCI	—	—	32	32	32	100
	total:			64	64	64	100
Han 2007 (parallel RCT)	I: pioglitazone 15 mg/day plus enalapril (dose not reported)	—	—	23	23	23	100	6 months
	C: enalapril (dose not reported)	—	—	20	20	20	100
	Total:			43	43	43	100
IDPP‐2 (parallel RCT)	I: pioglitazone 30 mg/day titrated up from 15 mg once daily plus BCI	"It was assumed that the cumulative incidence of diabetes in 3 years would be 40% in the control group with lifestyle modification and placebo and 25% in the group receiving lifestyle modification and pioglitazone. The sample sizes required in each of the two groups were 165 with a type 1 error of 5%, with 80% power. Higher numbers were recruited (204 in group A and 203 in group B) to allow for drop out. The intention‐to‐treat approach was used."	6589/882/407 (double screening procedure)	204	181	181	88.7	36 months
	C: placebo in matching doses plus BCI		6589/882/407 (double screening procedure)	203	186	186	91.6
	Total:			407	367	367	90.2
Ke 2006 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	32	30	30	93.8	12 months
	C: BCI	—	—	30	28	28	93.3
	Total:			62	58	58	93.5
Li 2017 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	75	75	75^b	100c	6 months
	C: BCI	—	—	75	75	75^b	100^c
	Total:			150	150	150^b	100^c
Liang 2004 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	30	29	29	96.7	12 months
	C: BCI	—	—	30	30	30	100
	Total:			60	59	59	98.3
Shi 2014 (parallel RCT)	I: pioglitazone 30 mg/day plus BCI	—	—	40	40	40^b	40^b	10 months
	C: placebo in matching doses plus BCI	—	—	40	40	40^b	40^b
	Total:			80	80	80^c	100^c
Tian 2015 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	36	36	36^b	100^b	24 weeks
	C: BCI	—	—	36	36	36^b	100^b
	Total:			72	72	72^c	100^c
Wu 2013 (parallel RCT)	I: pioglitazone 30 mg/day plus amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	—	—	34	34	34^b	100^c	6 months
	C: amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	—	—	33	33	33^b	100^c
	Total:			67	67	67^c	100^c
Xiu 2015 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	43	43	43	100	48 weeks
	C: BCI	—	—	43	43	43	100
	Total:			86	86	86	100
Xu 2011 (parallel RCT)	I: pioglitazone 30 mg/day plus BCI	—	—	60	60	60	100	48 weeks
	C: placebo in matching doses plus BCI	—	—	59	59	59	100
	Total:			119	119	119	100
Yi 2015 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	35	35	35	100	12 months
	C: BCI	—	—	35	35	35	100
	Total:			70	70	70	100
Yu 2011 (parallel RCT)	I: pioglitazone 4 mg/day plus BCI	—	—	60	60	60^b	100^c	6 months
	C: BCI	—	—	60	60	60^b	100^c
	Total:			120	120	120^b	100^c
Zeng 2013 (parallel RCT)	I1: pioglitazone 38 mg/day plus BCI	—	—	70	70	70	100	24 months
	I2: metformin 38 mg/day plus BCI			68	68	68	100
	C: BCI			66	66	66	100
	Total:			204	204	204	100
Zhang 2007 (parallel RCT)	I: pioglitazone 15 mg/day plus BCI	—	—	52	48	48	100	12 months
	C1: metformin 250 mg/day plus BCI			53	49	49	100
	C2: repaglinide 3 x 0.25 mg/day plus BCI			51	48	48	100
	C3: intensive BCI			51	48	48	100
	C4: BCI			56	54	54	100
	Total:			263	263	247	93.9
Zhang 2015 (parallel RCT)	I: pioglitazone 15 mg/day	—	—	26	26	26	100	6 months
	C: BCI	—	—	26	25	25	96.2
	Total:			52	51	51	98.1
Zhao 2009 (parallel RCT)	I: pioglitazone 15 mg/day	—	—	47	47	47^b	100^c	6 months
	C: BCI	—	—	45	45	45^b	100^c
	Total:			92	92	92^b	100^c

Grand total (all included studies)	All interventions			1921		NA^d
	All comparators			2265		NA^d
	All interventions and comparators			4186		NA^d
Total (studies reporting on dropouts)	All interventions			1258		1098	87.2
	All comparators			1765		1462	82.8
	All interventions and comparators			3023		2560	84.7
— denotes not reported BCI: behaviour‐changing intervention; C: comparator; GH: growth hormone; I: intervention; IGT: impaired glucose tolerance; NA: not applicable; RCT: randomised controlled trial; SD: standard deviation.

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^aFollow‐up under randomised conditions until end of study (= duration of intervention + follow‐up post‐intervention or identical to duration of intervention); extended follow‐up refers to follow‐up of participants once the original study was terminated as specified in the power calculation. ^bStudies did not report on dropouts or number of participants finishing study (assumed value). ^cValues calculated include assumptions on finishing rates of studies not reporting on dropout or finishing rates. ^dNot all included studies reported on dropouts.

We provided information including study identifier for potentially relevant ongoing studies in the Characteristics of ongoing studies table and in Appendix 15, 'Matrix of study endpoint (publications and study documents)'. We tried to find the protocol for each included study and reported primary, secondary, and other outcomes in comparison with data in publications.

We emailed all authors with available contact information of included studies to enquire whether they would be willing to answer questions regarding their studies. We presented the results of this survey in Appendix 21. We thereafter sought relevant missing information on the study from the primary study author(s), if required.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents, or multiple reports of a primary study, we maximised the information yield by collating all available data and used the most complete data set aggregated across all known publications. All duplicate publications, companion documents, multiple reports of a primary study, and trial documents of included studies (such as trial registry information) are listed as secondary references under the study ID of the included study. All duplicate publications, companion documents, multiple reports of a study, and trial documents of excluded studies (such as trial registry information) are listed as secondary references under the study ID of the excluded study.

Data from clinical trials registers

If data from included studies were available as study results in clinical trials registers, such as ClinicalTrials.gov or similar sources, we made full use of this information and extracted the data. If there was also a full publication of the study, we collated and critically appraised all available data. If an included study had been marked as a completed study in a clinical trials register but no additional information (study results, publication, or both) was available, we planned to add this study to the 'Characteristics of studies awaiting classification' table.

Assessment of risk of bias in included studies

Two review authors (EI, KM) independently assessed the risk of bias for each included English language study. Two review authors (EI, YC) independently assessed the risk of bias for each included Chinese language study. We resolved disagreements by consensus or by consulting a third review author (BH). In the case of disagreement, we planned to consult the remainder of the review author team and make a judgement based on consensus. If adequate information was unavailable from the publications, study protocols, or other sources, we contacted the study authors for more detail to request missing data on 'Risk of bias' items.

We used the Cochrane 'Risk of bias' assessment tool (Higgins 2019b), assigning assessments of low, high, or unclear risk of bias (for details, see Appendix 8; Appendix 9). We evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions, according to the criteria and associated categorisations contained therein (Higgins 2019b).

Summary assessment of risk of bias

We generated a 'Risk of bias' graph and a 'Risk of bias' summary figure (Figure 2; Figure 3).

We distinguished between self‐reported, investigator‐assessed and adjudicated outcome measures.

We considered the following self‐reported outcomes.

Non‐serious adverse events
Hypoglycaemia, if reported by participants
Health‐related quality of life
Blood glucose control, if measured by study participants

We considered the following outcomes to be investigator‐assessed.

All‐cause mortality
Incidence of T2DM
Time to progression to T2DM
Serious adverse events
Cardiovascular mortality
Non‐fatal myocardial infarction
Non‐fatal stroke
Congestive heart failure
Amputation of lower extremity
Blindness or severe vision loss
End‐stage renal disease
Hypoglycaemia, if measured by study personnel
Blood glucose control, if measured by study personnel
Socioeconomic effects

Risk of bias for a study across outcomes

Some 'Risk of bias' domains, such as selection bias (sequence generation and allocation sequence concealment), affect risk of bias across all outcome measures in a study. In case of high risk of selection bias, we planned to mark all endpoints investigated in the associated study as being at high risk. Otherwise, we did not perform a summary assessment of the risk of bias across all outcomes for a study.

Risk of bias for an outcome within a study and across domains

We assessed the risk of bias for an outcome measure by including all entries relevant to that outcome (i.e. both study‐level entries and outcome‐specific entries). We considered low risk of bias to denote a low risk of bias for all key domains, unclear risk to denote an unclear risk of bias for one or more key domains and high risk to denote a high risk of bias for one or more key domains.

Risk of bias for an outcome across studies and across domains

These are the main summary assessments that we incorporated into our judgements about the certainty of the evidence in the 'Summary of findings' tables. We defined outcomes as at low risk of bias when most information came from studies at low risk of bias, unclear risk when most information came from studies at low or unclear risk of bias and high risk when a sufficient proportion of information came from studies at high risk of bias.

Measures of treatment effect

When at least two included studies were available for a comparison of a given outcome, we expressed dichotomous data as a risk ratio (RR) or a Peto odds ratio with 95% confidence intervals (CIs). For continuous outcomes measured on the same scale (e.g. weight loss in kg) we estimated the intervention effect using the mean difference (MD) with 95% CIs. For continuous outcomes that measure the same underlying concept (e.g. health‐related quality of life) but use different measurement scales, we planned to calculate the standardised mean difference (SMD).

Unit of analysis issues

We considered the level at which randomisation occurred, such as cross‐over studies, cluster‐randomised trials, and multiple observations for the same outcome. If more than one comparison from the same study was eligible for inclusion in the same meta‐analysis, we planned either to combine groups to create a single pair‐wise comparison, or to appropriately reduce the sample size so that the same participants did not contribute data to the meta‐analysis more than once (splitting the 'shared' group into two or more groups). Although the latter approach offers some solution for adjusting the precision of the comparison, it does not account for correlation arising from inclusion of the same set of participants in multiple comparisons (Higgins 2019a).

We planned to re‐analyse cluster‐RCTs that did not appropriately adjust for potential clustering of participants within clusters in their analyses. Variance of the intervention effects would have been inflated by a design effect. Calculation of a design effect involves estimation of an intra‐cluster correlation coefficient (ICC). We planned to obtain estimates of ICCs by contacting study authors, or by imputing ICC values using either estimates from other included studies that report ICCs or external estimates from empirical research (e.g. Bell 2013). We planned to examine the impact of clustering by performing sensitivity analyses. We did not include any cluster‐RCTs in this review.

Dealing with missing data

If possible, we obtained missing data from the authors of included studies and carefully evaluated important numerical data such as screened, randomly assigned participants, as well as intention‐to‐treat and as‐treated and per‐protocol populations. We investigated attrition rates (e.g. dropouts, losses to follow‐up, withdrawals), and we critically appraised issues concerning missing data and use of imputation methods (e.g. last observation carried forward).

For studies in which the standard deviation (SD) of the outcome was not available at follow‐up or we could not recreate it, we standardised by the mean of the pooled follow‐up SD from studies that reported this information.

When included studies did report means and SDs for outcomes, and we did not receive requested information from study authors, we planned to impute these values by estimating the mean and the variance from the median, the range and the size of the sample (Hozo 2005).

We investigated the impact of imputation on meta‐analyses by performing sensitivity analyses.

Assessment of heterogeneity

In the event of substantial clinical or methodological heterogeneity, we did not report study results as the pooled effect estimate in a meta‐analysis.

We identified heterogeneity (inconsistency) by visually inspecting the forest plots and by using a standard Chi² test with a significance level of α = 0.1 (Deeks 2019). In view of the low power of this test, we also considered the I² statistic, which quantifies inconsistency across studies, to assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003).

When we found heterogeneity, we attempted to determine possible reasons for this by examining individual study and subgroup characteristics.

Assessment of reporting biases

For outcomes with 10 or more included studies that investigated a particular outcome, we used funnel plots to assess small‐study effects.

Data synthesis

We only displayed a meta‐analysis if we judged participants, interventions, comparisons, and outcomes to be sufficiently similar to ensure an answer that is clinically meaningful. We planned primarily to summarise low risk of bias data using a random‐effects model (Wood 2008), this was not possible because of methodological bias judgements (see Characteristics of included studies). We interpreted random‐effects meta‐analyses with due consideration for the whole distribution of effects and presented a prediction interval (Borenstein 2017a; Borenstein 2017b; Higgins 2009). A prediction interval requires at least three studies to be included in the calculations and specifies a predicted range for the true treatment effect in an individual study (Riley 2013). For rare events such as event rates below 1%, we used the Peto odds ratio method, provided there was no substantial imbalance between intervention and comparator group sizes, and intervention effects were not exceptionally large. In addition, we performed statistical analyses according to the statistical guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2019).

Subgroup analysis and investigation of heterogeneity

We expected the following characteristics to introduce clinical heterogeneity, and we carried out the following subgroup analyses including investigation of interactions (Altman 2003).

Studies with a long duration (four years and longer) versus studies with a shorter duration (less than four years)
Diagnostic 'prediabetes' criteria (IFG, IGT, elevated HbA1c)
Pioglitazone monotherapy versus pioglitazone dual combination therapy
Age, depending on data
Sex
Ethnicity, depending on data
Comorbid conditions, such as hypertension or obesity
Women with and without previous gestational diabetes mellitus

Sensitivity analysis

We performed sensitivity analyses to explore the influence of the following factors (when applicable) on effect sizes by restricting analysis to the following.

Published studies
Effect of risk of bias, as specified in the Assessment of risk of bias in included studies section
Very long or large studies to establish the extent to which they dominate the results
Use of the following filters: diagnostic criteria, imputation, language of publication, source of funding (industry versus other) or country

We also tested the robustness of results by repeating analyses using different measures of effect size (i.e. RR, odds ratio, etc.) and different statistical models (fixed‐effect and random‐effects models).

Summary of findings and assessment of the certainty of the evidence

We presented the overall certainty for each outcome specified below, according to the GRADE approach, which took into account issues related to internal validity (risk of bias, inconsistency, imprecision, publication bias) and also to external validity, such as directness of results. Two review authors (BH, BR) independently rated the certainty of the evidence for each outcome. We resolved differences in assessment by discussion or by consultation with a third review author (KM).

We included Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5 and Appendix 6 entitled 'Checklist to aid consistency and reproducibility of GRADE assessments', to help with standardisation of the 'Summary of findings' tables (Meader 2014). Alternatively, we planned to use the GRADEpro GDT software and would have presented evidence profile tables as an appendix (GRADEproGDT). We presented results for outcomes as described in the Types of outcome measures section. When meta‐analysis was not possible, we presented the results in a narrative format in the 'Summary of findings' table. We justified all decisions to downgrade the certainty of the evidence using footnotes, and we made comments to aid the reader's understanding of the Cochrane Review when necessary.

'Summary of findings' table

We presented a summary of the evidence in Table 1; Table 2; Table 3; Table 4. This provides key information about the best estimate of the magnitude of effect, in relative terms and as absolute differences for each relevant comparison of alternative management strategies, numbers of participants and studies addressing each important outcome, and a rating of overall confidence in effect estimates for each outcome. We created the 'Summary of findings' tables using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2019), along with Review Manager 5 software (Review Manager 2020).

Summary of findings 1. Summary of findings: pioglitazone monotherapy versus another pharmacological glucose‐lowering monotherapy.

Pioglitazone monotherapy versus another pharmacological glucose‐lowering monotherapy (acarbose, metformin, repaglinide)
Population: people at increased risk of developing T2DM Settings: outpatients Intervention: pioglitazone Comparison: acarbose, metformin, repaglinide
Outcomes	Acarbose, metformin, repaglinide	Pioglitazone	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
All‐cause mortality
Metformin	Not reported
Acarbose	Not reported
Repaglinide	Not reported
Incidence of T2DM (N)
Metformin Diagnostic criteria: 2 studies applied the WHO 1999 criteria for 'prediabetes' (FPG > 6.1 mmol/L and < 7.0 mmol/L and/or a 2‐h glucose < 11.1 mmol/L after a 75 g OGTT; Chen 2007a; Zeng 2013) 1 study applied the ADA 2010 criteria (FPG ≥ 5.6 mmol/L and < 6.9 mmol/L and 2‐h glucose ≥ 7.8 mmol/L or < 11.0 mmol/L after a 75 g OGTT; Zhang 2007) Follow‐up: 12‐24 months	55 per 1000	54 per 1000 (22 to 131)	RR 0.98 (0.40 to 2.38)	331 (3)	⊕⊕⊝⊝ Low^a	9/168 participants developed T2DM in the pioglitazone groups vs 9/163 participants in the metformin groups
Acarbose Diagnostic criteria: 1 study applied the WHO 1999 criteria for prediabetes (FPG > 6.1 mmol/L and < 7.0 mmol/L and/or a 2‐h glucose < 11.1 mmol/L after a 75 g OGTT; Chen 2007a) Follow‐up: 12 months	See comment			96 (1)	⊕⊝⊝⊝ Verylow^b	1/50 participants in the pioglitazone group vs 2/46 participants in the acarbose group developed T2DM (Chen 2007a)
Repaglinide Diagnostic criteria: 1 study applied the ADA 2010 criteria (FPG ≥ 5.6 mmol/L and < 6.9 mmol/L and 2‐h glucose ≥ 7.8 mmol/L or < 11.0 mmol/L after a 75 g OGTT; Zhang 2007) Follow‐up: 12 months	See comment			96 (1)	⊕⊕⊝⊝ Low^c	2/48 participants in the pioglitazone group vs 1/48 participants in the repaglinide group developed T2DM (Zhang 2007)
Serious adverse events (N)
Metformin Follow‐up: 12‐24 months	See comment			201 (2)	⊕⊕⊝⊝ Low^a	No participant experienced a serious adverse event (Chen 2007a; Zhang 2007)
Acarbose Follow‐up: 12 months	See comment			96 (1)	⊕⊝⊝⊝ Verylow^b	No participant experienced a serious adverse event (Chen 2007a)
Repaglinide Follow‐up: 12 months	See comment			103 (1)	⊕⊕⊝⊝ Low^c	No participant experienced a serious adverse event (Zhang 2007)
Cardiovascular mortality
Metformin	Not reported
Acarbose	Not reported
Repaglinide	Not reported
Non‐fatal myocardial infarction/stroke
Metformin	Not reported
Acarbose	Not reported
Repaglinide	Not reported
Health‐related quality of life
Metformin	Not reported
Acarbose	Not reported
Repaglinide	Not reported
Socioeconomic effects
Metformin	Not reported
Acarbose	Not reported
Repaglinide	Not reported
ADA: American Diabetes Association; CI: confidence interval; FPG: fasting plasma glucose; OGTT: oral glucose tolerance test; RR: risk ratio; HbA1c: glycosylated haemoglobin A1c; T2DM: type 2 diabetes mellitus; WHO: World Health Organization
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded by two levels because of serious imprecision (low median sample size, small number of studies), see Appendix 1. ^bDowngraded by one level because of attrition bias and by two levels because of serious imprecision (one study only, low median sample size), see Appendix 2. ^cDowngraded by two levels because of serious imprecision (one study only, low median sample size), see Appendix 3.

Summary of findings 2. Summary of findings: pioglitazone monotherapy versus intensive behaviour‐changing intervention.

Pioglitazone monotherapy versus intensive behaviour‐changing intervention
Population: people at increased risk for developing T2DM Settings: outpatients Intervention: pioglitazone Comparison: intensive diet plus exercise intervention
Outcomes	Personalised diet + exercise consultation	Pioglitazone	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
All‐cause mortality	Not reported
Incidence of T2DM (N) Follow‐up: 12 months	See comment			96^a (1)	⊕⊕⊝⊝ Low^b	2/48 participants developed T2DM in the pioglitazone group vs 5/48 participants in the personalised diet and exercise consultation group (Zhang 2007)
Serious adverse events (N)	See comment			103^a (1)	⊕⊕⊝⊝ Low^b	No participant experienced a serious adverse event (Zhang 2007)
Cardiovascular mortality	Not reported
Non‐fatal myocardial infarction/stroke	Not reported
Health‐related quality of life	Not reported
Socioeconomic effects	Not reported
CI: confidence interval; T2DM: type 2 diabetes mellitus
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

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^aOnly people finishing the study were included in analysis of incidence of type 2 diabetes mellitus. All randomised participants were included in the remaining analyses.  ^bDowngraded by two levels because of serious imprecision (one study only, low sample size), see Appendix 4.

Summary of findings 3. Summary of findings: pioglitazone monotherapy versus placebo.

Pioglitazone monotherapy versus placebo (identical behaviour‐changing interventions in both groups)
Population: people at increased risk for developing T2DM Settings: outpatients Intervention: pioglitazone Comparison: placebo
Outcomes	Placebo	Pioglitazone	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
All‐cause mortality (N) Follow‐up: 44 weeks to 2 years	3 per 1000	8 per 1000 (2 to 36)	Peto OR2.38 (0.54 to 10.50)	1156 (4)	⊕⊝⊝⊝ Very low^a	Only 2 studies reported events (ACT NOW; IDPP‐2)
Incidence of T2DM (N) Diagnostic criteria: 3 studies applied the WHO 1999 criteria for 'prediabetes' (FPG > 6.1 mmol/L and < 7.0 mmol/L and/or a 2‐h glucose < 11.1 mmol/L after a 75 g OGTT; Attallah 2007; IDPP‐2; Xu 2011) 1 study applied the ADA 2003 criteria (FPG ≥ 5.3 mmol/L and < 6.9 mmol/L or 2‐h glucose ≥ 7.8 mmol/L and < 11.0 mmol/L after a 75 g OGTT; Bone 2013) 1 study applied the ADA 2010 criteria (FPG ≥ 5.6 mmol/L and < 6.9 mmol/L and 2‐h glucose ≥ 7.8 mmol/L or < 11.0 mmol/L after a 75 g OGTT; Shi 2014) 1 study applied its own definition of 'prediabetes' (FPG = 95‐125 mg/dL and 2‐h glucose ≥ 140 mg/dL or < 199 mg/dL after a 75 g OGTT or FPG = 90‐125 mg/dL and 2‐h glucose of 170‐199 mg/dL plus at least one additional high risk characteristic of diabetes; ACT NOW) Follow‐up: 44 weeks to 2 years	188 per 1000	75 per 1000 (32 to 179)	RR 0.40 (0.17 to 0.95)	1395 (6)	⊕⊕⊝⊝ Low^b	The 95% prediction interval ranged from 0.03 to 4.68 Three studies reported the incidence of T2DM after extended follow‐up periods ranging between 3 weeks and 11.4 months. Data for T2DM at the end of the extension periods showed that the intervention effect was dismissed RR 0.89, 95% CI 0.49 to 1.60 (ACT NOW; Attallah 2007; Bone 2013)
Serious adverse events (N) Follow‐up: 44 weeks to 2 years	See comment		RR3.00 (0.32 to 28.22)	187 (2)	⊕⊝⊝⊝ Very low^c	Only Bone 2013 observed events: 3/93 participants experienced serious adverse events in the pioglitazone group vs 1/94 participants in the placebo group. The largest study for this comparison reported on adverse events without distinguishing between serious and non‐serious events (ACT NOW). 121/303 (39.9%) participants in the pioglitazone group compared with 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03; ACT NOW)
Cardiovascular mortality (N) Follow‐up: 44 weeks to 2 years	See comment		RR 5.14 (0.25 to 106.28)	1156 (4)	⊕⊝⊝⊝ Very low^d	Only IDPP‐2 observed events: 2/181 participants in the pioglitazone group vs 0/186 participants in the placebo group 3 studies reported no cardiovascular deaths
Non‐fatal myocardial infarction/stroke (N) Follow‐up: 44 weeks to 2 years	See comment		RR 1.97 (0.18 to 21.65)	789 (3)	⊕⊝⊝⊝ very low^a	Only ACT NOW observed non‐fatal myocardial infarction events: 2/303 participants in the pioglitazone group vs 1/299 participants in the placebo group 2 studies did not observe non‐fatal myocardial infarctions Non‐fatal strokes were not observed
Health‐related quality of life	Not reported
Socioeconomic effects	Not reported
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ADA: American Diabetes Association; CI: confidence interval;FPG: fasting plasma glucose; OGTT: oral glucose tolerance test; OR: odds ratio; RR: risk ratio; T2DM: type 2 diabetes mellitus; WHO: World Health Organization
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded by one level because of attrition bias and indirectness (insufficient time frame) and by two levels because of serious imprecision (95% confidence interval consistent with benefit and harm, small number of studies), see Appendix 5. ^bDowngraded by one level because of attrition bias and by one level because of imprecision (low median sample size), see Appendix 5. ^cDowngraded by one level because of attrition bias and by two levels because of severe imprecision (95% confidence interval consistent with benefit and harm, low median sample size, small number of studies), see Appendix 5.

Summary of findings 4. Summary of findings: pioglitazone monotherapy versus no intervention.

Pioglitazone as monotherapy versus no intervention (identical behaviour‐changing interventions in both groups)
Population: people at increased risk of developing T2DM Settings: outpatients (20 studies), inpatients (1 study) Intervention: pioglitazone Comparison: no intervention
Outcomes	No intervention	Pioglitazone	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
All‐cause mortality (N) Follow‐up: 24 weeks to mean of 2.2 years	28 per 1000	24 per 1000 (11 to 54)	RR 0.85 (0.38 to 1.91)	866 (3)	⊕⊝⊝⊝ Verylow^a
Incidence of T2DM (N) Diagnostic criteria: 9 studies applied the WHO 1999 criteria for 'prediabetes' (FPG > 6.1 mmol/L and < 7.0 mmol/L and/or a 2‐h glucose < 11.1 mmol/L after a 75 g OGTT; Che 2014; Chen 2007a; Gao 2011; Ke 2006; Liang 2004; Xiu 2015; Yi 2015; Yu 2011; Zeng 2013) 1 study applied the ADA 2003 criteria (FPG ≥ 5.3 mmol/L and < 6.9 mmol/L or 2‐h glucose ≥ 7.8 mmol/L and < 11.0 mmol/L after a 75 g OGTT; Fang 2013) 4 studies applied the ADA 2010 criteria (FPG ≥ 5.6 mmol/L and < 6.9 mmol/L and 2‐h glucose ≥ 7.8 mmol/L or < 11.0 mmol/L after a 75 g OGTT; Deng 2013; Wu 2013; Zhang 2007; Zhang 2015) 2 studies did not specify their diagnostic criteria (Chen 2007b; Li 2017) Follow‐up: 24 weeks to a mean of 2.2 years	193 per 1000	60 per 1000 (44 to 77)	RR 0.31 (0.23 to 0.40)	2053 (16)	⊕⊕⊕⊝ Moderate^b	The 95% prediction interval ranged between 0.23 and 0.41
Serious adverse events (N) Follow‐up: 6 months to a mean of 2.2 years	35 per 1000	25 per 1000 (13 to 46)	RR 0.71 (0.38 to 1.32)	1211 (7)	⊕⊕⊝⊝ Low^c	The 95% prediction interval ranged between 0.32 and 1.60
Cardiovascular mortality	Not reported
Non‐fatal myocardial infarction/stroke	Not reported
Health‐related quality of life	Not reported
Socioeconomic effects	Not reported
ADA: American Diabetes Association; CI: confidence interval;FPG: fasting plasma glucose; OGTT: oral glucose tolerance test; RR: risk ratio; T2DM: type 2 diabetes mellitus; WHO: World Health Organization
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded by one level because of indirectness (insufficient time frame) and by two levels because of serious imprecision (small sample size, small number of studies, 95% confidence interval consistent with benefit and harm), see Appendix 6. ^bDowngraded by one level because of imprecision (low median sample size) and unclear selection bias. ^cDowngraded by two levels because of imprecision (95% confidence interval consistent with benefit and harm, low median sample size).

We presented 'Summary of findings' tables for pioglitazone as monotherapy versus the comparator interventions: other glucose‐lowering drugs; behaviour‐changing interventions; placebo; and no intervention. We planned to present in the 'Summary of findings' tables the interventions pioglitazone as part of a dual combination therapy but we did not include any studies with this comparison.

We reported the following outcomes, listed according to priority.

All‐cause mortality
Incidence of T2DM
Serious adverse events
Cardiovascular mortality
Non‐fatal myocardial infarction/stroke
Health‐related quality of life
Socioeconomic effects

Results

Description of studies

For a detailed description of studies, see Table 5, 'Characteristics of included studies', 'Characteristics of excluded studies, and 'Characteristics of ongoing studies'.

Results of the search

The search of MECIR‐mandatory databases resulted in 779 records and of Chinese databases in 350 records, which after deduplication and use of the Cochrane Screen4Me service (known assessments and RCT classifier (Marshall 2018; McDonald 2017; Noel‐Storr 2018; Thomas 2017)), were reduced to 691 records.

We identified a total of 123 references as potentially eligible after screening title or abstract, or both. Of these, we excluded 57 after checking the full text. We also excluded one study on the basis of clinicaltrials.gov status as 'terminated' with a total enrolment of three participants and after we had received no response from the principal investigator (NCT01006018). Of the remaining eligible 65 records, there were two ongoing studies (Beijing prediabetes reversion programme (BPRP); NCT02969798). We did not categorise any studies as 'awaiting classification'. We identified one systematic review through the search (Norris 2007). We did not find any additional references for this review by evaluation of references. We identified 27 studies (60 records) meeting our inclusion criteria. The screening process is presented in the flowchart Figure 1.

Study flow diagram

**HTA**: health technology assessment; **RCT**: randomised controlled trial: **Screen4Me**: Cochrane´s screening service.

Included studies

A detailed description of the characteristics of included studies is presented in Characteristics of included studies; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14; Appendix 15; Appendix 16; Appendix 17; Appendix 18; Appendix 19; Appendix 20. The following is a succinct overview.

Source of data

All reported data were published in medical journals. One study reported data in a trials register (ACT NOW), no additional data were available from the clinical trials register. We contacted all study authors and one pharmaceutical company (Takeda Pharmaceutical Company) for additional data. One study provided extra data on events of hypoglycaemia through correspondence (Attallah 2007).

Comparisons

Six studies compared pioglitazone as monotherapy with placebo (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2; Shi 2014; Xu 2011). One study compared pioglitazone with placebo through a two by two factorial design with growth hormone (Attallah 2007). This study included four intervention groups; we could include only two of these in our review (pioglitazone plus placebo growth hormone versus placebo pioglitazone plus placebo growth hormone; Attallah 2007).

Twenty‐one studies compared pioglitazone with no intervention (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Tian 2015; Wu 2013; Xiu 2015; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). Five of these studies applied identical antihypertensive drugs to intervention and comparator groups (Che 2014; Chen 2007b; Gao 2011; Han 2007; Wu 2013). Three studies compared pioglitazone with other glucose‐lowering drugs (Chen 2007a; Zeng 2013; Zhang 2007). One study compared pioglitazone with personalised diet and exercise consultation (Zhang 2007).

Overview of study populations

Four studies provided information on sample size calculation (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). The same four studies reported a total number of participants screened (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). A total of 4344 participants were randomised in the included studies. Studies randomised a total of 1921 participants to pioglitazone as monotherapy or combined with antihypertensive drugs or calcium plus D‐vitamin with identical regimens in intervention and comparator groups. Studies randomised a total of 2423 participants to a comparator group. Eighteen studies reported on participant dropout (ACT NOW; Attallah 2007; Bone 2013; Chen 2007a; Chen 2007b; Fang 2013; Gao 2011; Guo 2010; Han 2007; IDPP‐2; Ke 2006; Liang 2004; Xiu 2015; Xu 2011; Yi 2015; Zeng 2013; Zhang 2007; Zhang 2015). Finishing rates in the 18 studies reporting on dropout were 87.3% (1098/1258) of the participants randomised to an intervention group and 82.9% (1464/1767) of the participants randomised to a comparator group (Table 5). The individual sample size across intervention and comparator groups ranged between 43 participants (Han 2007), and 605 participants (Deng 2013), see Table 5.

Study design

All but one studies were parallel RCTs. The one study was a two by two factorial RCT with growth hormone (Attallah 2007). Three studies included multiple arms of behaviour‐changing intervention and other glucose‐lowering drugs (Chen 2007a; Zeng 2013; Zhang 2007). Six studies applied placebo (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2; Shi 2014; Xu 2011). Twenty‐one studies compared pioglitazone with no intervention (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Tian 2015; Wu 2013; Xiu 2015; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). Two out of 27 studies were conducted in multiple centres (ACT NOW; Bone 2013), the number of centres ranged between 8 and 31. Four studies reported blinding of participants, personnel and outcome assessors (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). The remaining 23 studies reported no blinding or did not report on blinding (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). Studies were conducted between 2002 and 2014. Duration of intervention ranged between 6 and 36 months. Duration of follow‐up ranged between 6 and 48 months. One study reported a run‐in period of four weeks (Attallah 2007). Three studies reported titration periods (ACT NOW; Bone 2013; IDPP‐2). Titration periods ranged between four weeks and six months, after which pioglitazone and placebo doses were increased. None of the included studies reported early termination. Three studies reported wash‐out periods or extended follow‐ups (ACT NOW; Attallah 2007; Bone 2013). Three studies reported receiving commercial funding (ACT NOW; Attallah 2007; Bone 2013). Three studies reported receiving only non‐commercial funding (Fang 2013; IDPP‐2; Wu 2013). The remaining 21 studies did not report any details on funding (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Shi 2014; Tian 2015; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009).

Settings

Three out of 27 studies were conducted in the USA (ACT NOW; Attallah 2007; Bone 2013), 23 studies were conducted in China (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009), and one study was conducted in India (IDPP‐2). All but one study reported an outpatient setting (Wu 2013).

Participants

Four out of 27 studies reported distribution of ethnicity in study populations (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). The remaining 23 studies did not report on ethnicity of participants but were all assumed to have included participants of Chinese ethnicity (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). One study included only female participants (Bone 2013), the remaining studies reported distribution of sexes. The mean age of included participants ranged between 45 and 73 years (see Appendix 13). Four out of 27 studies included only elderly participants (Guo 2009; Guo 2010; Wu 2013; Xu 2011).

All but two studies reported baseline fasting plasma glucose (FPG) and two‐hour glucose post‐oral glucose tolerance test (OGTT; Chen 2007b; Gao 2011). Fifteen out of 27 studies reported baseline values for glycosylated haemoglobin (HbA1c; ACT NOW; Attallah 2007; Bone 2013; Che 2014; Deng 2013; Fang 2013; Guo 2009; Guo 2010; IDPP‐2; Ke 2006; Li 2017; Liang 2004; Shi 2014; Wu 2013; Zhang 2007). Mean values of FPG at baseline varied between 5.5 mmol/L and 6.9 mmol/L. Two‐hour glucose means at baseline varied between 7.9 mmol/L and 10.3 mmol/L. HbA1c means at baseline varied between 5.5% and 6.5%.

Five studies had hypertension as an inclusion criterion (Che 2014; Chen 2007b; Gao 2011; Han 2007; Wu 2013). None of the remaining 22 included studies reported data on comorbidities or comedications on study populations.

Twenty out of 27 studies reported exclusion criteria (ACT NOW; Attallah 2007; Bone 2013; Chen 2007a; Fang 2013; Guo 2009; Guo 2010; Han 2007; IDPP‐2; Li 2017; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhao 2009). Major exclusion criteria were diabetes; receiving glucose‐lowering drugs or drugs known to alter glucose metabolism; known disease of the heart, kidneys, liver or endocrine organs; acromegaly; chronic infections; pregnancy or breastfeeding; and excessive alcohol consumption.

Diagnosis

Seventeen out of 27 studies used the WHO 1999 criteria for intermediate hyperglycaemia or prediabetes (FPG > 6.1 mmol/L and < 7.0 mmol/L or two‐hour glucose ≥ 7.8 mmol/L and < 11.1 mmol/L: Attallah 2007; Che 2014; Chen 2007a; Gao 2011; Guo 2009; Guo 2010; Han 2007; IDPP‐2; Ke 2006; Liang 2004; Tian 2015; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhao 2009). Two studies applied the ADA 2003 criteria for intermediate hyperglycaemia or prediabetes (FPG ≥ 5.3 mmol/L and < 6.9 mmol/L and two‐hour glucose ≥ 7.8 mmol/L and < 11.0 mmol/L: Bone 2013; Fang 2013). Five out of 27 studies used ADA 2010 definitions (FPG ≥ 5.6 mmol/L and < 6.9 mmol/L and two‐hour glucose ≥ 7.8 mmol/L and < 11.0 mmol/L; Deng 2013; Shi 2014; Wu 2013; Zhang 2007; Zhang 2015). One study used authors' own definitions of intermediate hyperglycaemia or prediabetes (ACT NOW; see Appendix 10). The last two studies did not report their definitions of IGT, IFG or prediabetes (Chen 2007b; Li 2017).

Eleven out of 27 studies included participants on the basis of IGT only (Che 2014; Chen 2007a; Chen 2007b; Gao 2011; Guo 2009; Guo 2010; IDPP‐2; Ke 2006; Li 2017; Liang 2004; Zeng 2013). Eleven studies included participants with IGT plus IFG (Attallah 2007; Han 2007; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zhang 2007; Zhang 2015; Zhao 2009). Four studies included participants with IGT or IFG, or both (Bone 2013; Deng 2013; Fang 2013; Shi 2014). One study included participants with 'prediabetes' and did not specify their definition of 'prediabetes' (Tian 2015). None of the studies included participants based on elevated glycosylated haemoglobin (HbA1c).

Interventions

None of the included studies reported treatment at baseline. All studies applied pioglitazone in intervention groups. Two out of 27 studies applied a final dose of 45 mg once daily titrated up from 30 mg once daily after four weeks or one month (ACT NOW; Bone 2013). One study applied a final dose of 30 mg once daily with titration up from 15 mg after six months (IDPP‐2). Another study applied 30 mg once daily titrated up from 15 mg once daily after four weeks, with growth hormone injections after the fourth week in a two‐by‐two factorial design (Attallah 2007). We included the intervention arms with growth hormone placebo injections (Attallah 2007). One study applied a stable dose of 38 mg once daily (Zeng 2013). Nine studies applied a stable dose of 30 mg once daily (Che 2014; Deng 2013; Gao 2011; Guo 2009; Guo 2010; Shi 2014; Tian 2015; Wu 2013; Xu 2011). Twelve studies applied a stable dose of 15 mg once daily (Chen 2007a; Chen 2007b; Fang 2013; Han 2007; Ke 2006; Li 2017; Liang 2004; Xiu 2015; Yi 2015; Zhang 2007; Zhang 2015; Zhao 2009). One study applied a stable dose of 4 mg once daily (Yu 2011). All pharmacological interventions, except placebo growth hormone injections, were administered as pills.

One out of 27 studies applied intensive behaviour‐changing intervention as a sole intervention in one intervention arm (Zhang 2007).

Outcomes

Twenty‐two out of 27 included studies explicitly stated a primary outcome in their publication (ACT NOW; Attallah 2007; Bone 2013; Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; IDPP‐2; Ke 2006; Li 2017; Liang 2004; Shi 2014; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015). All included studies stated secondary outcomes. Included studies collected a median of seven (range 4 to 21) outcomes. Seven out of 27 studies reported on all‐cause mortality (ACT NOW; Attallah 2007; Bone 2013; Chen 2007b; Deng 2013; Gao 2011; IDPP‐2). A total of 22 out of 27 included studies reported incidence of type 2 diabetes mellitus (T2DM) (ACT NOW; Attallah 2007; Bone 2013; Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; IDPP‐2; Ke 2006; Li 2017; Liang 2004; Shi 2014; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015), this was the outcome most commonly defined as the primary outcome in the included studies. Sixteen out of 27 studies reported serious adverse events or non‐serious adverse events, or both (ACT NOW; Attallah 2007; Bone 2013; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Han 2007; IDPP‐2; Ke 2006; Li 2017; Liang 2004; Zhang 2007; Zhang 2015; Zhao 2009), see Appendix 18; Appendix 19; Appendix 20. Two studies reported on cardiovascular mortality, non‐fatal stroke and myocardial infarction (ACT NOW; IDPP‐2). Three out of 27 studies reported having external judiciary panels for assessing serious adverse events and deaths (ACT NOW; Bone 2013; IDPP‐2). We identified one out of the 27 studies reporting study results in a clinical trials register (ACT NOW). There were differences in data regarding adverse and serious adverse events in publications versus clinicaltrials.gov. We contacted the study authors and the sponsoring pharmaceutical company without clarification (see Appendix 21).

Excluded studies

We excluded 30 studies (58 records) after full‐text evaluation (Figure 1; Characteristics of excluded studies). We excluded 16 studies (44 records) due to population not being 'prediabetes' without comorbidity except obesity or hypertension (e.g. non‐alcoholic steatohepatitis (NASH) or prior stroke) (Belfort 2006; ChiCTR‐TRC‐08000099; ChiCTR‐TRC‐08000111; Cusi 2016; IRIS 2016; J‐SPIRIT 2015; Li 2009; Nam 2013; NCT00015626; NCT00722631; UMIN000001035; Wu 2008; Yang 2012; Yokoyama 2007; Zhang 2014; Zhao 2011). We excluded four studies (four records) because of wrong comparison (EudraCT2005‐004421‐26; Karim 2016; NCT00306826; Zhou 2006); four studies (four records) because of an intervention period of fewer than 24 weeks (EudraCT2006‐002084‐49; Liu 2015; NCT00470262; NCT00633282); four records as they were not RCTs (Kawamori 1996; Kobayashi 2005; Lan 2012; Norris 2007); one study (one record) because of wrong intervention (Durbin 2004); and one study (one record) because of being listed as terminated with three enrolled participants and no answer from the principal investigator following contact (NCT01006018).

Risk of bias in included studies

For details on the risk of bias of the included studies see Characteristics of included studies.

For an overview of review authors' judgements about each risk of bias item for individual studies and across all studies see Figure 2 and Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies)

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the particular outcome was not measured in some studies)

Allocation

We judged three studies to be at low risk of selection bias due to randomisation sequence and allocation concealment (ACT NOW; Attallah 2007; Bone 2013). One study did not describe a truly randomised sequence, but groups appeared similar for all important prognostic variables at baseline; we judged the study as low risk of selection bias (IDPP‐2; see Appendix 8). We judged 23 studies as unclear risk of selection bias due to not adequately describing their randomisation sequence or allocation concealment and reporting limited baseline characteristics (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009; see Characteristics of included studies and Appendix 8). We judged no included studies as having a high risk of selection bias.

Blinding

All‐cause mortality, incidence of T2DM, serious adverse events and measures of blood glucose control are unlikely to be influenced by performance or detection bias. We judged all studies as having low risk of performance or detection bias across these outcomes. Four out of 27 studies explicitly stated that they had undertaken blinding of participants and personnel (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). We judged all four of these studies as having low risk of performance and detection bias. The remaining 23 studies did not report any blinding (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). We judged 12 of these studies as having high risk of performance and detection bias for non‐serious adverse events, due to adverse events being likely to be influenced by the lack of blinding (Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Han 2007; Ke 2006; Li 2017; Liang 2004; Zhang 2007; Zhang 2015; Zhao 2009).

Incomplete outcome data

Eighteen out of 27 studies reported on total participants randomised and completion rates (ACT NOW; Attallah 2007; Bone 2013; Chen 2007a; Chen 2007b; Fang 2013; Gao 2011; Guo 2010; Han 2007; IDPP‐2; Ke 2006; Liang 2004; Xiu 2015; Xu 2011; Yi 2015; Zeng 2013; Zhang 2007; Zhang 2015), the attrition rate among these studies ranged from 0% to 31.8% for the intervention groups and from 0% to 23.7% for comparator groups. Two out of 27 studies did intention‐to‐treat analyses (Attallah 2007; Zhang 2007).

We judged one study as low risk of attrition bias across all outcomes due to balanced minor dropout between groups (Zhang 2007). We judged 21 out of 27 studies as unclear risk of bias due to missing or insufficient information regarding dropouts, reasons for dropout, evaluation or handling of missing data (Che 2014; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; IDPP‐2; Ke 2006; Liang 2004; Li 2017; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhao 2009; Zhang 2015). We judged five studies out of 27 as having high risk of attrition bias regarding at least one outcome in the scope of this review due to high dropouts or dropouts not balanced across intervention and comparator groups (ACT NOW; Attallah 2007; Bone 2013; Chen 2007a; Chen 2007b).

Selective reporting

One out of 27 studies provided a full‐length protocol (ACT NOW).

We judged two studies as having low risk of reporting bias (Attallah 2007; IDPP‐2). We judged three studies as unclear risk of reporting bias because of insufficient information (Bone 2013; Liang 2004; Zhang 2015). We judged one study as having high risk of reporting bias due to serious adverse events not sufficiently reported and analysed in publications despite being recorded according to protocol (ACT NOW). We judged 21 studies as having high risk of reporting bias due to no or insufficient reporting on key outcomes for this review (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Shi 2014; Tian 2015; Wu 2013; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhao 2009). The outcomes mostly unreported were mortality, incidence of T2DM, serious and non‐serious adverse events and hypoglycaemia (see Appendix 15; Appendix 16; Characteristics of included studies).

Other potential sources of bias

We judged all studies as being at unclear risk of bias regarding other potential sources of bias.

Three out of 27 studies were funded completely or partly by pharmaceutical companies (ACT NOW; Attallah 2007; Bone 2013). Twenty‐one studies did not report funding source (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Gao 2011; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Shi 2014; Tian 2015; Xiu 2015; Xu 2011; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). One study only gave 10 participants from each group the planned dose because of reported side effects in both groups (IDPP‐2). The remaining participants were treated with a lower dosage of pioglitazone. Another study altered inclusion criteria from the protocol and extended the recruitment period (ACT NOW). One study was conducted in 31 sites including 156 participants; six sites did not include anyone, details on recruitment and dropout across study sites were not available (Bone 2013).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4

Baseline characteristics

For details of baseline characteristics, see Appendix 12; Appendix 13.

Pioglitazone monotherapy versus any pharmacological glucose‐lowering monotherapy intervention (acarbose, metformin, sulphonylurea)

Three studies compared pioglitazone with another glucose‐lowering monotherapy intervention with matching behaviour‐changing interventions in each group (Chen 2007a; Zeng 2013; Zhang 2007). All three studies included a metformin group. Additionally, Chen 2007a included an acarbose group, and Zhang 2007 included a repaglinide group. For an overview of major results see Table 1.

Primary outcomes

All‐cause mortality

None of the three included studies reported all‐cause mortality.

Incidence of T2DM

Pioglitazone versus metformin

All three studies reported on incidence of T2DM compared with metformin. A total of 9 out of 168 participants developed T2DM in the pioglitazone group compared with 9 out of 163 participants in the metformin group (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low‐certainty evidence; Analysis 1.1). The 95% prediction interval did not provide a meaningful estimate.

1.1 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 1: Incidence of T2DM (comparator metformin)

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with IGT only did not show interaction between subgroups (P = 0.96; Analysis 1.2).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including studies only diagnosing by WHO 1999 did not substantially change the effect estimate (RR 0.96, 95% CI 0.35 to 2.64; P = 0.94; 2 studies, 234 participants; Chen 2007a; Zeng 2013). One study applied the ADA 2010 criteria and showed that 2 out of 48 participants in the pioglitazone group compared with 2 out of 49 participants in the metformin group developed T2DM (Zhang 2007).
- Studies had similar size, publications status, bias judgements, language, reported funding and no imputation was done. Therefore, we did not perform further sensitivity analyses.

1.2 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 2: Incidence of T2DM by 'prediabetes' criteria (comparator metformin)

Pioglitazone versus acarbose

One study reported on the incidence of T2DM comparing pioglitazone with acarbose: 1 out of 50 participants in the pioglitazone group developed T2DM compared with 2 out of 46 participants in the acarbose group (Chen 2007a; very low‐certainty evidence).

Pioglitazone versus repaglinide

One study reported on the incidence of T2DM comparing pioglitazone with repaglinide: 2 out of 48 participants in the pioglitazone group developed T2DM compared with 1 out of 48 participants in the repaglinide group (Zhang 2007; low‐certainty evidence).

Serious adverse events

Pioglitazone versus metformin

Two studies that compared pioglitazone with metformin reported that no participants experienced serious adverse events (0 out of 102 participants in the pioglitazone group and 0 out of 99 participants in the metformin group; low‐certainty evidence; Chen 2007a; Zhang 2007).

Pioglitazone versus acarbose

One study that compared pioglitazone with acarbose reported that no participants experienced serious adverse events (0 out of 50 participants in the pioglitazone group and 0/46 participants in the acarbose group; very low‐certainty evidence; Chen 2007a).

Pioglitazone versus repaglinide

One study that compared pioglitazone with repaglinide reported that no participants experienced serious adverse events (0 out of 52 participants in the pioglitazone group and 0 out of 51 participants in the repaglinide group; low‐certainty evidence; Zhang 2007).

Secondary outcomes

None of the included studies that compared pioglitazone with another glucose‐lowering drug reported on cardiovascular mortality, non‐fatal myocardial infarction, non‐fatal stroke, congestive heart failure, amputation of lower extremity, blindness or severe vision loss, end‐stage renal disease, hypoglycaemia, health‐related quality of life, time to progression to T2DM or socioeconomic effects.

Non‐serious adverse events

Pioglitazone versus metformin

Two studies reported on non‐serious adverse events (Chen 2007a; Zhang 2007).

A total of 4 out of 102 participants experienced non‐serious adverse events in the pioglitazone group compared with 9 out of 99 participants in the metformin group (RR 0.48, 95% CI 0.04 to 5.51; P = 0.55; 2 studies, 201 participants; Analysis 1.3).

1.3 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 3: Non‐serious adverse events (comparator metformin)

Subgroup analysis: comparing 'prediabetes' criteria of 'IFG plus IGT' with IGT only did not indicate subgroup interaction (P = 0.07; Analysis 1.4). Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis: could not be performed due to lack of data.

1.4 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 4: Non‐serious adverse events by 'prediabetes' criteria (comparator metformin)

Pioglitazone versus acarbose

One study reported 1 out of 50 participants in the pioglitazone group experienced a non‐serious adverse event compared with 2 out of 46 participants receiving acarbose (Chen 2007a).

Pioglitazone versus repaglinide

One study reported 3 out of 52 participants in the pioglitazone group experienced a non‐serious adverse event compared with 0 out of 51 participants receiving repaglinide (Zhang 2007).

Measures of blood glucose control

All three included studies that compared pioglitazone with another glucose‐lowering drug reported on measures of blood glucose control. None of the studies reported the statistical variation of the changes from baseline values. We imputed these using the correlation coefficient from IDPP‐2.

Fasting plasma glucose

Pioglitazone versus metformin

Pioglitazone compared with metformin showed a MD of 0.03 mmol/L (95% CI −0.17 to 0.23; P = 0.77; 3 studies, 339 participants; Analysis 1.5). The 95% prediction interval ranged between −1.3 mmol/L and 1.3 mmol/L.

1.5 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 5: Fasting plasma (comparator metformin)

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with IGT only did not show interaction between subgroups (P = 0.40; Analysis 1.6).
- Subgrouping by comorbidity into studies with hypertension as an inclusion criterion and studies without comorbidity in their inclusion criteria did not show subgroup interaction (P = 0.49; Analysis 1.7).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Two studies diagnosed the participants according to the WHO 1999 criteria (Chen 2007a; Zeng 2013). Analysing these two studies did not substantially change the effect estimate (MD 0.06 mmol/L, 95% CI −0.15 to 0.26; P = 0.59; 234 participants).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, size and duration, imputation, language, funding and country. No further sensitivity analyses were possible.

1.6 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 6: Fasting plasma glucose by 'prediabetes' criteria (comparator metformin)

1.7 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 7: Fasting plasma glucose by comorbidity (comparator metformin)

Pioglitazone versus acarbose

One study that compared pioglitazone with acarbose reported changes in FPG from baseline (Chen 2007a). The change from baseline was −1.26 mmol/L (SD 1.0) in the pioglitazone group compared with −1.19 mmol/L (SD 0.8) in the acarbose group (assumed standard errors (SEs) were recalculated to SDs).

Pioglitazone versus repaglinide

One study that compared pioglitazone with metformin reported changes in FPG from baseline (Zhang 2007). The change from baseline was −0.66 mmol/L (SD 1.7) in the pioglitazone group compared with −0.42 mmol/L (SD 1.8) in the repaglinide group (assumed SEs were recalculated to SDs).

Two‐hour glucose

Pioglitazone versus metformin

Pioglitazone compared with metformin for two‐hour glucose after an OGTT showed a MD of −0.23 mmol/L (95% CI −0.43 to −0.02; P = 0.03; 3 studies, 339 participants; Analysis 1.8) in favour of pioglitazone. The 95% prediction interval ranged between −1.59 mmol/L and 1.13 mmol/L.

1.8 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 8: 2‐hour blood glucose (comparator metformin)

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with IGT only did not show subgroup interaction (P = 0.19; Analysis 1.9).
- Subgrouping by comorbidity into populations with hypertension as an inclusion criterion and studies without comorbidity in their inclusion criteria did not show subgroup interaction (P = 0.92; Analysis 1.10).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Two studies diagnosed the participants according to the WHO 1999 criteria (Chen 2007a; Zeng 2013). Analysing these two studies did not substantially change the effect estimate (MD −0.27 mmol/L, 95% CI −0.47 to −0.08; P = 0.007; 234 participants).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, size and duration, imputation, language, funding and country. No sensitivity analyses were possible.

1.9 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 9: 2‐hour blood glucose by 'prediabetes' criteria (comparator metformin)

1.10 — Comparison 1: Pioglitazone versus another glucose‐lowering intervention, Outcome 10: 2‐hour blood glucose by comorbidity (comparator metformin)

Pioglitazone versus acarbose

One study that compared pioglitazone with metformin reported changes in two‐hour glucose from baseline (Chen 2007a). The change from baseline was −1.15 mmol/L (SD 1.2) in the pioglitazone group compared with −1.13 mmol/L (SD 1.4) in the acarbose group (assumed SEs were recalculated to SDs).

Pioglitazone versus repaglinide

One study that compared pioglitazone with repaglinide reported changes in two‐hour glucose from baseline (Zhang 2007). The change from baseline was −1.48% (SD 1.6) in the pioglitazone group compared with 1.39% (SD 1.5) in the repaglinide group (assumed SEs were recalculated to SDs).

HbA1c

Pioglitazone versus metformin

One study that compared pioglitazone with metformin reported change in HbA1c from baseline (Zhang 2007). The change from baseline was −0.15% (SD 1.8) in the pioglitazone group compared with −0.19% (SD 2.4) in the metformin group (assumed SEs were recalculated to SDs).

Pioglitazone versus acarbose

HbA1c at the end of follow‐up or change from baseline was not reported for this comparison.

Pioglitazone versus repaglinide

One study that compared pioglitazone with repaglinide reported change in HbA1c from baseline (Zhang 2007). The change from baseline was −0.15% (SD 1.8) in the pioglitazone group compared with −0.32% (SD 2.0) in the repaglinide group (assumed SEs were recalculated to SDs).

Pioglitazone monotherapy versus behaviour‐changing interventions (diet, exercise, diet and exercise)

One study compared pioglitazone combined with diet and exercise with an intensive behaviour‐changing intervention consisting of personalised diet and exercise consultation (Zhang 2007). For an overview of major results see Table 2.

Primary outcomes

All‐cause mortality

The included study did not report all‐cause mortality.

Incidence of T2DM

A total of 2 out of 48 participants developed T2DM in the pioglitazone group compared with 5 out of 48 in the personalised diet and exercise consultation group (low‐certainty evidence).

Serious adverse events

Zhang 2007 reported that no participants experienced a serious adverse event (low‐certainty evidence).

Secondary outcomes

The included study did not report on cardiovascular mortality, non‐fatal myocardial infarction, non‐fatal stroke, congestive heart failure, amputation of lower extremity, blindness or severe vision loss, end‐stage renal disease, hypoglycaemia, health‐related quality of life, time to progression to T2DM or socioeconomic effects.

Non‐serious adverse events

Zhang 2007 reported that 3 out of 52 participants in the pioglitazone group experienced non‐serious adverse events compared with 0 out of 51 participants in the personalised diet and exercise consultation group.

Measures of blood glucose control

Zhang 2007 did not report statistical variation on changes from baseline values. We imputed these using correlation coefficients from the IDPP‐2.

Fasting plasma glucose

The change from baseline was −0.66 mmol/L (SD 1.7) in 52 participants in the pioglitazone group compared with −0.15 mmol/L (SD 1.2) in 51 participants in the personalised diet and exercise consultation group (assumed SEs were recalculated to SDs).

Two‐hour glucose

The change from baseline was −1.48 mmol/L (SD 1.6) in 52 participants in the pioglitazone group compared with 0.17 mmol/L (SD 1.2) in 51 participants in the personalised diet and exercise consultation group (assumed SEs were recalculated to SDs).

HbA1c

The change from baseline was −0.15% (SD 1.8) in 52 participants in the pioglitazone group compared with −0.12% (SD 1.1) in 51 participants in the personalised diet and exercise consultation group (assumed SEs were recalculated to SDs)

Pioglitazone monotherapy versus placebo

Six studies compared pioglitazone as monotherapy with placebo (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2; Shi 2014; Xu 2011). Five out of six studies implemented behaviour‐changing interventions, which were identical in intervention and placebo groups (ACT NOW; Bone 2013; IDPP‐2; Shi 2014; Xu 2011). Two studies administered a dose of 45 mg once daily (ACT NOW; Bone 2013). Four studies administered a dose of 30 mg once daily (Attallah 2007; IDPP‐2; Shi 2014; Xu 2011). Two studies had wash‐out follow‐ups of three to four weeks (Attallah 2007), and six months (Bone 2013). One study did an extended follow‐up on a subpopulation with a median follow‐up of 11.4 months after medication stopped (ACT NOW). Three studies included participants of mixed ethnicity in the USA (ACT NOW; Attallah 2007; Bone 2013). One study included participants of Asian Indian ethnicity (IDPP‐2). Two studies did not report on ethnicity but we assumed the population to be of Chinese ethnicity (Shi 2014; Xu 2011). We judged all studies to have a high risk of bias in at least one 'Risk of bias' domain (see Figure 3). For an overview of major results see Table 3.

Primary outcomes

All‐cause mortality

Four out of six studies reported on all‐cause mortality (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). Two studies reported events (ACT NOW; IDPP‐2).

Five out of 577 participants in the pioglitazone groups died compared with 2 out of 579 participants in the placebo groups (Peto OR 2.38, 95% CI 0.54 to 10.50; 4 studies, 1156 participants; very low‐certainty evidence; Analysis 2.1).

2.1 — Comparison 2: Pioglitazone versus placebo, Outcome 1: All‐cause mortality

Subgroup analysis
- The two included studies with events could be subgrouped by country of origin, ethnicity of population, funding and diagnostic criteria. All these factors showed no subgroup interaction (P = 0.85; Analysis 2.2).
- Subgroup analysis for duration of intervention, mono/dual‐therapy, age, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- Two studies diagnosed participants according to the WHO 1999 criteria and showed that 2 out of 196 participants died in the pioglitazone groups compared with 1 out of 202 in the placebo groups (Attallah 2007; IDPP‐2). One study applied the ADA 2003 criteria and showed that no participants died (Bone 2013).
- The included studies were similar regarding publication status, bias judgements, duration and size, imputation, language, funding and country. No further sensitivity analyses were possible.

2.2 — Comparison 2: Pioglitazone versus placebo, Outcome 2: All‐cause mortality by subgroup

Incidence of T2DM

Intervention periods

All studies reported on incidence of T2DM. One study reported a cumulative incidence of participants developing T2DM as percentages, with 29.8% in the pioglitazone group developing T2DM compared with 31.6% in the placebo group (IDPP‐2). We calculated the incidence based on all randomised participants.

A total of 80 out of 700 participants developed T2DM in the pioglitazone groups compared with 131 out of 695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low‐certainty evidence; Analysis 2.3), favouring pioglitazone. However, the 95% prediction interval ranged between 0.03 and 4.68.

2.3 — Comparison 2: Pioglitazone versus placebo, Outcome 3: Incidence of T2DM

Subgroup analysis: comparing 'prediabetes' criteria of 'IFG plus IGT' with 'IFG or IGT' with IGT only showed interaction in subgroups favouring pioglitazone.
- IGT only compared with 'IFG plus IGT' showed a reduced incidence of T2DM for the 'IFG plus IGT' criteria (P < 0.001; Analysis 2.4).
- Subgrouping by ethnicity by mainly white (mixed American ethnicities), Asian Indian and assumed Chinese showed subgroup interaction and favoured pioglitazone with reduced T2DM incidence in studies including mixed American ethnicities (P < 0.001; Analysis 2.5).
- Subgrouping by age (cut‐off 65 years of age) did not show subgroup interaction (P = 1.0; Analysis 2.6).
- Subgrouping by sex (men and women versus women only) did not show subgroup interaction (P = 0.25; Analysis 2.7).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller studies (N < 100 participants) changed the effect estimate (RR 0.25, 95% CI 0.03 to 2.14; P = 0.21; 2 studies, 111 participants; Attallah 2007; Shi 2014), no longer favouring pioglitazone.
- Sensitivity analysis including only studies published in English also changed the effect estimate (RR 0.42, 95% CI 0.14 to 1.26; P = 0.12; 4 studies, 1196 participants; ACT NOW; Attallah 2007; Bone 2013; IDPP‐2), no longer favouring pioglitazone.
- Three studies diagnosed the participants according to the WHO 1999 criteria (Attallah 2007; IDPP‐2; Xu 2011). Analysing these studies changed the effect estimate (RR 0.88, 95% CI 0.54 to 1.43; P = 0.60; 3 studies, 557 participants; (Attallah 2007; IDPP‐2; Xu 2011), no longer favouring pioglitazone. One study diagnosed the participants according to the ADA 2003 criteria; this showed that 1 out of 78 participants in the pioglitazone group developed T2DM compared with 8 out of 78 participants in the placebo group (Bone 2013). One study diagnosed the participants according to the ADA 2010 criteria; this showed that 1 out of 40 participants in the pioglitazone group developed T2DM compared with 4 out of 40 participants in the placebo group (Shi 2014).
- The included studies were similar regarding publications status, 'Risk of bias' judgements, duration of intervention and imputation.

2.4 — Comparison 2: Pioglitazone versus placebo, Outcome 4: Incidence of T2DM by 'prediabetes' criteria

2.5 — Comparison 2: Pioglitazone versus placebo, Outcome 5: Incidence of T2DM by ethnicity

2.6 — Comparison 2: Pioglitazone versus placebo, Outcome 6: Incidence of T2DM by age

2.7 — Comparison 2: Pioglitazone versus placebo, Outcome 7: Incidence of T2DM by sex

Wash‐out and extended follow‐up

Three studies reported data for T2DM after an extended observational period ranging between three weeks and 11.4 months (ACT NOW; Attallah 2007; Bone 2013). ACT NOW invited completers of their main study to continue biannual follow‐ups after the end of intervention. About half of the participants randomised completed one‐year post‐treatment follow‐up. ACT NOW reported a hazard ratio (HR) of the cumulative incidence of T2DM across intervention and post‐treatment periods of pioglitazone compared with placebo during the intervention period of HR 0.44 (95% CI 0.29 to 0.67; P < 0.005; 290 participants), favouring pioglitazone.

A total of 19 out of 244 participants with prior pioglitazone treatment compared with 20 out of 224 participants with prior placebo treatment developed T2DM after the wash‐out follow‐up (RR 0.89, 95% CI 0.49 to 1.60; P = 0.70; 3 studies, 468 participants; Analysis 2.8).

2.8 — Comparison 2: Pioglitazone versus placebo, Outcome 8: Incidence of T2DM after intervention end, assessed at any time after intervention end

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with 'IFG or IGT' did not show subgroup interaction (P = 0.50; Analysis 2.9).
- Subgroup analysis for age was identical to the one with 'prediabetes' criteria.
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, ethnicity, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- There was one smaller‐size study (N < 100 participants; Attallah 2007). During wash‐out and within three to four weeks, 2 out of 15 participants developed T2DM in the pioglitazone group compared with 2 out of 16 participants in the placebo group (Attallah 2007).
- Sensitivity analysis strictly including protocol prespecified extension did not substantially change the effect estimate (RR 0.78, 95% CI 0.16 to 3.81; P = 0.76; 2 studies, 178 participants; Attallah 2007; Bone 2013).
- One study diagnosed the participants according to the WHO 1999 criteria (Attallah 2007). One study diagnosed the participants according to the ADA 2003 criteria, this showed that 0 out of 77 participants in the pioglitazone group developed T2DM compared with 1 out of 70 participants in the placebo group (Bone 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, duration of intervention, imputation, language, funding and country.

2.9 — Comparison 2: Pioglitazone versus placebo, Outcome 9: Incidence of T2DM after intervention end, assessed at any time after intervention end by 'prediabetes' criteria

Serious adverse events

Two studies reported on serious adverse events (Attallah 2007; Bone 2013). A total of 3 out of 93 participants experienced serious adverse events in the pioglitazone group compared with 1 out of 94 participants in the placebo group (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low‐certainty evidence; Analysis 2.10). Only Bone 2013 observed events.

2.10 — Comparison 2: Pioglitazone versus placebo, Outcome 10: Serious adverse events

IDPP‐2 reported 10 "major adverse events" in 181 participants in the pioglitazone group compared with 13 "major adverse events" in 186 participants in the placebo group.

ACT NOW reported only deaths as serious adverse events and listed all other adverse events without distinguishing between serious and non‐serious adverse events. We contacted study authors and the sponsoring pharmaceutical company but did not receive additional data.

Subgroup and sensitivity analyses were not possible because only one study reported any events.

Secondary outcomes

Cardiovascular mortality

Four included studies reported on cardiovascular mortality (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). Only IDPP‐2 observed two events of cardiovascular mortality in 181 participants in the pioglitazone group compared with no event in 186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low‐certainty evidence; Analysis 2.11).

2.11 — Comparison 2: Pioglitazone versus placebo, Outcome 11: Cardiovascular mortality

One study reported two unexplained deaths, one in each group of 303 participants in the pioglitazone group and 299 participants in the placebo group (ACT NOW).

Non‐fatal myocardial infarction

Three studies reported on non‐fatal myocardial infarction (ACT NOW; Attallah 2007; Bone 2013). Only ACT NOW observed two events in 303 participants in the pioglitazone group compared with one event in 299 participants in the placebo group (RR 1.97, 95% CI 0.18 to 21.65; very low‐certainty evidence; Analysis 2.12).

2.12 — Comparison 2: Pioglitazone versus placebo, Outcome 12: Non‐fatal myocardial infarction

One study reported two events of heart disease in 181 participants in the pioglitazone group and 186 participants in the placebo group without specifying the kind of event (IDPP‐2). We contacted study authors for details but did not receive a reply.

Non‐fatal stroke

None of the included studies reported any events of non‐fatal stroke. One study reported two events of transient ischaemic attacks in 303 participants in the pioglitazone group compared with no transient ischaemic attacks in 299 participants in the placebo group (ACT NOW).

Congestive heart failure

Two studies reported on events of congestive heart failure (ACT NOW; Bone 2013). Two studies provided complete lists of adverse events (Attallah 2007; IDPP‐2). Three studies were available for meta‐analysis (ACT NOW; Attallah 2007; Bone 2013).

There was a total of two events among 396 participants in the pioglitazone groups compared with one event among 393 participants in the placebo groups (Peto OR 1.93, 95% CI 0.20 to 18.60; P = 0.57; 3 studies, 789 participants; Analysis 2.13).

2.13 — Comparison 2: Pioglitazone versus placebo, Outcome 13: Congestive heart failure

One study reported 2 out of 181 participants with unspecified heart disease events in the pioglitazone group compared with 2 out of 186 in the placebo group (IDPP‐2).

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with 'IFG or IGT' did not show interaction in subgroups (P = 0.61; Analysis 2.14).
- Subgroup analysis for sex was identical to 'prediabetes' criteria (Analysis 2.15).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, ethnicity, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller studies was inconclusive due to no events in the one small study (N < 100 participants; Attallah 2007).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, duration of intervention, imputation, language, funding and country.

2.14 — Comparison 2: Pioglitazone versus placebo, Outcome 14: Congestive heart failure by 'prediabetes' criteria

2.15 — Comparison 2: Pioglitazone versus placebo, Outcome 15: Congestive heart failure by sex

Amputation of lower extremity

None of the included studies reported amputation of lower extremity.

Blindness or severe vision loss

None of the included studies reported blindness or severe vision loss.

End‐stage renal disease

None of the included studies reported end‐stage renal disease.

Non‐serious adverse events

Three included studies reported on non‐serious adverse events (ACT NOW; Attallah 2007; Bone 2013).

Two studies were available for meta‐analysis (Attallah 2007; Bone 2013). A total of 51 participants experienced a non‐serious adverse event in pioglitazone groups among 93 participants compared with 49 participants among 94 participants in placebo groups (RR 1.03, 95% CI 0.81 to 1.31; P = 0.82; 2 studies, 187 participants; Analysis 2.16).

2.16 — Comparison 2: Pioglitazone versus placebo, Outcome 16: Non‐serious adverse events

ACT NOW reported only deaths as serious adverse events and listed all other adverse events without distinguishing between serious and non‐serious adverse events. A total of 121 out of 303 (39.9%) participants in the pioglitazone group compared with 151 out of 299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03).

IDPP‐2 only reported the total number of non‐serious adverse events and not the number of participants with a non‐serious adverse event; they reported a total of 28 non‐serious adverse events among 181 participants in the pioglitazone group compared with 22 among 186 participants in the placebo group.

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with 'IFG or IGT' did not show significant interaction between subgroups (P = 0.53; Analysis 2.17).
- Subgroup analysis for sex was identical to 'prediabetes' criteria analysis.
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, ethnicity, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- There was one smaller‐sized study (N < 100 participants; Attallah 2007). This study diagnosed the participants according to the WHO 1999 criteria with 2 out of 15 participants experiencing non‐serious adverse events in the pioglitazone group compared with 1 out of 16 participants in the placebo group (Attallah 2007). One study diagnosed the participants according to the ADA 2003 criteria and showed 49 out of 78 participants in the pioglitazone group experiencing non‐serious adverse events compared with 48 out of 78 participants in the placebo group (Bone 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, duration, imputation, language, funding and country.

2.17 — Comparison 2: Pioglitazone versus placebo, Outcome 17: Non‐serious adverse events by 'prediabetes' criterion

Hypoglycaemia

Two studies reported on hypoglycaemic events (Attallah 2007; IDPP‐2).

Attallah 2007 reported by correspondence that no participant experienced hypoglycaemia.

IDPP‐2 reported a total of 15 hypoglycaemic events among 181 participants in the pioglitazone group compared with 9 hypoglycaemic events among 186 participants in the placebo group. They did not specify the number of participants who experienced hypoglycaemia.

Health‐related quality of life

None of the included studies reported health‐related quality of life.

Time to progression to T2DM

Two studies reported on time to progression to T2DM (ACT NOW; IDPP‐2). The studies showed considerable heterogeneity with an I² of 94% (P < 0.001). Therefore, we did not perform a meta‐analysis (Analysis 2.18).

2.18 — Comparison 2: Pioglitazone versus placebo, Outcome 18: Time to progression of T2DM

ACT NOW reported time to progression to T2DM with a HR of 0.28 (95% CI 0.16 to 0.49; P = 0.001; 602 participants). Adjustment for baseline characteristics did not alter the HR. The annual incidence of T2DM was 2.1% in the pioglitazone group compared with 7.6% in the placebo group.

IDPP‐2 reported time to progression to T2DM with an unadjusted HR of 1.08 (95% CI 0.75 to 1.56; P = 0.665; 407 participants). The HR adjusted for age, sex, study group, BMI, two‐hour glucose, insulin resistance, insulinogenic index, hypertension and family history of T2DM showed HR 0.98 (95% CI 0.67 to 1.44; P = 0.94). The cumulative incidence of T2DM was 29.8% in the pioglitazone group compared with 31.6% in the placebo group after 36 months of intervention.

Subgroup analysis
- The two included studies could be subgrouped by country of origin, ethnicity of population, funding and diagnostic criteria. All these factors showed subgroup interaction (P < 0.001; Analysis 2.19).
- Subgroup analysis for duration of intervention, mono/dual‐therapy, age, comorbidity and previous gestational diabetes was not possible.
Sensitivity analysis
- One study diagnosed participants by WHO 1999 criteria and reported an unadjusted HR of 1.08 (95% CI 0.75 to 1.56; P = 0.665; 407 participants; IDPP‐2). The incidence of T2DM was 29.8% in the pioglitazone group and 31.6% in the placebo group after 36 months of intervention.
- The included studies were similar regarding publication status, bias judgements, duration and size, imputation, language, funding and country.

2.19 — Comparison 2: Pioglitazone versus placebo, Outcome 19: Time to progression of T2DM by subgroup

Measures of blood glucose control

All included studies reported on measures of blood glucose control for intervention periods. One study reported measures of blood glucose control for a wash‐out period (Bone 2013).

Fasting plasma glucose

Intervention periods

Five studies reported FPG (ACT NOW; Bone 2013; IDPP‐2; Shi 2014; Xu 2011). Shi 2014 and Xu 2011 did not report statistical variation for changes from baseline, we imputed these values using IDPP‐2's correlation coefficients. The studies showed considerable heterogeneity with an I² of 96% (P < 0.001). Excluding studies with imputed values still showed an I^{2 of} 86% (Shi 2014; Xu 2011). The MD between the pioglitazone and placebo groups ranged between ‐1.35 mmol/L and 0.05 mmol/L (1125 participants; 5 studies; Analysis 2.20).

2.20 — Comparison 2: Pioglitazone versus placebo, Outcome 20: Fasting plasma glucose

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with 'IFG or IGT' or IGT only showed interaction between subgroups (P = 0.002; Analysis 2.21), favouring pioglitazone, contrasting 'IFG or IGT' with IGT only.
- Subgrouping by ethnicity into mainly white (mixed American ethnicities), Asian Indians and assumed Chinese ethnicity showed an interaction between groups with a lesser effect on Asian Indians (P = 0.0006; Analysis 2.22) favouring pioglitazone, contrasting mainly white people with Asian Indian people.
- Subgrouping by sex into studies with men and women versus women only did not show interaction between subgroups (P = 0.91; Analysis 2.23).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- There was one smaller‐sized study (N < 100 participants; Shi 2014).
- The same study was the only study diagnosing participants by ADA 2010 criteria. The reported change in FPG from baseline was −0.44 mmol/L (SD 1.3) in 40 participants in the pioglitazone group compared with −0.02 mmol/L (SD 1.3) in 40 participants in the placebo group (Shi 2014). Two studies diagnosed participants with the WHO 1999 criteria (IDPP‐2; Xu 2011). Including only these studies showed a MD of −0.65 mmol/L (95% CI −2.02 to 0.72; P = 0.35; 2 studies, 486 participants). One study applied the ADA 2003 criteria and reported a change from baseline of −0.16 mmol/L (SD 0.7) in 57 participants in the pioglitazone group compared with 0.33 mmol/L (SD 0.7) in 61 participants in the placebo group (Bone 2013).
- One study received non‐commercial funding and reported a change in FPG from baseline of 0.24 mmol/L (SD 1.1) in 181 participants in the pioglitazone group compared with 0.19 mmol/L (SD 1) mmol/L in 186 participants in the placebo group (IDPP‐2).
- Including only studies published in English showed a MD of −0.27 mmol/L (95% CI −0.55 to 0.01; P = 0.06; 3 studies, 926 participants; ACT NOW; Bone 2013; IDPP‐2), in favour of placebo.
- Sensitivity analysis regarding imputation was identical to the analysis regarding language.
- Including only studies from the USA showed a MD of −0.39 mmol/L (95% CI −0.48 to −0.29; P < 0.001; 2 studies, 559 participants; ACT NOW; Bone 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements and duration; no sensitivity analyses regarding these factors were possible.

2.21 — Comparison 2: Pioglitazone versus placebo, Outcome 21: Fasting plasma glucose by 'prediabetes' criteria

2.22 — Comparison 2: Pioglitazone versus placebo, Outcome 22: Fasting plasma glucose by ethnicity

2.23 — Comparison 2: Pioglitazone versus placebo, Outcome 23: Fasting plasma glucose by sex

Wash‐out and extended follow‐up

One study reported change in FPG from baseline for wash‐out periods (Bone 2013). The MD was 0.06 mmol/L (SD 0.1) in 57 participants in the pioglitazone group compared with 0.02 mmol/L (SD 0.1) in 54 participants in the placebo group (Bone 2013).

Two‐hour glucose

Intervention periods

All included studies reported on two‐hour glucose after OGTT. Five studies were available for meta‐analysis (ACT NOW; Bone 2013; IDPP‐2; Shi 2014; Xu 2011). Shi 2014 and Xu 2011 did not report statistical variation for changes from baseline; we imputed these values using IDPP‐2's correlation coefficients. The studies showed considerable heterogeneity with an I² of 81%. The MD was −0.89 mmol/L (95% CI −1.43 to −0.34; P = 0.001; 5 studies, 1119 participants; Analysis 2.24), in favour of pioglitazone. The 95% prediction interval ranged between −2.87 mmol/L and 1.09 mmol/L.

2.24 — Comparison 2: Pioglitazone versus placebo, Outcome 24: 2‐hour blood glucose

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with 'IFG or IGT', or with IGT only showed interaction between subgroups demonstrating a stronger effect in favour of pioglitazone for the 'IFG plus IGT' categorisation than for IGT only (P = 0.0003; Analysis 2.25).
- Subgrouping by ethnicity of mainly white ethnicity (mixed American ethnicity), Asian Indian and assumed Chinese ethnicity did not show subgroup interaction (P = 0.05; Analysis 2.26).
- Subgrouping by sex into groups of men and women versus women only did not show subgroup interaction (P = 0.35; Analysis 2.27).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- There was one smaller‐sized study (N < 100 participants; Shi 2014).
- The same study was the only study that diagnosed participants by ADA 2010 criteria. The reported change in two‐hour glucose from baseline was −0.81 mmol/L (SD 1.5) in 40 participants in the pioglitazone group compared with −0.05 mmol/L (SD 1.3) in 40 participants in the placebo group (Shi 2014). Two studies diagnosed participants with the WHO 1999 criteria (IDPP‐2; Xu 2011). Including only these studies did not substantially change the effect estimate: MD −0.88 mmol/L (95% CI −2.42 to 0.65; P = 0.26; 42 studies, 86 participants; IDPP‐2; Xu 2011). One study applied the ADA 2003 criteria and reported a change from baseline of −1.47 mmol/L (SD 1.8) in 54 participants in the pioglitazone group compared with −0.94 mmol/L (SD 1.7) in 58 participants in the placebo group (Bone 2013).
- One study received non‐commercial funding and reported a change in two‐hour glucose from baseline of 0.59 mmol/L (SD 3) in 181 participants in the pioglitazone group compared with 0.68 mmol/L (SD 2.6) in 186 participants in the placebo group (IDPP‐2).
- Including only studies published in English did not substantially change the effect estimate (MD −0.65 mmol/L, 95% CI −1.40 to 0.09; P = 0.09; 3 studies, 920 participants; ACT NOW; Bone 2013; IDPP‐2).
- Sensitivity analysis regarding imputation was identical to the analysis regarding language.
- Including only studies from the USA did not substantially change the effect estimate (MD −0.94 mmol/L, 95% CI −1.65 to −0.23; P = 0.009; 2 studies, 559 participants; ACT NOW; Bone 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements and duration of intervention.

2.25 — Comparison 2: Pioglitazone versus placebo, Outcome 25: 2‐hour blood glucose by 'prediabetes' criteria

2.26 — Comparison 2: Pioglitazone versus placebo, Outcome 26: 2‐hour blood glucose by ethnicity

2.27 — Comparison 2: Pioglitazone versus placebo, Outcome 27: 2‐hour blood glucose by sex

Wash‐out and extended follow‐up

No studies reported on two‐hour glucose for wash‐out or extended follow‐up periods.

HbA1c

Intervention periods

All but one of the included studies reported on HbA1c (Xu 2011). Shi 2014 did not report statistical variation for changes from baseline; we imputed these values using IDPP‐2's correlation coefficients. Effects of pioglitazone compared with placebo showed a MD of −0.13% (95% CI −0.20 to −0.07; P < 0.001; 5 studies, 1001 participants; Analysis 2.28), in favour of pioglitazone. The 95% prediction interval ranged between −0.23% and −0.03%.

2.28 — Comparison 2: Pioglitazone versus placebo, Outcome 28: HbA1C

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with 'IFG or IGT', or IGT only did not show subgroup interaction (P = 0.09; Analysis 2.29).
- Subgrouping by ethnicity of mainly white ethnicity (mixed American races), Asian Indian and assumed Chinese ethnicities did not show subgroup interaction (P = 0.70; Analysis 2.30).
- Subgrouping by sex into studies with men and women versus women only did not show subgroup interaction (P = 0.18; Analysis 2.31).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller studies (N < 100 participants) did not substantially change the effect estimate (MD −0.07%, 95% CI −0.23 to 0.09; P 0.37; 2 studies, 111 participants; Attallah 2007; Shi 2014).
- Two studies diagnosed participants by WHO 1999 criteria (Attallah 2007; IDPP‐2). Analysing these studies did not substantially change the effect estimate (MD −0.10%, 95% CI −0.24 to 0.04; P = 0.16; 2 studies, 398 participants; Attallah 2007; IDPP‐2). One study applied the ADA 2003 criteria and reported a HbA1c change from baseline of −0.15% (SD 0.2) in 58 participants in the pioglitazone group compared with −0.06% (SD 0.2) in 61 participants in the placebo group (Bone 2013).
- One study only received non‐commercial funding (IDPP‐2). The reported change in HbA1c from baseline was 0.45% (SD 0.8) in 181 participants in the pioglitazone group compared with 0.55% (0.8) in 186 participants in the placebo group (IDPP‐2).
- Including only studies published in English did not substantially change the effect estimate (MD −0.14%, 95% CI −0.21 to −0.07; P < 0.001; 4 studies, 921 participants; ACT NOW; Attallah 2007; Bone 2013; IDPP‐2).
- Sensitivity analysis regarding imputation was identical to the analysis regarding language.
- Including only studies from the USA showed a MD of −0.15% (95% CI −0.24 to −0.05; P = 0.003; 3 studies, 554 participants; ACT NOW; Attallah 2007; Bone 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements and duration of intervention.

2.29 — Comparison 2: Pioglitazone versus placebo, Outcome 29: HbA1C by 'prediabetes' criteria

2.30 — Comparison 2: Pioglitazone versus placebo, Outcome 30: HbA1C by ethnicity

2.31 — Comparison 2: Pioglitazone versus placebo, Outcome 31: HbA1c by sex

Wash‐out and extended follow‐up

One study reported change in HbA1c from baseline to the end of the wash‐out period (Bone 2013). The reported change showed a difference of −0.07% (SD 0.03) in 57 participants in the pioglitazone group compared with −0.03% (SD 0)% in 53 participants in the placebo group (Bone 2013).

Socioeconomic effects

None of the included studies reported on socioeconomic effects.

Pioglitazone monotherapy versus no intervention

Twenty‐one studies compared pioglitazone with no intervention; all but one (Han 2007), had matching behaviour‐changing interventions. Five studies applied identical antihypertensive medication to intervention and comparator groups (Che 2014; Chen 2007b; Gao 2011; Han 2007; Wu 2013; see Characteristics of included studies). One of the 21 studies reported a run‐in period (Xu 2011). One study applied a daily dose of 38 mg (Zeng 2013). Six studies applied a dose of 30 mg once daily (Che 2014; Deng 2013; Gao 2011; Guo 2009; Guo 2010; Tian 2015; Wu 2013). Thirteen studies applied a dose of 15 mg once daily (Chen 2007a; Chen 2007b; Fang 2013; Han 2007; Ke 2006; Li 2017; Liang 2004; Tian 2015; Xiu 2015; Yi 2015; Zhang 2007; Zhang 2015; Zhao 2009). One study applied a daily dose of 4 mg (Yu 2011). None of the included studies reported any wash‐out or extension periods. We judged all 21 studies as having a high risk of bias in at least one risk of bias domain (see Figure 3). For an overview of major results see Table 4.

Primary outcomes

All‐cause mortality

Three of the 21 studies reported on all‐cause mortality (Chen 2007b; Deng 2013; Gao 2011).

A total of 11 deaths occurred among 441 participants randomised to the pioglitazone groups compared with 12 out of 425 in comparator groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low‐certainty evidence; Analysis 3.1). The 95% prediction interval did not provide a meaningful estimate.

3.1 — Comparison 3: Pioglitazone versus no intervention, Outcome 1: All‐cause mortality

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG or IGT' with IGT only did not show subgroup interaction (P = 0.76; Analysis 3.2).
- Subgroup analysis comparing studies with comorbidity as part of the inclusion criteria (hypertension) compared with no comorbidity in the inclusion criteria showed no interaction between subgroups (P = 0.90; Analysis 3.3).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- One study diagnosed participants by the WHO 1999 criteria and reported that 2 out of 50 participants died in the pioglitazone group compared with 3 out of 50 participants in the comparator group (Gao 2011). One study diagnosed participants by the ADA 2010 criteria and reported that 4 out of 303 participants died in the pioglitazone group compared with 5 out of 302 participants in the comparator group (Deng 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, length and size, language, imputation, source of funding and country.

3.2 — Comparison 3: Pioglitazone versus no intervention, Outcome 2: All‐cause mortality by 'prediabetes' criteria

3.3 — Comparison 3: Pioglitazone versus no intervention, Outcome 3: All‐cause mortality by comorbidity

Incidence of T2DM

Sixteen of the 21 studies reported on the incidence of T2DM (Che 2014; Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Ke 2006; Li 2017; Liang 2004; Wu 2013; Xiu 2015; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015).

A total of 60 participants out of 1034 participants in the pioglitazone groups developed T2DM compared with 197 out of 1019 participants in the comparator groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate‐certainty evidence; Analysis 3.4), in favour of pioglitazone. The 95% prediction interval ranged between 0.23 and 0.41.

3.4 — Comparison 3: Pioglitazone versus no intervention, Outcome 4: Incidence of T2DM

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT', 'IFG or IGT', or IGT only did not show subgroup interaction (P = 0.79; Analysis 3.5).
- Subgrouping by age showed no interaction between subgroups (P = 0.76; Analysis 3.6).
- Subgroup analysis comparing studies with comorbidity as part of inclusion criteria (hypertension) versus no comorbidity in inclusion criteria showed no interaction (P = 0.56; Analysis 3.7).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller‐sized studies (N < 100 participants) did not substantially change the effect estimate (RR 0.25, 95% CI 0.15 to 0.44; P < 0.001; 7 studies, 464 participants; Che 2014; Ke 2006; Tian 2015; Wu 2013; Xiu 2015; Yi 2015; Zhang 2015).
- Nine studies diagnosed participants by WHO 1999 criteria (Che 2014; Chen 2007a; Gao 2011; Ke 2006; Liang 2004; Xiu 2015; Yi 2015; Yu 2011; Zeng 2013). Analysing these studies did not substantially change the effect estimate (RR 0.24, 95% CI 0.15 to 0.38; P < 0.001; 9 studies, 802 participants). Four studies diagnosed participants by ADA 2010 criteria (Deng 2013; Wu 2013; Zhang 2007; Zhang 2015). Including only these studies did not substantially change the effect estimate (RR 0.33, 95% CI 0.21 to 0.50; P < 0.001; 4 studies, 825 participants). One study diagnosed participants by ADA 2003 criteria and reported that 5 out of 60 participants developed T2DM in the pioglitazone group compared with 12 out of 60 participants in the no‐intervention group (Fang 2013).
- Including only studies that reported on funding did not substantially change the effect estimate (RR 0.41, 95% CI 0.18 to 0.94; P = 0.03; 2 studies, 187 participants; Fang 2013; Wu 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, length, imputation, language and country.

3.5 — Comparison 3: Pioglitazone versus no intervention, Outcome 5: Incidence of T2DM by 'prediabetes' criteria

3.6 — Comparison 3: Pioglitazone versus no intervention, Outcome 6: Incidence of T2DM by age

3.7 — Comparison 3: Pioglitazone versus no intervention, Outcome 7: Incidence of T2DM by comorbidity

Serious adverse events

Seven out of 21 studies reported on serious adverse events (Chen 2007a; Chen 2007b; Deng 2013; Gao 2011; Zhang 2007; Zhang 2015; Zhao 2009). Three of these reported actual events (Chen 2007b; Deng 2013; Gao 2011).

A total of 16 out of 610 participants in the pioglitazone groups experienced serious adverse events compared with 21 out of 601 in the comparator groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low‐certainty evidence; Analysis 3.8). The 95% prediction interval ranged between 0.32 and 1.60.

3.8 — Comparison 3: Pioglitazone versus no intervention, Outcome 8: Serious adverse events

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT' with IGT only did not show subgroup interaction (P = 0.94; Analysis 3.9).
- Subgroup analysis comparing studies with comorbidity as part of inclusion criteria (hypertension) versus no comorbidity in inclusion criteria showed no subgroup interaction (P = 0.68; Analysis 3.10).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Three studies diagnosed participants by WHO 1999 criteria (Chen 2007a; Gao 2011; Zhao 2009). The three studies reported that a total of 2 out of 147 participants experienced serious adverse events in the pioglitazone groups compared with 3 out of 145 participants in the no‐intervention groups. Three studies diagnosed participants by ADA 2010 criteria (Deng 2013; Zhang 2007; Zhang 2015). The three studies reported that a total of 6 out of 380 participants experienced serious adverse events in the pioglitazone groups compared with 3 out of 383 participants in the no‐intervention groups (Deng 2013; Zhang 2007; Zhang 2015).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, size and length, language, source of funding, country and no imputation was done.

3.9 — Comparison 3: Pioglitazone versus no intervention, Outcome 9: Serious adverse events by 'prediabetes' criteria

3.10 — Comparison 3: Pioglitazone versus no intervention, Outcome 10: Serious adverse events by comorbidity

Secondary outcomes

None of the included studies that compared pioglitazone with no intervention reported on cardiovascular mortality, non‐fatal myocardial infarction, non‐fatal stroke, amputation of lower extremity, blindness or severe vision loss, end‐stage renal disease, hypoglycaemia, health‐related quality of life, time to progression to T2DM or socioeconomic effects.

Cardiovascular events

One study reported unspecified coronary heart disease events in 3 out of 83 participants in the pioglitazone group compared with 7 events in 73 participants in the no‐intervention group (Chen 2007b). One study reported 27 unspecified cardiovascular events in 303 participants in the pioglitazone group compared with 23 events among 302 participants in the no‐intervention group (Deng 2013). One study reported two unspecified events of coronary heart disease among 50 participants in the pioglitazone group compared with six events among 50 participants in the placebo group (Gao 2011). We contacted the study authors but did not receive a reply (see Appendix 21).

One study reported one unspecified cerebrovascular disease event among 50 participants in the pioglitazone group compared with three events among 50 participants in the no‐intervention group (Gao 2011).

Congestive heart failure

Deng 2013 reported on congestive heart failure. Two out of 303 participants in the pioglitazone group experienced congestive heart failure compared with 2 out of 302 participants in the no‐intervention group.

Non‐serious adverse events

Eleven studies reported non‐serious adverse events (Chen 2007a; Chen 2007b; Deng 2013; Fang 2013; Gao 2011; Han 2007; Ke 2006; Li 2017; Liang 2004; Zhang 2015; Zhao 2009).

A total of 189 out of 781 participants experienced non‐serious adverse events in the pioglitazone groups compared with 151 out of 765 participants in the no‐intervention groups (RR 1.26, 95% CI 0.81 to 1.97; P = 0.31; 11 studies, 1546 participants; Analysis 3.11). The 95% prediction interval ranged between 0.49 and 3.22.

3.11 — Comparison 3: Pioglitazone versus no intervention, Outcome 11: Non‐serious adverse events

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT', 'IFG or IGT', and IGT only did not show subgroup interaction (P = 0.47; Analysis 3.12).
- Subgroup analysis comparing studies with hypertension as part of the inclusion criteria versus no hypertension as an inclusion criterion showed interaction between subgroups (P = 0.01; Analysis 3.13). The hypertension subgroup showed fewer non‐serious adverse events in the pioglitazone groups.
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller studies (N < 100 participants) changed the effect estimate, substantially favouring no‐intervention (RR 4.05, 95% CI 1.41 to 11.66; P = 0.04; 5 studies, 303 participants; Han 2007; Ke 2006; Liang 2004; Zhang 2015; Zhao 2009).
- Six studies diagnosed participants by WHO 1999 criteria (Chen 2007a; Gao 2011; Han 2007; Ke 2006; Liang 2004; Zhao 2009). Including only these studies did not substantially change the effect estimate (RR 1.90, 95% CI 0.57 to 6.36; P = 0.29; 6 studies, 452 participants). Two studies diagnosed by ADA 2010 criteria (Deng 2013; Zhang 2015). Including these studies only did not substantially influence the effect estimate (RR 1.23, 95% CI 1.02 to 1.47; P = 0.03; 2 studies, 656 participants). One study applied ADA 2003 criteria and reported that 16 out of 60 participants in the pioglitazone group experienced non‐serious adverse events compared with 12 out of 60 participants in the no‐intervention group (Fang 2013).
- Fang 2013 was also the only study that reported its funding source.
- The included studies were similar regarding publication status, length, 'Risk of bias' judgements, language, country and no imputation was done.

3.12 — Comparison 3: Pioglitazone versus no intervention, Outcome 12: Non‐serious adverse events by 'prediabetes' criteria

3.13 — Comparison 3: Pioglitazone versus no intervention, Outcome 13: Non‐serious adverse events by comorbidity

Hypoglycaemia

Four studies reported on hypoglycaemic events (Fang 2013; Han 2007; Liang 2004; Zhao 2009). Two studies reported actual events (Fang 2013; Liang 2004).

A total of 8 out of 159 participants experienced hypoglycaemia in the pioglitazone groups compared with 3 out of 155 participants in the no‐intervention groups (RR 2.71, 95% CI 0.76 to 9.75; P = 0.13; 4 studies, 314 participants; Analysis 3.14).

3.14 — Comparison 3: Pioglitazone versus no intervention, Outcome 14: Participants with events of hypoglycaemia

Subgroup analysis
- Comparing 'prediabetes' criteria of IGT only with a pooled population of IFG only, IGT only and 'IFG and IGT' did not show subgroup interaction (P = 0.91; Analysis 3.15).
- Subgroup analyses for duration of intervention, mono/dual‐therapy, age, sex, ethnicity, comorbidity and previous gestational diabetes were not possible.
Sensitivity analysis
- Three studies were of smaller size (N < 100 participants; Han 2007; Liang 2004; Zhao 2009). They reported a total of 5 out of 99 participants with hypoglycaemia in the pioglitazone groups compared with 2 out of 95 participants in the no‐intervention groups.
- One study reported on funding and noted that 3 out of 60 participants experienced hypoglycaemia in the pioglitazone group compared with 1 out of 60 in the no‐intervention groups (Fang 2013).
- Three studies diagnosed participants by WHO 1999 criteria (Han 2007; Liang 2004; Zhao 2009). The analysis was identical to the analysis for smaller‐sized studies (see above). One study diagnosed participants by ADA 2003 (Fang 2013). The sensitivity analysis was identical to analysis for funding status (see above).
- The included studies were similar regarding publication status, length, 'Risk of bias' judgements, language, country and no imputation was done.

3.15 — Comparison 3: Pioglitazone versus no intervention, Outcome 15: Participants with events of hypoglycaemia by 'prediabetes' criteria

Health‐related quality of life

None of the included studies reported on health‐related quality of life.

Time to progression to T2DM

One study reported on time to progression to T2DM (Deng 2013). The time to progression of T2DM showed a HR of 0.28 (95% CI 0.16 to 0.49; P < 0.001; 605 participants). The study did not specify whether the HR was unadjusted or adjusted for any factors. The annual incidence of T2DM across the intervention period with a mean duration of 2.2 years was 2.7% in the pioglitazone group compared with 8.1% in the comparator group.

Measures of blood glucose control

Nineteen studies reported on measures of blood glucose (Che 2014; Chen 2007a; Chen 2007b; Fang 2013; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Tian 2015; Wu 2013; Xiu 2015; Yi 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). None of the included studies reported statistical variations for the changes from baseline, which we imputed using the correlation coefficient from IDPP‐2.

Fasting plasma glucose

All 19 studies reported FPG. All but one (Chen 2007b), were available for meta‐analysis. The studies showed considerable heterogeneity (I² = 93%). We transformed published SEs in three studies to SDs because the statistical variation appeared extremely small (Chen 2007a; Zhang 2007; Zhang 2015). The overall MD comparing pioglitazone with no intervention was −0.70 mmol/L (95% CI −0.96 to −0.44; P < 0.001; 18 studies, 1533 participants; Analysis 3.16), in favour of pioglitazone. The 95% prediction interval ranged between −1.84 mmol/L and 0.44 mmol/L.

3.16 — Comparison 3: Pioglitazone versus no intervention, Outcome 16: Fasting plasma glucose

One study reported a decrease in FPG in the pioglitazone group compared with the comparator group (P < 0.05) without specifying values (Chen 2007b).

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT', 'IFG or IGT', IGT only, categories 'unspecified definition' and 'mixed definitions' showed subgroup interaction (P = 0.003; Analysis 3.18) with greater reduction of FPG in the pioglitazone groups using the 'IFG or IGT' criterion compared with the categories 'mixed' and 'unspecified'.
- Subgrouping by age showed no subgroup interaction (P = 0.98; Analysis 3.17).
- Subgroup analysis comparing studies with comorbidity as part of inclusion criteria (hypertension) versus no comorbidity in inclusion criteria showed subgroup interaction (P = 0.002; Analysis 3.19). Studies with hypertensive cohorts showed greater reductions of FPG in the pioglitazone groups.
- Subgroup analyses for duration of intervention, mono/dual‐therapy sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller‐sized studies (N < 100 participants) did not substantially change the effect estimate (MD −0.79 mmol/L, 95% CI −1.01 to −0.57; P < 0.001; 12 studies, 800 participants; Che 2014; Guo 2009; Guo 2010; Han 2007; Ke 2006; Liang 2004; Tian 2015; Wu 2013; Xiu 2015; Yi 2015; Zhang 2015; Zhao 2009).
- Thirteen studies diagnosed participants by WHO 1999 criteria (Che 2014; Chen 2007a; Guo 2009; Guo 2010; Han 2007; Ke 2006; Liang 2004; Tian 2015; Xiu 2015; Yi 2015; Yu 2011; Zeng 2013; Zhao 2009). Including these studies only did not substantially change the effect estimate (MD −0.60 mmol/L, 95% CI −0.92 to −0.28; P < 0.001; 13 studies, 1037 participants). Three studies diagnosed participants by ADA 2010 criteria (Wu 2013; Zhang 2007; Zhang 2015). Including these studies only did not substantially change the effect estimate (MD −1.22 mmol/L, 95% CI −1.45 to −1.00; P < 0.001; 3 studies, 226 participants). One study applied the ADA 2003 criteria (Fang 2013). The reported change in FPG from baseline was −0.5 mmol/L (SD 0.6) in 60 participants in the pioglitazone group compared with −0.1 mmol/L (SD 0.4) in 60 participants in the no‐intervention group (Fang 2013).
- Restricting meta‐analysis to studies reporting on funding did not substantially change the effect estimate (MD −0.77 mmol/L, 95% CI −1.66 to 0.11; P = 0.09; 2 studies, 187 participants; Fang 2013; Wu 2013).
- The included studies were similar regarding publication status, 'Risk of bias' judgements, length, imputation, language and country.

3.18 — Comparison 3: Pioglitazone versus no intervention, Outcome 18: Fasting plasma glucose by 'prediabetes' criteria

3.17 — Comparison 3: Pioglitazone versus no intervention, Outcome 17: Fasting plasma glucose by age

3.19 — Comparison 3: Pioglitazone versus no intervention, Outcome 19: Fasting plasma glucose by comorbidity

Two‐hour glucose

Seventeen studies reported on two‐hour glucose (Che 2014; Chen 2007a; Fang 2013; Guo 2009; Guo 2010; Han 2007; Ke 2006; Li 2017; Liang 2004; Tian 2015; Wu 2013; Xiu 2015; Yu 2011; Zeng 2013; Zhang 2007; Zhang 2015; Zhao 2009). We transformed published SEs in three studies to SDs because the statistical variation appeared extremely small (Chen 2007a; Zhang 2007; Zhang 2015). There was considerable heterogeneity (I² = 86%). Comparing pioglitazone with no intervention showed a MD of −1.58 mmol/L (95% CI −1.88 to −1.28; P < 0.001; 17 studies, 1463 participants; Analysis 3.20). The 95% prediction interval ranged between −2.81 mmol/L and −0.35 mmol/L.

3.20 — Comparison 3: Pioglitazone versus no intervention, Outcome 20: 2‐hour blood glucose

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT', 'IFG or IGT', IGT only, categories 'unspecified definition' and 'mixed definitions' showed subgroup interaction (P = 0.0007; Analysis 3.21) but only for the category 'unspecified definition' versus IGT only.
- Subgrouping by age showed statistical subgroup interaction (P = 0.02; Analysis 3.23). However, this was not reliable because the CIs slightly overlapped.
- Subgroup analysis comparing studies with comorbidity as part of the inclusion criteria (hypertension) versus no comorbidity in the inclusion criteria showed statistical subgroup interaction (P = 0.04; Analysis 3.24). However, this was not reliable because the CIs slightly overlapped.
- Subgroup analyses for duration of intervention, mono/dual‐therapy sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller‐sized studies (N < 100 participants) did not substantially change the effect estimate (MD −1.61 mmol/L, 95% CI −2.11 to −1.10; P < 0.001; 11 studies, 730 participants; Che 2014; Guo 2009; Guo 2010; Han 2007; Ke 2006; Liang 2004; Tian 2015; Wu 2013; Xiu 2015; Zhang 2015; Zhao 2009).
- Twelve studies diagnosed participants by WHO 1999 criteria (Che 2014; Chen 2007a; Guo 2009; Guo 2010; Han 2007; Ke 2006; Liang 2004; Tian 2015; Xiu 2015; Yu 2011; Zeng 2013; Zhao 2009). Restricting meta‐analysis to these studies did not substantially change the effect estimate (MD −1.55 mmol/L, 95% CI −1.92 to −1.18; P < 0.001; 12 studies, 967 participants). Three studies diagnosed participants by ADA 2010 criteria (Wu 2013; Zhang 2007; Zhang 2015). Including these studies only did not substantially change the effect estimate (MD −1.93 mmol/L, 95% CI −2.37 to −1.48; P < 0.001; 3 studies, 226 participants). One study applied the ADA 2003 criteria (Fang 2013). The reported change in two‐hour glucose from baseline was −1.0 mmol/L (SD 1.4) in 60 participants in the pioglitazone group compared with −0.1 mmol/L (SD 1.2) in 60 participants in the no‐intervention groups.
- Including only studies that reported funding did not change the effect estimate (MD −1.54 mmol/L, 95% CI −2.92 to −0.17; P = 0.03; 2 studies, 187 participants; Fang 2013; Wu 2013). The included studies were similar regarding publication status, 'Risk of bias' judgements, length, imputation, language and country.

3.21 — Comparison 3: Pioglitazone versus no intervention, Outcome 21: 2‐hour blood glucose by 'prediabetes' criteria

3.23 — Comparison 3: Pioglitazone versus no intervention, Outcome 23: 2‐hour blood glucose by age

3.24 — Comparison 3: Pioglitazone versus no intervention, Outcome 24: 2‐hour blood glucose by comorbidity

HbA1c

Nine studies reported on HbA1c (Che 2014; Fang 2013 Guo 2009; Guo 2010; Ke 2006; Li 2017; Liang 2004; Wu 2013; Zhang 2007). We transformed published SEs in two studies to SDs because statistical variation appeared extremely small (Fang 2013; Zhang 2007). There was considerable heterogeneity (I² = 92%). Comparing pioglitazone with no intervention showed a MD of −0.77% (95% CI −1.32 to −0.23; P < 0.005; 9 studies, 762 participants; Analysis 3.25). The 95% prediction interval ranged between −2.71% and to 1.17%.

3.25 — Comparison 3: Pioglitazone versus no intervention, Outcome 25: HbA1C

Subgroup analysis
- Comparing 'prediabetes' criteria of 'IFG plus IGT'. IGT only or category 'unspecified' did not show subgroup interaction (P = 0.11; Analysis 3.26).
- Subgrouping by age showed no subgroup interaction (P = 0.80; Analysis 3.27).
- Subgroup analysis comparing studies with comorbidity as part of the inclusion criteria (hypertension) versus no comorbidity in the inclusion criteria showed no subgroup interaction (P = 0.67; Analysis 3.28).
- Subgroup analyses for duration of intervention, mono/dual‐therapy sex, ethnicity and previous gestational diabetes were not possible.
Sensitivity analysis
- Including only smaller‐sized studies (N < 100 participants) did not substantially change the effect estimate (MD −0.50%, 95% CI −0.68 to −0.32; P < 0.001; 6 studies, 385 participants; Che 2014; Guo 2009; Guo 2010; Ke 2006; Liang 2004; Wu 2013).
- Five studies diagnosed participants by WHO 1999 criteria (Che 2014; Guo 2009; Guo 2010; Ke 2006; Liang 2004). Including only these studies did not substantially change the effect estimate (MD −0.43%, 95% CI −0.63 to −0.24; P < 0.001; 5 studies, 318 participants). Two studies applied the ADA 2010 criteria (Wu 2013; Zhang 2007). Only including theses studies did not substantially change the effect estimate (MD −0.69%, 95% CI −1.18 to −0.20; P = 0.006; 2 studies, 174 participants). One study applied the ADA 2003 criteria (Fang 2013). The reported change in HbA1c from baseline was −1.5% (SD 1.0) in 60 participants in the pioglitazone group compared with −0.1% (SD 1.9) in 60 participants in the no‐intervention group (Fang 2013).
- Including only studies that reported funding did not substantially change the effect estimate (MD −1.15%, 95% CI −1.66 to −0.63; P < 0.001; 2 studies, 187 participants; Fang 2013; Wu 2013).
- Included studies were similar regarding publication status, 'Risk of bias' judgements, length, imputation, language and country.

3.26 — Comparison 3: Pioglitazone versus no intervention, Outcome 26: HbA1C by 'prediabetes' criteria

3.27 — Comparison 3: Pioglitazone versus no intervention, Outcome 27: HbA1C by age

3.28 — Comparison 3: Pioglitazone versus no intervention, Outcome 28: HbA1c by comorbidity

Socioeconomic effects

None of the included studies reported on socioeconomic effects.

Pioglitazone as a part of a dual combination therapy versus any pharmacological glucose‐lowering agent (e.g. acarbose, metformin, sulphonylurea)

We identified no studies investigating pioglitazone as part of a dual combination therapy compared with another pharmacological glucose‐lowering agent.

Ongoing studies

We identified two ongoing studies, one comparing pioglitazone with placebo and one comparing pioglitazone with other glucose‐lowering drugs, which could provide data of interest for this review (Beijing prediabetes reversion programme (BPRP); NCT02969798). The studies plan to include 2645 randomised participants. Both studies will evaluate one or more of the primary or secondary outcomes of interest in this review. The durations of the studies are estimated to be 24 months (NCT02969798) and three years (Beijing prediabetes reversion programme (BPRP)).

One study has published baseline results and is in the process of publishing a final manuscript (Beijing prediabetes reversion programme (BPRP)). The other study is estimated to finish enrolment in 2023 (NCT02969798).

Studies awaiting assessment

We identified no RCTs that are awaiting assessment.

Discussion

Summary of main results

This Cochrane Review is the first systematic review investigating the effects of pioglitazone in people at increased risk of developing T2DM compared with other glucose‐lowering pharmacological interventions, behaviour‐changing interventions, placebo or no intervention. We included 27 studies with a total of 4186 participants. We judged all included studies as having high risk of bias in at least one 'Risk of bias' domain.

Pioglitazone compared with placebo reduced or delayed the incidence of developing T2DM (low‐certainty evidence), but the intervention effect disappeared after an extended post‐follow‐up period. There was limited information on beneficial or harmful effects of pioglitazone compared with placebo regarding all‐cause mortality, serious adverse events and macro‐ and microvascular complications (very low‐certainty evidence). Notably, the largest study for this comparison reported adverse events without distinguishing between serious and non‐serious events (ACT NOW). The study showed a decreased risk of adverse events with pioglitazone compared with placebo. Pioglitazone compared with no intervention showed a reduction or delay in the incidence of developing T2DM (moderate‐certainty evidence). However, none of the studies with this comparison reported T2DM after an observational, drug‐free study period. The comparison with no intervention did not show any beneficial or harmful effects regarding all‐cause mortality (very low‐certainty evidence) or serious adverse events (low‐certainty evidence), the reporting of these outcomes was sparse. None of the included studies reported on macro‐ or microvascular complications for the comparison with no intervention. Pioglitazone compared with metformin did not reduce or delay the incidence of T2DM (low‐certainty evidence), data on other outcomes for the comparison were minimal. We found only one study comparing pioglitazone with a behaviour‐changing intervention, and no studies compared pioglitazone as part of dual therapy with other glucose‐lowering drugs. None of the included studies reported on health‐related quality of life or socioeconomic effects of pioglitazone intervention.

Overall completeness and applicability of evidence

We performed an extensive search for studies with no restriction on language. We tried to contact all authors of included studies for additional data and questions regarding 'Risk of bias' assessments. We did not receive any information from the majority of study authors. One study author provided additional data (Attallah 2007). We also contacted one pharmaceutical company for additional data on two included studies (ACT NOW; Bone 2013), without further data being provided. We screened other reviews and meta‐analyses for additional references and cross‐checked our extracted data (if the reviews included any studies included in this review), but we found no additional references or data in this way (Haw 2017; Merlotti 2014; Norris 2007).

The included studies' definition of 'prediabetes' varied. Most studies used criteria issued by medical associations for definitions of IFG and IGT (ADA 2003; ADA 2010; WHO 1999). Studies using these criteria included participants based on: people with IFG plus IGT; people with IFG or IGT; or people with IGT only. One study used the authors' own definition of 'prediabetes' (ACT NOW). Two studies did not report on their definitions of people at increased risk for development of T2DM (Chen 2007b; Li 2017). None of the included studies included participants on the basis of elevated HbA1c.

The vast majority of participants in this review were from Chinese studies without specification on ethnicity. We assumed participants of these studies to be of Chinese ethnicity. Three studies included people of mixed ethnicities, mainly white ethnicity from the USA (ACT NOW; Attallah 2007; Bone 2013). One study included people of Asian Indian ethnicity (IDPP‐2). Therefore, not all ethnicities were represented in the included studies.

The applied dosages of pioglitazone varied from 4 mg once daily to 45 mg once daily. All but three studies included some degree of diet and exercise intervention (Attallah 2007; Bone 2013; Han 2007). Information about these behaviour‐changing interventions was generally minimal. One study included only women (Bone 2013), the remaining studies included men and women.

A substantial amount of studies did not report on key outcomes for this review. Only 7 out of 27 studies reported on all‐cause mortality (ACT NOW; Attallah 2007; Bone 2013; Chen 2007b; Deng 2013; Gao 2011; IDPP‐2). Five studies did not report on incidence of T2DM (Guo 2009; Guo 2010; Han 2007; Tian 2015; Zhao 2009). Eleven out of 27 studies reported on serious adverse events (ACT NOW; Attallah 2007; Bone 2013; Chen 2007a; Chen 2007b; Deng 2013; Gao 2011; IDPP‐2; Zhang 2007; Zhang 2015; Zhao 2009). Nine out of 27 studies did not account for participants or reported on losses to follow‐up or missing data (Che 2014; Deng 2013; Guo 2009; Li 2017; Shi 2014; Tian 2015; Wu 2013; Yu 2011; Zhao 2009). The overall rate of reporting on all‐cause mortality, complications of T2DM and key study characteristics was low among the 23 studies conducted in China.

Quality of the evidence

We judged none of the 27 included studies as having low risk of bias across all 'Risk of bias' domains (Figure 3). Four out of 27 studies reported sufficient information on randomisation sequence generation and allocation concealment and we judged them as having low risk of selection bias (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). Only four studies reported any blinding of participants, personnel and outcome assessors (ACT NOW; Attallah 2007; Bone 2013; IDPP‐2). We judged all studies as having low risk of performance or detection bias with regard to all‐cause mortality, incidence of T2DM, serious adverse events and measure of blood glucose control. These outcomes are objective and unlikely to be influenced by a lack of blinding. We judged all of the included studies as unclear or high risk of attrition bias for at least one outcome. Main reasons for judgement were substantial or unbalanced dropout rates, no report on missing data or handling of missing data. We were only able to retrieve one protocol for our included studies (ACT NOW). We judged all but five studies as having a high risk of outcome reporting bias (Attallah 2007; Bone 2013; IDPP‐2; Liang 2004; Zhang 2015), mainly due to not reporting on key outcomes for this review, which we would have expected for these kinds of studies (see Appendix 16). Six out of 27 studies reported some details on funding (ACT NOW; Attallah 2007; Bone 2013; Fang 2013; IDPP‐2; Wu 2013). Three studies received financial funding, free drugs or both from pharmaceutical companies (ACT NOW; Attallah 2007; Bone 2013). A prior Cochrane Review has shown that studies with commercial funding are more likely to report favourable outcomes for the intervention (Lundh 2017). Overall reporting of key study characteristics for 'Risk of bias' assessment and outcome reporting was sparse and the main contributor for the uncertainty of our effect estimates.

We judged the incidence of T2DM in comparison with no intervention as moderate‐certainty evidence. All other outcomes across all comparisons we judged as low‐ to very low‐certainty evidence, mainly due to few studies reporting outcomes and various 'Risk of bias' assessments (see Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6).

Potential biases in the review process

Out of 27 included studies only two study authors supplied contact information and replied to our inquiry about their study (ACT NOW; Attallah 2007). Therefore, a substantial part of our 'Risk of bias' assessment is judged unclear due to missing information. Most of the studies included in this review were underpowered, with a small number of participants and relatively short timeframe (< 3 years). The meta‐analyses were limited in their assessment of specific clinical characteristics due to not being able to retrieve individual participant data for any study. Few of the included studies reported the assessment and diagnosis of T2DM (e.g. by OGTT or FPG, and/or multiple tests on multiple days should be undertaken for certainty of diagnosis) besides cut‐off values. The diagnosis could have been subject to heterogeneity across studies and could affect the meta‐analysis. Only three of 27 included studies reported on their assessment of serious adverse events and stated that an external adjudication panel validated events. This could affect the effect estimates, depending on the remaining studies' assessment of serious adverse events. We excluded studies with participants with 'prediabetes' and concomitant diseases (e.g. non‐alcoholic steatohepatitis and prior stroke) except for hypertension. We examined the potential effects of hypertension by subgroup analysis. We limited the minimum intervention period for studies to 24 weeks and we excluded four studies based on this criteria (EudraCT2006‐002084‐49; Liu 2015; NCT00470262; NCT00633282).

Two review authors independently carried out data extraction for studies. However, authors were not blinded to which study they were extracting data from.

Agreements and disagreements with other studies or reviews

As T2DM is a major health problem worldwide (IDF 2013), interest in identifying people at increased risk of developing T2DM, and early intervention has increased. Several RCTs have assessed the effects of different pharmacological glucose‐lowering interventions for the prevention of T2DM (ACT NOW; Diabetes Prevention Program 2009; Pi‐Sunyer 2015). A pharmacological approach to the prevention or delay of T2DM is appealing to both the clinician and the pharmaceutical industry. However, although a reduction in or delay of the incidence of T2DM is important, the major public health impact of prevention studies will be determined by the extent to which prevention or delay of T2DM translates into a reduction in diabetes‐specific macrovascular and microvascular complications. Furthermore, the individual psychological effects of having a condition and receiving drugs, when potentially unnecessary, need to be discussed.

A recent meta‐analysis investigated the effects of glucose‐lowering interventions after treatment withdrawal in people at high risk of developing T2DM (Haw 2017). The review showed that the reduction in the incidence of T2DM was not sustained after drug intervention withdrawal (mixed group of glucose‐lowering drugs, no studies included with prior pioglitazone intervention). In the present review, we saw the same tendency, with three studies that compared pioglitazone to placebo and extended follow‐up after intervention end (ACT NOW; Attallah 2007; Bone 2013).

Other recent meta‐analyses have examined the effects of different interventions for the prevention of T2DM in people at increased risk (Merlotti 2014; Pang 2018). They have included glitazones as a group instead of focusing on pioglitazone. The results suggested for glitazones as a group were broadly similar to the results of our review. Although, the results are not completely comparable.

One older review investigated the effects of pioglitazone and rosiglitazone in people with T2DM, 'prediabetes' or the metabolic syndrome (Norris 2007). The review did not draw any conclusion for people at increased risk of development of T2DM due to insufficient data on the effects of pioglitazone in people with 'prediabetes'.

Authors' conclusions

Implications for practice.

There is low‐certainty evidence that pioglitazone compared with placebo reduces or delays the development of type 2 diabetes mellitus (T2DM) in people with increased risk of T2DM (risk ratio (RR) 0.40, 95% confidence interval (CI) 0.17 to 0.95); 95% prediction interval ranging between 0.03 and 4.68). There is moderate‐certainty evidence that pioglitazone compared with no intervention reduces or delays the development of T2DM in people with increased risk of T2DM (RR 0.31, 95% CI 0.23 to 0.40; 95% prediction interval ranging between 0.23 and 0.41). There is no advantage or disadvantage of pioglitazone treatment compared with metformin on the incidence of T2DM in people with increased risk of T2DM (RR 0.98, 95% CI 0.40 to 2.38; low‐certainty evidence).

Data and reporting of serious adverse events, micro‐ and macrovascular complications and mortality were generally sparse. None of the included studies reported on health‐related quality of life or socioeconomic effects of pioglitazone intervention.

Most studies applied behaviour‐changing interventions in the intervention and comparator groups. Most studies identified people at increased risk of T2DM by impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). None of the included studies identified increased risk of T2DM by elevated glycosylated haemoglobin (HbA1c), and the effect in this population is unknown.

Implications for research.

We are uncertain whether the beneficial effects of pioglitazone on the incidence of T2DM when compared to placebo or no intervention are sustained after discontinuation of the drug. Additionally, the effects of pioglitazone treatment on diabetes‐specific complications are unclear. There are no data on the effects of pioglitazone on health‐related quality of life and socioeconomic effects in people with increased risk of developing T2DM. Future studies should focus on these factors.

History

Protocol first published: Issue 1, 2020 Review first published: Issue 11, 2020

Notes

Portions of the background and methods sections, the appendices, additional tables and Figures 1 to 3 of this review are based on a standard template established by the Cochrane Metabolic and Endocrine Disorders Group.

This review was handed in as EI's Master's thesis at the University of Copenhagen in summer 2020.

Acknowledgements

The review authors, and the Cochrane Metabolic and Endocrine Disorders editorial base, are grateful to the following peer reviewers for their time and comments: Jesper Krogh, Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; Carsten Dirksen, Department of Endocrinology, Hvidovre Hospital, Denmark.

We thank Dr. DeFronzo, Dr. L Yingying and Dr Hoffman for answering our inquiries on their respective studies.

Appendices

Appendix 1. Checklist to aid consistency and reproducibility of GRADE assessments: pioglitazone versus metformin

Items		(1) All‐cause mortality	(2) Incidence of T2DM	(3) Serious adverse events	(4) Cardiovascular mortality	(5) Non‐fatal myocardial infarction/stroke	(6) Health‐related quality of life	(7) Socioeconomic effects
Study limitations (risk of bias)^a	Was random sequence generation used (i.e. no potential for selection bias)?	NR	Unclear	Unclear	NR	NR	NR	NR
	Was allocation concealment used (i.e. no potential for selection bias)?		Unclear	Unclear
	Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?		Yes	Yes
	Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?		Yes	Yes
	Was an objective outcome used?		Yes	Yes
	Were more than 80% of participants enrolled in studies included in the analysis (i.e. no potential reporting bias)?^e		Yes	Yes
	Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?		Yes	Yes
	No other biases reported (i.e. no potential of other bias)?		Yes	Yes
	Did the studies end up as scheduled (i.e. not stopped early)?		Yes	Yes
Inconsistency^b	Point estimates did not vary widely?		Yes	Yes
	To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?		Substantial	Substantial
	Was the direction of effect consistent?		Yes	Yes
	What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40%‐60%), high I² > 60%)?		Low	Low
	Was the test for heterogeneity statistically significant (P < 0.1)?		Not statistically significant	Not statistically significant
Indirectness	Were the populations in included studies applicable to the decision context?		Highly applicable	Highly applicable
	Were the interventions in the included studies applicable to the decision context?		Highly applicable	Highly applicable
	Was the included outcome not a surrogate outcome?		Yes	Yes
	Was the outcome timeframe sufficient?		Sufficient	Sufficient
	Were the conclusions based on direct comparisons?		Yes	Yes
Imprecision^c	Was the confidence interval for the pooled estimate not consistent with benefit and harm?		Yes	Yes
	What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e		Low (↓)	Low (↓)
	What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e		Small (↓)	Small (↓)
	Was the outcome a common event (e.g. occurs more than 1/100)?		Yes	Yes
Publication bias^d	Was a comprehensive search conducted?		Yes	Yes
	Was grey literature searched?		Yes	Yes
	Were no restrictions applied to study selection on the basis of language?		Yes	Yes
	There was no industry influence on studies included in the review?		Unclear	Unclear
	There was no evidence of funnel plot asymmetry?		NA	NA
	There was no discrepancy in findings between published and unpublished studies?		NA	NA
^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual studies. ^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I². ^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful. ^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished studies. ^eDepends on the context of the systematic review area. (↓): key item for potential downgrading the certainty of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); NA: not applicable; NR: not reported; T2DM: type 2 diabetes mellitus.

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Appendix 2. Checklist to aid consistency and reproducibility of GRADE assessments: pioglitazone versus acarbose

Items		(1) All‐cause mortality	(2) Incidence of T2DM	(3) Serious adverse events	(4) Cardiovascular mortality	(5) Non‐fatal myocardial infarction/stroke	(6) Health‐related quality of life	(7) Socioeconomic effects
Study limitations (risk of bias)^a	Was random sequence generation used (i.e. no potential for selection bias)?	NR	Unclear	Unclear	NR	NR	NR	NR
	Was allocation concealment used (i.e. no potential for selection bias)?		Unclear	Unclear
	Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?		Yes	Yes
	Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?		Yes	Yes
	Was an objective outcome used?		Yes	Yes
	Were more than 80% of participants enrolled in studies included in the analysis (i.e. no potential reporting bias)?^e		Yes	Yes
	Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?		Yes	Yes
	No other biases reported (i.e. no potential of other bias)?		Yes	Yes
	Did the studies end up as scheduled (i.e. not stopped early)?		Yes	Yes
Inconsistency^b	Point estimates did not vary widely?		NA	NA
	To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?
	Was the direction of effect consistent?
	What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40%‐60%), high I² > 60%)?
	Was the test for heterogeneity statistically significant (P < 0.1)?
Indirectness	Were the populations in included studies applicable to the decision context?		Highly applicable	Highly applicable
	Were the interventions in the included studies applicable to the decision context?		Highly applicable	Highly applicable
	Was the included outcome not a surrogate outcome?		Yes	Yes
	Was the outcome timeframe sufficient?		Sufficient	Sufficient
	Were the conclusions based on direct comparisons?		Yes	Yes
Imprecision^c	Was the confidence interval for the pooled estimate not consistent with benefit and harm?		NA	NA
	What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e		Low (↓)	Low (↓)
	What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e		Small (↓)	Small (↓)
	Was the outcome a common event (e.g. occurs more than 1/100)?		Yes	Yes
Publication bias^d	Was a comprehensive search conducted?		Yes	Yes
	Was grey literature searched?		Yes	Yes
	Were no restrictions applied to study selection on the basis of language?		Yes	Yes
	There was no industry influence on studies included in the review?		Unclear	Unclear
	There was no evidence of funnel plot asymmetry?		NA	NA
	There was no discrepancy in findings between published and unpublished studies?		NA	NA
^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual studies. ^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I². ^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful. ^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished studies. ^eDepends on the context of the systematic review area. (↓): key item for potential downgrading the certainty of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); NA: not applicable; NR: not reported; T2DM: type 2 diabetes mellitus.

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Appendix 3. Checklist to aid consistency and reproducibility of GRADE assessments: pioglitazone versus repaglinide

Items		(1) All‐cause mortality	(2) Incidence of T2DM	(3) Serious adverse events	(4) Cardiovascular mortality	(5) Non‐fatal myocardial infarction/stroke	(6) Health‐related quality of life	(7) Socioeconomic effects
Study limitations (risk of bias)^a	Was random sequence generation used (i.e. no potential for selection bias)?	NR	Unclear	Unclear	NR	NR	NR	NR
	Was allocation concealment used (i.e. no potential for selection bias)?		Unclear	Unclear
	Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?		Yes	Yes
	Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?		Yes	Yes
	Was an objective outcome used?		Yes	Yes
	Were more than 80% of participants enrolled in studies included in the analysis (i.e. no potential reporting bias)?^e		Yes	Yes
	Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?		Yes	Yes
	No other biases reported (i.e. no potential of other bias)?		Yes	Yes
	Did the studies end up as scheduled (i.e. not stopped early)?		Yes	Yes
Inconsistency^b	Point estimates did not vary widely?		NA	NA
	To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?
	Was the direction of effect consistent?
	What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40%‐60%), high I² > 60%)?
	Was the test for heterogeneity statistically significant (P < 0.1)?
Indirectness	Were the populations in included studies applicable to the decision context?		Highly applicable	Highly applicable
	Were the interventions in the included studies applicable to the decision context?		Highly applicable	Highly applicable
	Was the included outcome not a surrogate outcome?		Yes	Yes
	Was the outcome timeframe sufficient?		Sufficient	Sufficient
	Were the conclusions based on direct comparisons?		Yes	Yes
Imprecision^c	Was the confidence interval for the pooled estimate not consistent with benefit and harm?		NA	NA
	What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e		Low (↓)	Low (↓)
	What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e		Small (↓)	Small (↓)
	Was the outcome a common event (e.g. occurs more than 1/100)?		Yes	Yes
Publication bias^d	Was a comprehensive search conducted?		Yes	Yes
	Was grey literature searched?		Yes	Yes
	Were no restrictions applied to study selection on the basis of language?		Yes	Yes
	There was no industry influence on studies included in the review?		Unclear	Unclear
	There was no evidence of funnel plot asymmetry?		NA	NA
	There was no discrepancy in findings between published and unpublished studies?		NA	NA
^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual studies. ^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I². ^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful. ^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished studies. ^eDepends on the context of the systematic review area. (↓): key item for potential downgrading the certainty of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); NA: not applicable; NR: not reported; T2DM: type 2 diabetes mellitus.

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Appendix 4. Checklist to aid consistency and reproducibility of GRADE assessments: pioglitazone versus intensive behaviour‐changing intervention

Items		(1) All‐cause mortality	(2) Incidence of T2DM	(3) Serious adverse events	(4) Cardiovascular mortality	(5) Non‐fatal myocardial infarction/stroke	(6) Health‐related quality of life	(7) Socioeconomic effects
Study limitations (risk of bias)^a	Was random sequence generation used (i.e. no potential for selection bias)?	NR	Unclear	Unclear	NR	NR	NR	NR
	Was allocation concealment used (i.e. no potential for selection bias)?		Unclear	Unclear
	Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?		Yes	Yes
	Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?		Yes	Yes
	Was an objective outcome used?		Yes	Yes
	Were more than 80% of participants enrolled in studies included in the analysis (i.e. no potential reporting bias)?^e		Yes	Yes
	Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?		Yes	Yes
	No other biases reported (i.e. no potential of other bias)?		Yes	Yes
	Did the studies end up as scheduled (i.e. not stopped early)?		Yes	Yes
Inconsistency^b	Point estimates did not vary widely?		NA	NA
	To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?
	Was the direction of effect consistent?
	What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40%‐60%), high I² > 60%)?
	Was the test for heterogeneity statistically significant (P < 0.1)?
Indirectness	Were the populations in included studies applicable to the decision context?		Highly applicable	Highly applicable
	Were the interventions in the included studies applicable to the decision context?		Highly applicable	Highly applicable
	Was the included outcome not a surrogate outcome?		Yes	Yes
	Was the outcome timeframe sufficient?		Sufficient	Sufficient
	Were the conclusions based on direct comparisons?		Yes	Yes
Imprecision^c	Was the confidence interval for the pooled estimate not consistent with benefit and harm?		NA	NA
	What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e		Low (↓)	Low (↓)
	What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e		Small (↓)	Small (↓)
	Was the outcome a common event (e.g. occurs more than 1/100)?		Yes	Yes
Publication bias^d	Was a comprehensive search conducted?		Yes	Yes
	Was grey literature searched?		Yes	Yes
	Were no restrictions applied to study selection on the basis of language?		Yes	Yes
	There was no industry influence on studies included in the review?		Unclear	Unclear
	There was no evidence of funnel plot asymmetry?		NA	NA
	There was no discrepancy in findings between published and unpublished studies?		NA	NA
^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual studies. ^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I². ^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful. ^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished studies. ^eDepends on the context of the systematic review area. (↓): key item for potential downgrading the certainty of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); NA: not applicable; NR: not reported; T2DM: type 2 diabetes mellitus.

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Appendix 5. Checklist to aid consistency and reproducibility of GRADE assessments: pioglitazone versus placebo

Items		(1) All‐cause mortality	(2) Incidence of T2DM	(3) Serious adverse events	(4) Cardiovascular mortality	(5) Non‐fatal myocardial infarction/stroke	(6) Health‐related quality of life	(7) Socioeconomic effects
Study limitations (risk of bias)^a	Was random sequence generation used (i.e. no potential for selection bias)?	Yes	Yes	Yes	Yes	Yes	NR	NR
	Was allocation concealment used (i.e. no potential for selection bias)?	Yes	Yes	Yes	Yes	Yes
	Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?	Yes	Yes	Yes	Yes	Yes
	Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?	Yes	Yes	Yes	Yes	Yes
	Was an objective outcome used?	Yes	Yes	Yes	Yes	Yes
	Were more than 80% of participants enrolled in studies included in the analysis (i.e. no potential reporting bias)?^e	No (↓)	No (↓)	No (↓)	No (↓)	No (↓)
	Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?	Yes	Yes	Yes	Yes	Yes
	No other biases reported (i.e. no potential of other bias)?	Yes	Yes	Yes	Yes	Yes
	Did the studies end up as scheduled (i.e. not stopped early)?	Yes	Yes	Yes	Yes	Yes
Inconsistency^b	Point estimates did not vary widely?	Yes	Yes	NA	NA	NA
	To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?	Substantial	Substantial
	Was the direction of effect consistent?	Yes	Yes
	What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40%‐60%), high I² > 60%)?	Low	High
	Was the test for heterogeneity statistically significant (P < 0.1)?	Not statistically significant	Statistically significant
Indirectness	Were the populations in included studies applicable to the decision context?	Highly applicable	Highly applicable	Highly applicable	Highly applicable	Highly applicable
	Were the interventions in the included studies applicable to the decision context?	Highly applicable	Highly applicable	Highly applicable	Highly applicable	Highly applicable
	Was the included outcome not a surrogate outcome?	Yes	Yes	Yes	Yes	Yes
	Was the outcome timeframe sufficient?	Insufficient (↓)	Sufficient	Sufficient	Insufficient (↓)	Insufficient (↓)
	Were the conclusions based on direct comparisons?	Yes	Yes	Yes	Yes	Yes
Imprecision^c	Was the confidence interval for the pooled estimate not consistent with benefit and harm?	No (↓)	Yes	NA	NA	NA
	What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e	Intermediate	Low (↓)	Low (↓)	Intermediate	High
	What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e	Small (↓)	Moderate	Small (↓)	Small (↓)	Small (↓)
	Was the outcome a common event (e.g. occurs more than 1/100)?	No	Yes	Yes	Yes	No
Publication bias^d	Was a comprehensive search conducted?	Yes	Yes	Yes	Yes	Yes
	Was grey literature searched?	Yes	Yes	Yes	Yes	Yes
	Were no restrictions applied to study selection on the basis of language?	Yes	Yes	Yes	Yes	Yes
	There was no industry influence on studies included in the review?	Unclear	Unclear	Unclear	Unclear	Unclear
	There was no evidence of funnel plot asymmetry?	NA	NA	NA	NA	NA
	There was no discrepancy in findings between published and unpublished studies?	NA	NA	NA	NA	NA
^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual studies. ^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I². ^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful. ^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished studies. ^eDepends on the context of the systematic review area. (↓): key item for potential downgrading the certainty of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); NA: not applicable; NR: not reported; T2DM: type 2 diabetes mellitus.

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Appendix 6. Checklist to aid consistency and reproducibility of GRADE assessments: pioglitazone versus no intervention

Items		(1) All‐cause mortality	(2) Incidence of T2DM	(3) Serious adverse events	(4) Cardiovascular mortality	(5) Non‐fatal myocardial infarction/stroke	(6) Health‐related quality of life	(7) Socioeconomic effects
Study limitations (risk of bias)^a	Was random sequence generation used (i.e. no potential for selection bias)?	Unclear	Unclear	Unclear	NR	NR	NR	NR
	Was allocation concealment used (i.e. no potential for selection bias)?	Unclear	Unclear	Unclear
	Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?	Yes	Yes	Yes
	Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?	Yes	Yes	Yes
	Was an objective outcome used?	Yes	Yes	Yes
	Were more than 80% of participants enrolled in studies included in the analysis (i.e. no potential reporting bias)?^e	Unclear	Unclear	Unclear
	Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?	Yes	Yes	Yes
	No other biases reported (i.e. no potential of other bias)?	Yes	Yes	Yes
	Did the studies end up as scheduled (i.e. not stopped early)?	Yes	Yes	Yes
Inconsistency^b	Point estimates did not vary widely?	Yes	Yes	Yes
	To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?	Substantial	Substantial	Substantial
	Was the direction of effect consistent?	Yes	Yes	Yes
	What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40%‐60%), high I² > 60%)?	Low	Low	Low
	Was the test for heterogeneity statistically significant (P < 0.1)?	Not statistically significant	Not statistically significant	Not statistically significant
Indirectness	Were the populations in included studies applicable to the decision context?	Highly applicable	Highly applicable	Highly applicable
	Were the interventions in the included studies applicable to the decision context?	Highly applicable	Highly applicable	Highly applicable
	Was the included outcome not a surrogate outcome?	Yes	Yes	Yes
	Was the outcome timeframe sufficient?	Insufficient (↓)	Sufficient	Sufficient
	Were the conclusions based on direct comparisons?	Yes	Yes	Yes
Imprecision^c	Was the confidence interval for the pooled estimate not consistent with benefit and harm?	No (↓)	Yes	No (↓)
	What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e	Low (↓)	High	Low (↓)
	What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e	Small (↓)	Large	Small (↓)
	Was the outcome a common event (e.g. occurs more than 1/100)?	Yes	Yes	Yes
Publication bias^d	Was a comprehensive search conducted?	Yes	Yes	Yes
	Was grey literature searched?	Yes	Yes	Yes
	Were no restrictions applied to study selection on the basis of language?	Yes	Yes	Yes
	There was no industry influence on studies included in the review?	Unclear	Unclear	Unclear
	There was no evidence of funnel plot asymmetry?	NA	NA	NA
	There was no discrepancy in findings between published and unpublished studies?	NA	NA	NA
^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual studies. ^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I². ^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful. ^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished studies. ^eDepends on the context of the systematic review area. (↓): key item for potential downgrading the certainty of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); NA: not applicable; NR: not reported; T2DM: type 2 diabetes mellitus.

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Appendix 7. Search strategies

MEDLINE (Ovid SP)

1. Prediabetic state/
2. Glucose Intolerance/
3. (prediabet* or pre diabet*).tw.
4. (intermediate hyperglyc?emi*).tw.
5. ((impaired fasting adj2 glucose) or IFG or impaired FPG).tw.
6. glucose intoleran*.tw.
7. ((impaired glucose adj (tolerance or metabolism)) or IGT).tw.
8. ((risk or progress* or prevent* or inciden* or conversion or develop* or delay*) adj4 (diabetes or T2D* or NIDDM or "type 2" or "type II")).tw.
9. or/1‐8
10. Pioglitazone/
11. (pioglitazon* or "U 72107A" or "U72,107A" or "U72107A" or "AD 4833" or "AD4833").tw.
12. 10 or 11
13. 9 and 12
[Cochrane Handbook RCT filter ‐ sensitivity max. version + Cooper 2019 "phase3 filter"]
14. randomized controlled trial.pt.
15. controlled clinical trial.pt.
16. randomi?ed.ab.
17. placebo.ab.
18. drug therapy.fs.
19. randomly.ab.
20. trial.ab.
21. groups.ab.
22. or/14‐21
23. exp animals/ not humans/
24. 22 not 23
25. Clinical Trial, Phase III/
26. ("phase 3" or "phase3" or p3 or "pIII").ti,ab,kw.
27. 25 or 26
28. 24 or 27
13 and 28

Cochrane Central Register of Controlled Trials (CENTRAL) via Cochrane Register of Studies Online

1. MESH DESCRIPTOR Prediabetic state
2. MESH DESCRIPTOR Glucose Intolerance
3. (prediabet* OR pre diabet*):TI,AB,KY
4. (intermediate hyperglyc?emi*):TI,AB,KY
5. ((impaired fasting ADJ3 glucose) OR IFG OR impaired FPG):TI,AB,KY
6. glucose intoleran*:TI,AB,KY
7. ((impaired glucose ADJ2 (tolerance OR metabolism)) OR IGT):TI,AB,KY
8. ((risk OR progress* OR prevent* OR inciden* OR conversion OR develop* OR delay*) ADJ5 (diabetes OR T2D* OR NIDDM OR "type 2" OR "type II")):TI,AB,KY
9. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8
10. MESH DESCRIPTOR Pioglitazone
11. (pioglitazon* OR “U 72107A” OR “U72,107A” OR “U72107A” OR “AD 4833” OR “AD4833”):TI,AB,KY
12. #10 OR #11
13. #9 AND #12

WHO ICTRP (Standard search)

prediabet* AND pioglitazone OR
pre‐diabet* AND pioglitazone OR
impaired* AND glucose* AND pioglitazone OR
impaired* AND fasting* AND pioglitazone OR
glucose* AND intoleran* AND pioglitazone OR
IFG* AND pioglitazone OR
IGT* AND pioglitazone

ClinicalTrials.gov(Expert search)

(prediabetes OR prediabetic OR "pre diabetes" OR "pre diabetic" OR "impaired glucose" OR "impaired fasting" OR "glucose intolerance" OR IGT OR IFG OR ((diabetes OR "type 2" OR "type II" OR T2D OR T2DM) AND (risk OR progress OR progression OR progressed OR incident OR incidence OR conversion OR developed OR development OR develop OR delay OR delayed OR prevention OR prevent OR prevented))) [DISEASE] AND pioglitazone [TREATMENT]

China Network Knowledge Infrastructure (CNKI)

(SU = 吡格列酮 + 匹格列酮) and (SU=糖尿病前期 + 高血糖症 + 前驱糖尿病 + 糖耐量低减 + 糖耐量减低 + 糖耐量受损 + 糖耐量异常 + 葡糖耐受不良 + IGT + IFG + 空腹血糖受损 + 空腹血糖低减 + 空腹血糖减低 + 空腹血糖异常 + 高血糖症 + 糖调节受损 + 葡萄糖耐受不良 + 糖代谢异常) and (SU = 对照 + 试验 + 临床 + 临床观察 + 临床研究 + 临床疗效 + 临床效果 + 疗效)

Chinese Scientific Journals Database (VIP)

任意字段=吡格列酮 + 匹格列酮 AND 任意字段 = 糖尿病前期 + 高血糖症 + 前驱糖尿病 + 糖耐量低减 + 糖耐量减低 + 糖耐量受损 + 糖耐量异常 + 葡糖耐受不良 + IGT + IFG + 空腹血糖受损 + 空腹血糖低减 + 空腹血糖减低 + 空腹血糖异常 + 高血糖症 + 糖调节受损 + 葡萄糖耐受不良 + 糖代谢异常 AND
题名或关键词 = 对照 + 试验 + 临床 + 临床观察 + 临床研究 + 临床疗效 + 临床效果 + 疗效

Wan Fang data

主题: (吡格列酮+匹格列酮) * 主题: (糖尿病前期 + 高血糖症 + 前驱糖尿病 + 糖耐量低减 + 糖耐量减低 + 糖耐量受损 + 糖耐量异常 + 葡糖耐受不良 + IGT + IFG + 空腹血糖受损 + 空腹血糖低减 + 空腹血糖减低 + 空腹血糖异常 + 高血糖症 + 糖调节受损 + 葡萄糖耐受不良 + 糖代谢异常) * 题名或关键词: (对照 + 试验 + 临床 + 临床观察 + 临床研究 + 临床疗效 + 临床效果+疗效)

SinoMed

("吡格列酮"[常用字段:智能] OR "匹格列酮"[常用字段:智能]) AND ("糖尿病前期"[常用字段:智能] OR "高血糖症"[常用字段:智能] OR "前驱糖尿病"[常用字段:智能] OR "糖耐量低减"[常用字段:智能] OR "糖耐量减低”[常用字段:智能] OR “糖耐量受损”[常用字段:智能] OR “糖耐量异常”[常用字段:智能] OR “葡糖耐受不良”[常用字段:智能] OR “IGT”[常用字段:智能] OR “IFG”[常用字段:智能] OR “空腹血糖受损”[常用字段:智能] OR “空腹血糖低减”[常用字段:智能] OR “空腹血糖减低”[常用字段:智能] OR “空腹血糖异常”[常用字段:智能] OR “高血糖症”[常用字段:智能] OR “糖调节受损”[常用字段:智能] OR “葡萄糖耐受不良”[常用字段:智能] OR “糖代谢异常") AND ("临床试验"[不加权:扩展] OR "对照"[常用字段:智能] OR "试验"[常用字段:智能] OR "临床"[常用字段:智能] OR "临床观察"[常用字段:智能] OR "临床研究"[常用字段:智能] OR "临床疗效"[常用字段:智能] OR "临床效果"[常用字段:智能] OR "疗效"[常用字段:智能])

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Appendix 8. Selection bias decisions

Selection bias decisions for studies that reported unadjusted analyses: comparison of results obtained using method details alone versus results obtained using method details and study baseline information^a
Reported randomisation and allocation concealment methods	'Risk of bias' judgement using methods reporting	Information gained from study characteristics data	'Risk of bias' using baseline information and methods reporting
Unclear methods	Unclear risk	Baseline imbalances present for important prognostic variable(s)	High risk
		Groups appear similar at baseline for all important prognostic variables	Low risk
		Limited or no baseline details	Unclear risk
Would generate a truly random sample, with robust allocation concealment	Low risk	Baseline imbalances present for important prognostic variable(s)	Unclear risk^b
		Groups appear similar at baseline for all important prognostic variables	Low risk
		Limited baseline details, showing balance in some important prognostic variables^c	Low risk
		No baseline details	Unclear risk
Sequence is not truly randomised or allocation concealment is inadequate	High risk	Baseline imbalances present for important prognostic variable(s)	High risk
		Groups appear similar at baseline for all important prognostic variables	Low risk
		Limited baseline details, showing balance in some important prognostic variables^c	Unclear risk
		No baseline details	High risk
^aTaken from Corbett 2014; judgements highlighted in bold indicate situations in which the addition of baseline assessments would change the judgement about risk of selection bias compared with using methods reporting alone. ^bImbalance was identified that appears likely to be due to chance. ^cDetails for the remaining important prognostic variables are not reported.

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Appendix 9. 'Risk of bias' assessment

'Risk of bias' domains

Random sequence generation (selection bias due to inadequate generation of a randomised sequence)
For each included study, we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

Low risk of bias: study authors achieved sequence generation using computer‐generated random numbers or a random numbers table. Drawing of lots, tossing a coin, shuffling cards or envelopes, and throwing dice are adequate if an independent person performed this who was not otherwise involved in the study. We considered the use of the minimisation technique as equivalent to being random.
Unclear risk of bias: insufficient information about the sequence generation process.
High risk of bias: the sequence generation method was non‐random or quasi‐random (e.g. sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number; allocation by judgement of the clinician; allocation by preference of the participant; allocation based on the results of a laboratory test or a series of tests; or allocation by availability of the intervention).

Allocation concealment (selection bias due to inadequate concealment of allocation prior to assignment)
We described for each included study the method used to conceal allocation to interventions prior to assignment and we assessed whether intervention allocation could have been foreseen in advance of or during recruitment or changed after assignment.

Low risk of bias: central allocation (including telephone, interactive voice‐recorder, Internet‐based and pharmacy‐controlled randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes.
Unclear risk of bias: insufficient information about the allocation concealment.
High risk of bias: used an open random allocation schedule (e.g. a list of random numbers); assignment envelopes used without appropriate safeguards; alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

We also evaluated study baseline data to incorporate assessment of baseline imbalance into the 'Risk of bias' judgement for selection bias (Corbett 2014).
Chance imbalances may also affect judgements on the risk of attrition bias. In the case of unadjusted analyses, we distinguished between studies that we rate as being at low risk of bias on the basis of both randomisation methods and baseline similarity, and studies that we judge as being at low risk of bias on the basis of baseline similarity alone (Corbett 2014). We reclassified judgements of unclear, low, or high risk of selection bias as specified in Appendix 9.
Blinding of participants and study personnel (performance bias due to knowledge of the allocated interventions by participants and personnel during the study)
We evaluated the risk of detection bias separately for each outcome (Hróbjartsson 2013). We noted whether endpoints were self‐reported, investigator‐assessed, or adjudicated outcome measures (see below).

Low risk of bias: blinding of participants and key study personnel was ensured, and it was unlikely that the blinding could have been broken; no blinding or incomplete blinding, but we judge that the outcome is unlikely to have been influenced by lack of blinding.
Unclear risk of bias: insufficient information about the blinding of participants and study personnel; the study does not address this outcome.
High risk of bias: no blinding or incomplete blinding, and the outcome is likely to have been influenced by lack of blinding; blinding of study participants and key personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias due to knowledge of the allocated interventions by outcome assessment)
We evaluated the risk of detection bias separately for each outcome (Hróbjartsson 2013). We noted whether endpoints were self‐reported, investigator‐assessed, or adjudicated outcome measures (see below).

Low risk of bias: blinding of outcome assessment is ensured, and it is unlikely that the blinding could have been broken; no blinding of outcome assessment, but we judge that the outcome measurement is unlikely to have been influenced by lack of blinding.
Unclear risk of bias: insufficient information about the blinding of outcome assessors; the study did not address this outcome.
High risk of bias: no blinding of outcome assessment, and the outcome measurement was likely to have been influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement was likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias due to quantity, nature or handling of incomplete outcome data)
For each included study or each outcome, or both, we described the completeness of data, including attrition and exclusions from the analyses. We stated whether the study reported attrition and exclusions, and we reported the number of participants included in the analysis at each stage (compared with the number of randomised participants per intervention/comparator groups). We also noted if the study reported the reasons for attrition or exclusion, and whether missing data were balanced across groups or were related to outcomes. We considered the implications of missing outcome data per outcome such as high dropout rates (e.g. above 15%) or disparate attrition rates (e.g. difference of 10% or more between study arms).

Low risk of bias: no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to introduce bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes was not enough to have a clinically relevant impact on observed effect size; appropriate methods, such as multiple imputation, were used to handle missing data.
Unclear risk of bias: insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias; the study did not address this outcome.
High risk of bias: reason for missing outcome data was likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes enough to induce clinically relevant bias in observed effect size; 'as‐treated' or similar analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Selective reporting (reporting bias due to selective outcome reporting)
We assessed outcome reporting bias by integrating the results of the appendix 'Matrix of study endpoints (publications and trial documents)' (Boutron 2014; Jones 2015; Mathieu 2009), with those of the appendix 'High risk of outcome reporting bias according to the Outcome Reporting Bias In Trials (ORBIT) classification' (Kirkham 2010). This analysis formed the basis for the judgement of selective reporting.

Low risk of bias: the study protocol was available and all the study's prespecified (primary and secondary) outcomes that were of interest to this review were reported in the prespecified way; the study protocol was unavailable, but it was clear that the published reports included all expected outcomes (ORBIT classification).
Unclear risk of bias: insufficient information about selective reporting.
High risk of bias: not all the study's prespecified primary outcomes were reported; one or more primary outcomes were reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting was provided, such as an unexpected adverse effect); one or more outcomes of interest in the Cochrane Review were reported incompletely so that we cannot enter them into a meta‐analysis; the study report failed to include results for a key outcome that we would expect to have been reported for such a study (ORBIT classification).

Other bias

Low risk of bias: the study appears to be free from other sources of bias.
Unclear risk of bias: information was insufficient to assess whether an important risk of bias existed; insufficient rationale or evidence that an identified problem introduced bias.
High risk of bias: the study had a potential source of bias related to the specific study design used; the study was claimed to be fraudulent; or the study had some other serious problem.

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Appendix 10. Descriptions of participants

Study ID	Criteria	Description
ACT NOW	Inclusion criteria	IFG = FPG ≥ 5.3 and < 7 mmol/L and IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L plus at least one other high‐risk factor for diabetes or FPG ≥ 5 and < 7 mmol/L and IGT = 2‐h glucose ≥ 9.4 to ≤ 11.1 mmol/L plus at least one other high‐risk factor for diabetes, ≥ 18 years of age, BMI > 25 kg/m² High‐risk characteristics: (i) ≥ 1 components of the insulin resistance syndrome (low HDL cholesterol (< 40 mg/dL in women; < 35 mg/dL in men), fasting plasma triglyceride ≥ 150 mg/dL, sitting blood pressure > 135/85 mmHg or on active therapy for hypertension, BMI ≥ 25 kg/m² (BMI ≥ 22 kg/m² for Asian Americans), waist circumference > 102 cm in men and > 88 cm in women (> 90 cm in Asian American men and > 80 cm in Asian American women)), (ii) family history of T2DM (≥ 1 first‐degree relatives); (iii) history of gestational diabetes mellitus; (iv) polycystic ovarian syndrome; (v) minority ethnic background (Mexican American, African American, Asian, Pacific Islander, Native American))
	Exclusion criteria	T2DM; ever treated with a thiazolidinedione; received metformin within 1 year; treatment within last 3 months or for > 1 week the last year with sulphonylurea, meglitinide or alpha glucosidase inhibitor; treatment within last 3 months or for > 1 week the last year with insulin (excluding pregnancy); cardiovascular disease; renal disease; anaemia; gastrointestinal disease; recent significant abdominal surgery; pulmonary disease; chronic infections; unable to accept treatment assigned by randomisation; participation in another trial; recent major weight loss; pregnancy or childbearing; planning of pregnancy during trial; major psychiatric disorders; acute or chronic alcohol abuse; use of: thiazide diuretics exceeding a dose of 25 mg/day, non‐cardioselective systemic beta‐blockers, niacin, systemic glucocorticoids, weight‐gain or loss medications; thyroid disease with abnormal TSH; other endocrine disorders; fasting plasma triglyceride > 400 mg/dL; history of bladder cancer; untreatable hematuria at screening
	Diagnostic criteria^a	IFG = FPG ≥ 5.3 and < 7 mmol/L and IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L plus at least one other high‐risk factor for diabetes or FPG ≥ 5 and < 7 mmol/L and IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L plus at least one other high‐risk factor for diabetes
Attallah 2007	Inclusion criteria	IGT and IFG, age 40‐75 years, BMI ≥ 27 kg/m², waist circumference > 100 cm for men and > 88 cm for women
	Exclusion criteria	Known diabetes; history of malignancy, congestive heart failure, recent treatment with weight‐reducing medications or corticosteroids in doses exceeding standard replacement; pregnant or breastfeeding; declining contraception throughout the treatment period; history of acromegaly, cardiac, pulmonary, hepatic or renal disease; ALT > three times above the upper normal limit; uncontrolled hypertension
	Diagnostic criteria^a	IFG = FPG < 6.9 mmol/L; IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L
Bone 2013	Inclusion criteria	IFG or IGT, female, age ≤ 70 years, no menses for at least 5 years, BMI ≥16 and ≤ 40 kg/m² and weight < 300 lbs (~136 kg), agreeing to take daily supplements of vitamin D and calcium during the study, clinical laboratory evaluations normal deemed by physician at screening
	Exclusion criteria	Fasting triglyceride level > 500 mg/dL; haemoglobinopathy causing anaemia or interfering with HbA1c assays; ALT ≥ 2.5 times the upper limit of normal or active liver disease; jaundice; vitamin D (25‐OH‐D) < 20 ng/mL; BMD with T‐score < −2.0 at the total hip, spine, or femoral neck based on white reference values; unexplained haematuria confirmed by repeated testing; following disorders: rheumatoid arthritis, thyroid, parathyroid, pituitary, nutritional, inflammatory, gastrointestinal, autoimmune, renal, diseases known to affect bone metabolism; history of kidney stones; clinical history of wrist, hip, or leg fractures after age 45; history of > 1 asymptomatic vertebral deformity or any vertebral deformity attributed to osteoporosis; history of drug abuse; history of alcohol abuse within 2 years of screening; signs and/or symptoms of heart failure; taking any of the protocol‐specified excluded medication; not capable of understanding and/or complying with protocol requirements; unable to understand the approved consent form; currently participating in another investigational study or had participated in an investigational study within the past 30 days or 5 half lives of the investigational product; other serious condition making it difficult to follow protocol; history of cancer, other than basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin that had not been in remission for ≥ 5 years; taking or ever had taken pioglitazone hydrochloride or other thiazolidinediones; study site employees or immediate family member of a study site employee; received or donated blood or blood products within 30 days preceding the screening visit or planned to donate blood during the study
	Diagnostic criteria^a	IFG = FPG ≥ 5.6 to < 7 mmol/L; IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L
Che 2014	Inclusion criteria	IGT, hypertension
	Exclusion criteria	—
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L; hypertension = ND
Chen 2007a	Inclusion criteria	IGT, age > 25 years
	Exclusion criteria	Hyperthyroidism; hypercortisolaemia; acromegaly; chronic pancreatitis; secondary diabetes; fever; acute infection; trauma; surgery; other stress factors
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Chen 2007b	Inclusion criteria	IGT, hypertension
	Exclusion criteria	—
	Diagnostic criteria	IGT = ND; hypertension = prior diagnosis of hypertension, in pharmacological treatment for hypertension, or blood pressure ≥ 140/90 mmHg
Deng 2013	Inclusion criteria	Age > 18 years, IGT or IFG, having > 1 risk factor for development of T2DM, BMI ≥ 25 kg/m²
	Exclusion criteria	—
	Diagnostic criteria	IFG = FPG > 5.3 and < 6.9 mmol/L, IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Fang 2013	Inclusion criteria	IFG or IGT, age 40‐70 years, blood pressure < 160/95 mmHg, hypertensive drugs used unchanged within last month
	Exclusion criteria	Secondary reason for elevated blood glucose; severe cerebrovascular or cardiovascular disease; gastrointestinal disease; abnormal liver function; use of blood glucose‐altering drugs within last 2 months; history of family bladder malignancy; pregnancy or currently lactating; mental disorders; deemed ineligible by study physicians
	Diagnostic criteria	IFG = FPG > 5.3 and < 6.9 mmol/L, IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Gao 2011	Inclusion criteria	IGT, hypertension
	Exclusion criteria	—
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L; hypertension = prior diagnosis of hypertension, in pharmacological treatment for hypertension, or blood pressure > 140/90 mmHg
Guo 2009	Inclusion criteria	Elderly (ND), IGT, blood pressure < 150/90 mmHg
	Exclusion criteria	Smoking; creatinine > 115 mmol/L; vascular disease; liver disease; severe infectious disease; heart failure
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Guo 2010	Inclusion criteria	Elderly (ND), IGT, blood pressure < 150/90 mmHg, creatinine < 115 mmol/L, non‐smoker for a minimum of 5 years
	Exclusion criteria	Blood disease; liver insufficiency; severe infectious diseases; heart failure
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Han 2007	Inclusion criteria	IFG and IGT, hypertension
	Exclusion criteria	Secondary hypertension; diabetes; liver or kidney disease
	Diagnostic criteria	IFG = FPG < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L; hypertension = blood pressure > 140/90 mmHg
IDPP‐2	Inclusion criteria	IGT, age 35‐55 years
	Exclusion criteria	Known coronary artery disease; history of stroke; major Q wave abnormalities; liver disorders; kidney disorders
	Diagnostic criteria	IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L
Ke 2006	Inclusion criteria	IGT
	Exclusion criteria	—
	Diagnostic criteria	IGT = 2‐h glucose > 7.8 and < 11.0 mmol/L
Li 2017	Inclusion criteria	IGT
	Exclusion criteria	Thyroid, heart, liver, kidney or heart disease; secondary reason for intermediate hyperglycaemia
	Diagnostic criteria	—
Liang 2004	Inclusion criteria	IGT, age 25‐60 years
	Exclusion criteria	—
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 to < 11.1 mmol/L
Shi 2014	Inclusion criteria	IFG or IGT (or both)
	Exclusion criteria	Known diabetes; severe heart, liver or kidney disease; prior usage of glucocorticoids in large doses; pregnant women; lactating women
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Tian 2015	Inclusion criteria	'Prediabetes'
	Exclusion criteria	Medical disease; mental disease; allergy; secondary reason for elevated blood glucose
	Diagnostic criteria	—
Wu 2013	Inclusion criteria	IFG and IGT, age > 65 years, essential hypertension
	Exclusion criteria	Liver disease; hypertension crisis; secondary hypertension; multi‐organ failure; mental disorders; diabetes; cardiac or renal insufficiency
	Diagnostic criteria	IFG = FPG > 5.6 and < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Xiu 2015	Inclusion criteria	IFG and IGT
	Exclusion criteria	Secondary hyperglycaemia; severe heart, liver or kidney disease; other major disease; taking hypoglycaemic drug within last 3 months prior to randomisation
	Diagnostic criteria	IFG = FPG < 6.1 mmol/L to > 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 to < 11.1 mmol/L
Xu 2011	Inclusion criteria	IFG and IGT after 1 month of intensive lifestyle intervention
	Exclusion criteria	Secondary reasons for elevated blood glucose; microvascular complications; severe heart, liver or kidney disease; other serious organic disease
	Diagnostic criteria	IFG = FPG > 6.1 mmol/L to < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 to < 11.1 mmol/L
Yi 2015	Inclusion criteria	IFG and IGT
	Exclusion criteria	Heart, liver or kidney disease; secondary hyperglycaemia; use of glucose‐lowering drugs within last 3 months prior to randomisation
	Diagnostic criteria	IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Yu 2011	Inclusion criteria	IFG and IGT
	Exclusion criteria	Heart, lung, liver or kidney disease; use of glucose‐lowering drugs; thyroid disease; diabetes; acute or chronic pancreatitis; no recent infection or trauma
	Diagnostic criteria	IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Zeng 2013	Inclusion criteria	IFG and IGT
	Exclusion criteria	Liver or kidney disease; cardiovascular disease; cerebrovascular disease
	Diagnostic criteria	IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Zhang 2007	Inclusion criteria	IGT only
	Exclusion criteria	Secondary reasons for elevated blood glucose; recent history of glucocorticoid usage; heart, liver, kidney disease
	Diagnostic criteria	IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Zhang 2015	Inclusion criteria	IFG and IGT
	Exclusion criteria	—
	Diagnostic criteria	IFG = FPG > 5.6 and < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
Zhao 2009	Inclusion criteria	IFG and IGT
	Exclusion criteria	Heart, lung, liver, or kidney disease
	Diagnostic criteria	IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L
— denotes not reported ^aStudies reporting glucose cut‐offs in mg/dL, these were converted to mmol/L by dividing by 18. 2‐h glucose: 2‐hour post oral glucose tolerance test glucose; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AV: atrioventricular; BMD: bone mineral density; BMI: body mass index; FPG: fasting plasma glucose; HDL: high density lipoprotein; IFG: impaired fasting glucose; IGT: impaired glucose tolerance; LBBB: left bundle branch block; ND: not defined; NYHA: New York Heart Association; OGTT: oral glucose tolerance test; T2DM: type 2 diabetes

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Appendix 11. Description of interventions

Study ID	Description
ACT NOW
Intervention/comparator	Intervention: pioglitazone in a dose of 45 mg once daily, titrated up from 30 mg once daily after 1 month plus BCI Comparator: placebo in matching doses once daily plus BCI
Recipient	People with increased risk of diabetes and isolated IGT, or IGT and IFG (authors' definitions, see Appendix 10)
Why?	To investigate whether pioglitazone can prevent or delay conversion from IGT to T2DM and cardiovascular events in people with increased risk of diabetes
Procedures	Participants received instructions on reducing calorie and fat intake, walking 30 minutes per day 4‐5 times a week. Instructions consistent with the goals of the Diabetes Prevention Program, given prior to randomisation with a duration of 30 min. These instructions were repeated at each follow‐up
Who provided	Site co‐ordinators, all site co‐ordinators were medical doctors
How (mode of delivery; individual or group)	Face‐to‐face, not specified if in a group or individually
Where	8 centres, USA
When and how much	Pioglitazone/placebo was given at follow‐up visits at 2, 4, 6, 8, 10, and 12 months thereafter every 3 months subsequently with a dose of 30 mg/day or 45 mg/day. Pills were counted
Tailoring	NA
Modification of intervention throughout the study	NA
Strategies to improve or maintain intervention fidelity	NA
Extent of intervention fidelity	NA
Attallah 2007
Intervention/comparator	Interventions: pioglitazone and recombinant human growth hormone in a 2 x 2 factorial design Comparators: matching placebo once daily
Recipient	Obese men and women with IGT and IFG by WHO 1999 definitions
Why?	Assessing the theory that pioglitazone in combination with GH would attenuate the GH‐induced increase in blood glucose, reduce the visceral adipose tissue and improve insulin sensitivity
Procedures	Participants underwent non‐contrast CT scans at baseline and after 40 weeks
Who provided	An investigational pharmacist dispensed all study medication. Not further specified
How (mode of delivery; individual or group)	—
Where	Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA. Not further specified
When and how much	Participants underwent baseline evaluation, and follow‐up each month. And final visit 3‐4 weeks after intervention end
Tailoring	NA
Modification of intervention throughout the study	NA
Strategies to improve or maintain intervention fidelity	NA
Extent of intervention fidelity	NA
Bone 2013
Intervention/comparator	Intervention: pioglitazone in a dose of 45 mg once daily, titrated up from 30 mg once daily after 4 weeks Comparator: matching placebo once daily
Recipient	Menopausal women with IFG or IGT ADA 2003 definitions
Why?	To assess the effects of pioglitazone on BMD and bone turnover
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	—
Where	25 sites in the USA, not further specified
When and how much	—
Tailoring	NA
Modification of intervention throughout the study	After 1 year of intervention drug, the participants were followed‐up after 6 months of wash‐out
Strategies to improve or maintain intervention fidelity	NA
Extent of intervention fidelity	NA
Che 2014
Intervention/comparator	Intervention: L‐amlodipine 5 mg once daily plus pioglitazone 30 mg once daily Comparator: L‐amlodipine 5 mg once daily
Recipient	Older people with IGT WHO 1999 definitions and hypertension (not defined)
Why?	—
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Orally; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 6 months
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Chen 2007a
Intervention/comparator	Intervention 1: pioglitazone 15 mg once daily plus BCI Intervention 2: acarbose 50 mg three times daily plus BCI Intervention 3: metformin 250 mg three times daily plus BCI Intervention 4: BCI Comparator: no intervention
Recipient	Adults with IGT by WHO 1999 definitions
Why?	To investigate the effect of different pharmacological and behaviour‐changing interventions on people with IGT compared with no intervention
Procedures	All study group received individual exercise and dietary instructions. Repeated every 3 months
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient, not further described
When and how much	Daily, 12 months
Tailoring	All study group received individual exercise and dietary instructions, this was not further specified
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Chen 2007b
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus captopril 25 twice daily and Betaloc 25 mg twice daily plus BCI Comparator: captopril 25 twice daily and Betaloc 25 mg twice daily plus BCI
Recipient	Adults with IGT (not defined) and hypertension defined by: prior diagnosis of hypertension, in pharmacological treatment for hypertension, or blood pressure ≥ 140/90 mmHg
Why?	Hypertension correlates closely to insulin resistance and is a predictor for the development of T2DM. The theory was whether pioglitazone can slow the progression of T2DM
Procedures	BCI consisted of dietary and exercise therapy, this is not further specified
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 12 months
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Deng 2013
Intervention/comparator	Intervention: pioglitazone 30 mg once daily plus BCI Comparator: BCI
Recipient	Adults with IGT by ADA 2010 definitions and a BMI above 25 kg/m². Participants were recruited from a single hospital in China
Why?	To assess whether pioglitazone can help prevent the development of T2DM and decrease the incidence of cardiovascular comorbidity
Procedures	Participants had a 30‐minute session on diet and exercise after enrolment
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, mean duration 2.2 years
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Fang 2013
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI Comparator: BCI
Recipient	Adults with IFG or IGT or both by ADA 2003 definitions, age between 40‐70 and blood pressure below 160/95 mmHg. Participants were recruited from a single hospital in China
Why?	To investigate the efficacy of pioglitazone on participants with impaired glucose metabolism on their progression to T2DM
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, duration 1 year
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Gao 2011
Intervention/comparator	Intervention: pioglitazone 30 mg once daily, captopril and other antihypertensive drugs (not further described) plus BCI Comparator: antihypertensive drugs (not further described) plus BCI
Recipient	Adults with IGT by WHO 1999 definitions and hypertension defined by prior diagnosis of hypertension, in pharmacological treatment for hypertension, or blood pressure > 140/90 mmHg
Why?	To investigate the efficacy of pioglitazone on participants with impaired glucose tolerance and hypertension compared with no intervention
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, duration 18 months
Tailoring	Participants who developed T2DM, cardiovascular or cerebrovascular disease during the 18 months were treated
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Guo 2009
Intervention/comparator	Intervention: pioglitazone 30 mg daily BCI on diet and exercise Comparator: BCI on diet and exercise
Recipient	—
Why?	Quote: "To investigate the effects of pioglitazone on endothelial function in elderly patients with impaired glucose tolerance (IGT)"
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 6 months
Tailoring	The diet and exercise programs of both groups were individually designed
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Guo 2010
Intervention/comparator	Intervention: pioglitazone 30 mg daily plus BCI on diet and exercise Comparator: BCI on diet and exercise
Recipient	—
Why?	Quote: "Pioglitazone belongs to thiazolidinedione, which can selectively activate the receptor receptors γ (PPARγ) activated by the proliferator of the target organ peroxide, enhance insulin sensitivity and reduce blood glucose"
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 12 months
Tailoring	The diet and exercise programmes of both groups were individually designed
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Han 2007
Intervention/comparator	Intervention: pioglitazone 15 mg daily plus enalapril (dose not reported) Comparator: enalapril (dose not reported)
Recipient	Participants with IFG and IGT by WHO 1999 definitions and blood pressure > 140/90 mmHg
Why?	—
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 24 weeks
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
IDPP‐2
Intervention/comparator	Intervention: pioglitazone 30 mg once daily titrated up from 15 mg once daily after 6 months plus BCI. 10 participants in each group were titrated up to 45 mg once daily Comparator placebo in matching doses once daily plus BCI
Recipient	Men and women aged 35‐55 with IGT by WHO 1999 definitions. Participants were recruited among employees, and their families, of service organisations such as the railways and electricity board. To participate participants had to respond to a workplace announcement
Why?	The study aimed to assess whether pioglitazone would enhance the effect of BCI in the prevention of type 2 diabetes in Asian Indians with IGT
Procedures	Participants were instructed in healthy lifestyle regarding diet and physical activity. Activity by assessing mode of transport and occupational activity. Diet including a reduction in calories and cutting refined foods and sugar, and a focus on a fibre‐rich diet
Who provided	Quote: "The team members included a physician, three laboratory technicians, a dietitian, a social worker and a helper. The measurements were repeated by the same members throughout the study, to eliminate inter‐observer variations" Not further described
How (mode of delivery; individual or group)	Each person's BCI was given and fitted individually. Instructions were repeated after the first 2 weeks and hereafter each month by telephone
Where	—
When and how much	Each 6 months participants underwent personal sessions with the study team. This accounts for a total of 6 sessions. Delivery of the intervention was not specified
Tailoring	The BCI was fitted according to participants' work, daily transportation and free‐time activities
Modification of intervention throughout the study	Pioglitazone was titrated up from 15 mg/day to 30 mg/day at 6‐month visit. Up‐titration of the drug part of normal practice when prescribing pioglitazone. 10 participants of each group were titrated to 45 mg/day
Strategies to improve or maintain intervention fidelity	Participant adherence to BCI was scored at follow‐up visits. The advice was repeated each month by telephone
Extent of intervention fidelity	—
Ke 2006
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI on diet and exercise Comparator: BCI on diet and exercise
Recipient	Participants with relatives with type 2 diabetes mellitus and IGT by WHO 1999 definitions
Why?	To evaluate the therapeutic effect of pioglitazone in participants with IGT
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Drug: daily, 12 months Health education on diabetes and IGT were carried out in the form of group lectures once a month
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Li 2017
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI on diet and exercise Comparator: BCI on diet and exercise
Recipient	Participants with IGT (not further specified)
Why?	Quote (translated): "To explore the value of pioglitazone in treatment of patients with impaired glucose tolerance (IGT)"
Procedures	Participants were given advice on diet and physical activity. Dietary advice consisted of controlled intake of 25‐30 kJ/kg/day with a distribution of 55%‐65% carbohydrates, 10%‐15% protein and 25%‐30% fat. Activity advice on exercises like brisk walking, jogging, Tai Chi, riding or other aerobic exercises for a minimum of 150 minutes per week. Other advice included quitting smoking and alcohol and reducing sugar intake
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 6 months
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Liang 2004
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI on diet and exercise Comparator: BCI on diet and exercise
Recipient	Participants with IGT by WHO 1999 definitions
Why?	Quote: "To investigate the interventive effect of pioglitazone hydrochloride on the subjects with impaired glucose tolerance (IGT)."
Procedures	Participants of both groups were given individual counselling on diabetes knowledge and modifications on diet and exercise. This was repeated for participants every second month
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 12 months
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Shi 2014
Intervention/comparator	Intervention: pioglitazone 30 mg once daily plus BCI on diet and exercise Comparator: BCI on diet and exercise
Recipient	Participants with newly diagnosed IFG, IGT or both by ADA 2010 definitions
Why?	Quote: "To observe the therapeutic effect of pioglitazone on patients with impaired fasting glucose regulation and impaired glucose tolerance in pre‐diabetes"
Procedures	Participants of both groups were given BCI on diet and exercise, this was not further specified
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 10 months
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Tian 2015
Intervention/comparator	Intervention: pioglitazone 30 mg once daily plus BCI on diet and exercise Comparator: BCI on diet and exercise
Recipient	Participants diagnosed with increased risk of diabetes. This is not further defined or specified
Why?	Quote (translated): "To investigate the effect of pioglitazone treatment in pre‐diabetes and its improvement on C‐reactive protein (CRP)"
Procedures	Participants of both groups were given BCI on diet and exercise, this was not further specified
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 24 weeks
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Wu 2013
Intervention/comparator	Intervention: pioglitazone 30 mg once daily plus amlodipine 5 mg once daily and valsartan 80 mg once daily plus BCI Comparator: amlodipine 5 mg once daily and valsartan 80 mg once daily plus BCI
Recipient	Participants with IFG and IGT by ADA 2010; hypertension (2010 Chinese hypertension prevention and treatment guidelines for the elderly hypertension diagnosis and compliance standards)
Why?	Quote: "To observe the effect of pioglitazone on blood glucose, blood lipid, dynamic pulse pressure index (PPI) and Effects of arteriosclerosis index (ASI) and plasma amino‐terminal brain natriuretic peptide precursor (NT‐proBNP)"
Procedures	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Inpatient; administered from 1 site
When and how much	Daily, 24 weeks
Tailoring	—
Modification of intervention throughout the study	Participants who developed T2DM, cardiovascular or cerebrovascular disease within the 24 weeks of intervention received relevant treatment
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Xiu 2015
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI Comparator: BCI
Recipient	Participants with IFG and IGT by WHO 1999 definitions
Why?	—
Procedures	BCI consisted of advice on general health, diet and exercise. Not further specified
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 48 weeks
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Xu 2011
Intervention/comparator	Intervention: pioglitazone 30 mg once daily plus BCI Comparator: placebo in matching doses BCI
Recipient	Participants with IFG and IGT by WHO 1999 definitions
Why?	Quote (translated): "To observe the therapeutic effect of pioglitazone on patients with impaired glucose tolerance"
Procedures	BCI not described
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 48 weeks
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Yi 2015
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI Comparator: BCI
Recipient	Participants with IFG and IGT by WHO 1999 definitions
Why?	Quote (translated): "To analyze and explore the effect of pioglitazone on pre‐diabetic patients and the effect of C‐reactive protein (CRP)."
Procedures	BCI included diet control, exercise regimens and health education
Who provided
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily, 12 months
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Yu 2011
Intervention/comparator	Intervention: pioglitazone 4 mg once daily plus BCI Comparator: BCI
Recipient	Participants with IFG and IGT by WHO 1999 definitions
Why?	Quote (translated): "To observe the plasma endothelin (ET) and C‐reversal levels in patients with impaired glucose tolerance (IGT) before and after treatment with pioglitazone."
Procedures	BCI on diet and exercise, these were individually designed according to the participant's condition, not further specified
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily; 6 months; participants were contacted by telephone once a week and seen in an outpatient clinic once every 2 weeks. Not clear when the medication was delivered
Tailoring	BCI were designed according to participant's condition
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Zeng 2013
Intervention/comparator	Intervention 1: pioglitazone 38 mg once daily plus BCI Intervention 2: metformin 38 mg once daily plus BCI Comparator: BCI
Recipient	Participants with IFG and IGT by WHO 1999 definitions
Why?	Quote (translated): "To explore the clinical effects of different intervention methods in impaired glucose regulation (IGR) population."
Procedures	BCI consisted of diet control and exercise therapy. This was not further specified. The intervention groups were titrated up on their doses of pioglitazone and metformin until a level of FPG < 6.1 mmol/L. Details on this were not available
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily; 24 months
Tailoring	—
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Zhang 2007
Intervention/comparator	Intervention 1: pioglitazone 15 mg once daily plus BCI Comparator 1: metformin 250 mg once daily plus BCI Comparator 2: repaglinide 0.25 mg three times daily plus BCI Comparator 3: intensive BCI Comparator 4: BCI
Recipient	Participants with IFG and IGT by ADA 2003 definitions
Why?	Quote (translated): "To evaluate the effects of pharmacological and non‐pharmacological interventions on patients with impaired glucose regulation (IGR)"
What (materials)	BCI consisted of diet control and exercise therapy. Not further specified Intensive BCI consisted of a personalised diet and exercise consultation. Transport and activity guidance once a month. Fat and saturated fat of a maximum of 30% and 10% of energy in the diet. Physical activity of > 4 hours per week. The goal of weight loss was 5%
What (procedures)	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily; 12 months
Tailoring	FPG and 2‐h glucose was measured once every month, and the dosage of medication was adjusted according to blood glucose
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Zhang 2015
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI Comparator: BCI
Recipient	Participants with IFG, IGT or IFG and IGT by WHO 1999 definitions
Why?	Quote (translated): "To observe and analyze the clinical effects of pioglitazone hydrochloride intervention therapy on impaired glucose regulation"
What (materials)	BCI consisted of diet control and exercise therapy. Not further specified
What (procedures)	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily; 6 months
Tailoring	Hypertensive participants were given antihypertensive therapy
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Zhao 2009
Intervention/comparator	Intervention: pioglitazone 15 mg once daily plus BCI Comparator: BCI
Recipient	Participants with IFG, IGT or IFG and IGT by WHO 1999 definitions
Why?	—
What (materials)	BCI consisted of diet control and exercise therapy. Not further specified
What (procedures)	—
Who provided	—
How (mode of delivery; individual or group)	Taken orally, delivered face‐to‐face; individually
Where	Outpatient; administered from 1 site
When and how much	Daily; 6 months
Tailoring	All participants with IGT were given individually designed education and specific diet and exercise plans. Participants were guided in BCI once a month individually
Modification of intervention throughout the study	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
— denotes not reported 2‐h glucose: 2‐h post oral glucose tolerance test glucose; BCI: behaviour‐changing intervention; BMD: bone mineral density; BMI: body mass index; CT: computed tomography; GH: growth hormone; IFG: impaired fasting glucose; IGT: impaired glucose tolerance; OGTT: oral glucose tolerance test; T2DM: type 2 diabetes mellitus; WHO: World Health Organization

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Appendix 12. Baseline characteristics (I)

Study ID	Intervention(s) and comparator(s)	Duration of intervention/duration of follow‐up^a (days, weeks, months, years ...)	Description of participants	Study period (year to year)	Country	Setting	Ethnic groups (%)
ACT NOW	I: pioglitazone 45 mg/day titrated up from 30 mg/day after 1 month if no adverse effects plus BCI	Median of 2.4 years (2‐4 years)	Adults with IFG and IGT	2004‐2008	USA	Outpatient	Hispanic: 26 White: 51 Black: 19 Other: 4
	C: placebo once daily, placebo dose titrated up after 1 month if no adverse effects plus BCI						Hispanic: 25 White: 57 Black: 15 Other: 3
Attallah 2007	I: pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks plus GH placebo from 4‐40 weeks	40 weeks, with wash‐out visit 3‐4 weeks after invention end	Obese adults with IFG and IGT	2003‐2004	USA	Outpatient	Of total population African Americans: 23.5 Hispanic: 6.2 Pacific Islander: 2.5 Asian: 2.5 European descent: 65.4
	C: pioglitazone placebo plus GH placebo from 4‐40 weeks
Bone 2013	I: pioglitazone 45 mg once daily titrated up from 30 mg once daily plus vitamin D and Calcium	12 months of intervention followed by 6 months of follow‐up	Menopausal women with IGT or IFG	—	USA	Outpatient	Asian: 3 Black: 8 White: 40 Hispanic: 49 Other: 1
	C: matching placebo once daily plus vitamin D and Calcium						Asian: 5 Black: 8 White: 44 Hispanic: 44 Other: 0
Che 2014	I: L‐amlodipine 5 mg/day plus pioglitazone 30 mg/day plus BCI	6 months	Adults with IGT and hypertension	2008‐2013	China	Outpatient	Assumed Chinese: 100
	C: L‐amlodipine 5 mg/day plus BCI
Chen 2007a	I: pioglitazone 15 mg/day plus BCI	12 months	Adults with IGT	2003‐2004	China	Outpatient	Assumed Chinese: 100
	C1: acarbose 150 mg/day plus BCI
	C2: metformin 750 mg/day plus BCI
	C3: BCI
	C4: no intervention
Chen 2007b	I: pioglitazone 15 mg/day plus captopril 50 mg/day and Betaloc 50 mg/day plus BCI	24 months	Adults with IGT and hypertension	2002‐2004	China	Outpatient	Assumed Chinese: 100
	C: captopril 50 mg/day and Betaloc 50 mg/day plus BCI
Deng 2013	I: pioglitazone 30 mg/day plus BCI	Mean of 2.2 years	Adults with IFG or IGT	—	China	Outpatient	Assumed Chinese: 100
	C: BCI
Fang 2013	I: pioglitazone 15 mg/day plus BCI	12 months	Adults with IFG or IGT	2009‐2011	China	Outpatient	Assumed Chinese: 100
	C: BCI
Gao 2011	I: pioglitazone 30 mg/day, captopril and other antihypertensive drug(s)^b plus BCI	18 months	Adults with IGT and hypertension	2009‐2011	China	Outpatient	Assumed Chinese: 100
	C: captopril and other antihypertensive drug(s)^b plus BCI
Guo 2009	I: pioglitazone 30 mg/day plus BCI	6 months	Older people with IGT	2007‐2009	China	Outpatient	Assumed Chinese: 100
	C: BCI
Guo 2010	I: pioglitazone 30 mg/day plus BCI	12 months	Older people with IGT	2006‐2008	China	Outpatient	Assumed Chinese: 100
	C: BCI
Han 2007	I: pioglitazone 15 mg/day plus enalapril (dose not reported)	6 months	Adults with IFG, IGT and hypertension	—	China	Outpatient	Assumed Chinese: 100
	C: enalapril (dose not reported)
IDPP‐2	I: pioglitazone 30 mg/day titrated up from 15 mg/day plus BCI	36 months	Adults with IGT	2003‐2008	India	Outpatient	Asian Indian: 100
	C: placebo in matching doses plus BCI
Ke 2006	I: pioglitazone 15 mg/day plus BCI	12 months	Adults with IGT and relatives with T2DM	2002‐2004	China	Outpatient	Assumed Chinese: 100
	C: BCI
Li 2017	I: pioglitazone 15 mg/day plus BCI	6 months	Adults with IGT	2013‐2016	China	Outpatient	Assumed Chinese: 100
	C: BCI
Liang 2004	I: pioglitazone 15 mg/day plus BCI	12 months	Adults with IGT	2001‐2003	China	Outpatient	Assumed Chinese: 100
	C: BCI
Shi 2014	I: pioglitazone 30 mg/day plus BCI	10 months	Adults with IFG or IGT	2012‐2013	China	Outpatient	Assumed Chinese: 100
	C: placebo in matching doses plus BCI
Tian 2015	I: pioglitazone 30 mg/day plus BCI	24 weeks	Adults with prediabetes	2013‐2015	China	Outpatient	Assumed Chinese: 100
	C: BCI
Wu 2013	I: pioglitazone 30 mg/day plus amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	6 months	Older people with IFG, IGT and essential hypertension	2011‐2012	China	Inpatient	Assumed Chinese: 100
	C: amlodipine 5 mg/day and valsartan 80 mg/day plus BCI
Xiu 2015	I: pioglitazone 15 mg/day plus BCI	48 weeks	Adults with IFG and IGT	2011‐2012	China	Outpatient	Assumed Chinese: 100
	C: BCI
Xu 2011	I: pioglitazone 30 mg/day plus BCI	48 weeks	Older people with IFG and IGT	—	China	Outpatient	Assumed Chinese: 100
	C: placebo in matching doses plus BCI
Yi 2015	I: pioglitazone 15 mg/day plus BCI	12 months	Adults with IFG and IGT	2013‐2014	China	Outpatient	Assumed Chinese: 100
	C: BCI
Yu 2011	I: pioglitazone 4 mg/day plus BCI	6 months	Adults with IFG and IGT	2008‐2009	China	Outpatient	Assumed Chinese: 100
	C: BCI
Zeng 2013	I: pioglitazone 38 mg/day plus BCI	24 months	Adults with IGT	2009‐2010	China	Outpatient	Assumed Chinese: 100
	I: metformin 38 mg/day plus BCI
	C: BCI
Zhang 2007	I: pioglitazone 15 mg/day plus BCI	12 months	Adults with IFG and IGT	—	China	Outpatient	Assumed Chinese: 100
	C1: metformin 250 mg/day plus BCI
	C2: repaglinide 3 x 0.25 mg/day plus BCI
	C3: personalised diet and exercise consultation
	C4: BCI
Zhang 2015	I: pioglitazone 15 mg/day plus BCI	6 months	Adults with IFG or IGT	2012‐2013	China	Outpatient	Assumed Chinese: 100
	C: BCI
Zhao 2009	I: pioglitazone 15 mg/day plus BCI	6 months	Adults with IFG and IGT	2005‐2008	China	Outpatient	Assumed Chinese: 100
	C: BCI
— denotes not reported ^aFollow‐up under randomised conditions until end of study (= duration of intervention + follow‐up post‐intervention or identical to duration of intervention). ^bStudy does not specify dosages and which antihypertensive drugs were used. BCI: behaviour‐changing intervention; C: comparator; GH: growth hormone; I: intervention; IFG: impaired fasting glucose; IGT: impaired glucose tolerance; SD: standard deviation; T2DM: type 2 diabetes mellitus

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Appendix 13. Baseline characteristics (II)

Study ID	Intervention(s) and comparator(s)	Sex (female %)	Age (mean/range years (SD), or as reported)	FPG (mean mmol/L (SD))	2‐h glucose (mean mmol/L (SD))	Indicator of increased risk: HbA1c (mean % (SD))	BMI (mean kg/m² (SD))	Comedications/cointerventions (%)	Comorbidities (%)
ACT NOW	I: pioglitazone 45 mg/day titrated up from 30 mg/day after 1 month if no adverse effects plus BCI	58	53.0 (7.0)	5.8 (0.4)	9.3 (1)	5.5 (0.4)	33.0 (7.0)	—	—
ACT NOW	C: placebo, dose titrated up after 1 month if no adverse effects plus BCI	58	51.5 (12.1)	5.8 (0.4)	9.3 (1)	5.5 (0.4)	34.5 (7.0)	—	—
Attallah 2007	I: pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks plus GH placebo from 4‐40 weeks	40	54.7 (8.5)	6.0 (0.8)	9.0 (1.6)	5.5 (0.1)	36.9 (5.5)	—	—
Attallah 2007	C: pioglitazone placebo plus GH placebo from 4‐40 weeks	31	55.4 (9.0)	5.9 (0.8)	9.4 (1.1)	5.6 (0.2)	34.5 (5.8)	—	—
Bone 2013	I: pioglitazone 45 mg/day titrated up from 30 mg/day plus vitamin D and calcium	100	60.2 (6.2)	5.5 (0.8)	7.9 (1.9)	6.2 (0.4)	29.6 (5.1)	—	—
Bone 2013	C: matching placebo once daily plus vitamin D and calcium	100	59.0 (5.0)	5.6 (0.8)	8.2 (1.9)	6.1 (0.4)	30.3 (4.9)	—	—
Che 2014	I: L‐amlodipine 5 mg/day plus pioglitazone 30 mg/day	—	58 (range 45 ‐ 71)	6.4 (0.3)	10.3 (0.4)	6.1 (0.4)	—	—	—
Che 2014	C: L‐amlodipine 5 mg/day	—	58 (range 43 ‐ 83)	6.5 (0.4)	9.9 (0.3)	6.1 (0.4)	—	—	—
Chen 2007a^a	I: pioglitazone 15 mg/day plus BCI	24	47.2 (8.5)	6.9 (1.0)	9.1 (0.8)	—	25.1 (2.1)	—	—
	C1: acarbose 150 mg/day plus BCI	22	50.1 (8.5)	6.9 (0.6)	9.1 (1.2)	—	24.9 (2.1)	—	—
	C2: metformin 750 mg/day plus BCI	24	50.3 (7.1)	6.9 (0.9)	9.0 (0.8)	—	25.1 (2.1)	—	—
	C3: BCI	34	48.2 (8.5)	6.9 (1.0)	9.1 (0.8)	—	25.3 (2.8)	—	—
	C4: no intervention	28	49.2 (8.5)	6.9 (1.1)	9.0 (1.1)	—	24.5 (2.1)	—	—
Chen 2007b	I: pioglitazone 15 mg/day plus captopril 50 mg/day and Betaloc 50 mg/day plus BCI	35	52.1 (6.9)	—	—	—	—	—	—
Chen 2007b	C: captopril 50 mg/day and Betaloc 50 mg/day plus BCI	38	52.6 (7.1)	—	—	—	—	—	—
Deng 2013	I: pioglitazone 30 mg/day plus BCI	47	53.4 (4.4)	5.8 (0.3)	9.3 (0.9)	5.5 (0.4)	34.5 (7.0)	—	—
Deng 2013	C: BCI	48	52.7 (5.6)	5.8 (0.5)	9.3 (1.0)	5.5 (0.4)	34.3 (12.2)	—	—
Fang 2013^b	I: pioglitazone 15 mg/day plus BCI	45	54.5 (8.5)	6.3 (0.3)	8.6 (0.8)	6.2 (0.8)	—	^c
Fang 2013^b	C: BCI	57	55.6 (8.2)	6.3 (0.3)	8.7 (1.2)	6.3 (1.2)	—	^c
Gao 2011	I: pioglitazone 30 mg/day, captopril and other antihypertensive drug(s)^c plus BCI	40	53.3 (5.8)	—	—	—	—	—	—
Gao 2011	C: captopril and other antihypertensive drug(s)^c plus BCI	36	54.6 (5.1)	—	—	—	—	—	—
Guo 2009	I: pioglitazone 30 mg/day plus BCI	33	73.3 (9.4)	5.7 (0.9)	9.3 (1.3)	6.4 (0.9)	23.9 (1.9)	—	—
Guo 2009	C: BCI	33	73.3 (9.4)	5.8 (1.2)	9.1 (1.5)	6.5 (1.1)	23.9 (1.9)	—	—
Guo 2010	I: pioglitazone 30 mg/day plus BCI	38	73.0 (9.3)	5.7 (0.9)	9.1 (1.5)	6.4 (0.9)	24.8 (1.8)	—	—
Guo 2010	C: BCI	38	73.0 (9.3)	5.9 (1.3)	9.0 (1.2)	6.4 (1.0)	24.8 (1.8)	—	—
Han 2007	I: pioglitazone 15 mg/day plus enalapril (dose not reported)	39	53.1 (8.6)	5.7 (0.9)	9.9 (1.1)	—	27.7 (3.2)	—	—
Han 2007	C: enalapril (dose not reported)	40	52.6 (8.2)	5.7 (0.9)	9.8 (1.1)	—	27.6 (3.1)	—	—
IDPP‐2	I: pioglitazone 30 mg/day titrated up from 15 mg/day plus BCI	13	45.1 (6.1)	5.6 (0.7)	8.9 (0.8)	5.8 (0.4)	26.0 (3.5)	—	—
IDPP‐2	C: placebo in matching doses plus BCI	14	45.5 (6.3)	5.7 (0.6)	8.9 (0.9)	5.8 (0.4)	26.2 (3.3)	—	—
Ke 2006	I: pioglitazone 15 mg/day plus BCI	45	30 ‐ 70	6.6 (0.4)	9.4 (0.7)	5.9 (1.0)	25.4 (1.3)	—	—
Ke 2006	C: BCI	45	30 ‐ 70	6.5 (0.8)	9.2 (0.6)	6.0 (1.2)	24.6 (1.7)	—	—
Li 2017	I: pioglitazone 15 mg/day plus BCI	45	65.5 (5.4)	6.9 (0.7)	9.0 (1.3)	6.5 (0.5)	25.6 (2.3)	—	—
Li 2017	C: BCI	47	66.5 (5.3)	6.9 (0.7)	8.9 (1.4)	6.2 (0.6)	25.3 (2.3)	—	—
Liang 2004	I: pioglitazone 15 mg/day plus BCI	52	47.1 (1.3)	6.7 (0.7)	9.3 (1.1)	5.8 (0.6)	24.1 (1.4)	—	—
Liang 2004	C: BCI	47	49.4 (1.0)	6.7 (0.9)	9.6 (1.2)	5.9 (1.0)	24.4 (1.5)	—	—
Shi 2014	I: pioglitazone 30 mg/day plus BCI	50	Range 52 ‐ 60	6.2 (0.4)	8.9 (1.2)	6.2 (0.3)	—	—	—
Shi 2014	C: placebo in matching doses plus BCI	45	Range 50 ‐ 59	6.2 (0.4)	8.9 (1.3)	6.2 (0.4)	—	—	—
Tian 2015	I: pioglitazone 30 mg/day plus BCI	43	54.8 (5.1)	6.7 (0.5)	8.2 (2.3)	—	—	—	—
Tian 2015	C: BCI	43	54.8 (5.1)	6.6 (0.6)	8.2 (2.3)	—	—	—	—
Wu 2013	I: pioglitazone 30 mg/day plus amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	—	72.4 (7.4)	6.6 (0.4)	10.2 (0.6)	5.7 (0.6)	25.6 (2.2)	—	—
Wu 2013	C: amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	—	72.2 (5.8)	6.6 (0.4)	10.3 (0.6)	5.6 (0.8)	25.2 (2.8)	—	—
Xiu 2015	I: pioglitazone 15 mg/day plus BCI	49	48.5 (8.5)	6.7 (0.5)	9.2 (1.3)	—	26.3 (4.4)	—	—
Xiu 2015	C: BCI	54	48.7 (7.8)	6.6 (0.4)	9.4 (1.1)	—	26.3 (3.4)	—	—
Xu 2011	I: pioglitazone 30 mg/day plus BCI	49	66.4 (8.5)	6.7 (0.4)	9.6 (1.2)	—	—	—	—
Xu 2011	C: placebo in matching doses plus BCI	49	66.4 (8.5)	6.6 (0.7)	9.2 (0.9)	—	—	—	—
Yi 2015	I: pioglitazone 15 mg/day plus BCI	49	45.3 (6.7)	6.6 (0.4)	9.2 (1.3)	—	—	—	—
Yi 2015	C: BCI	49	45.3 (6.7)	6.6 (0.5)	9.4 (1.3)	—	—	—	—
Yu 2011	I: pioglitazone 4 mg/day plus BCI	47	51.3 (5.6)	6.4 (0.4)	9.3 (1.0)	—	24.4 (2.2)	—	—
Yu 2011	C: BCI	47	51.3 (5.6)	6.4 (0.4)	9.2 (1.0)	—	24.4 (2.2)	—	—
Zeng 2013	I: pioglitazone 38 mg/day plus BCI	46	47.2 (4.4)	5.7 (0.2)	8.9 (0.6)	—	25.2 (3.2)	—	—
	I: metformin 38 mg/day plus BCI	44	47.7 (5.8)	5.5 (0.4)	8.8 (0.6)	—	25.2 (1.8)	—	—
	C: BCI	42	48.6 (7.4)	5.6 (0.3)	8.9 (0.4)	—	25.3 (2.6)	—	—
Zhang 2007^c	I: pioglitazone 15 mg/day plus BCI	49	52 (6.2)	6.2 (1.1)	9.0 (0.9)	6.2 (1.0)	—	—	—
	C1: metformin 250 mg/day plus BCI			6.2 (1.4)	9.0 (0.9)	6.2 (1.7)	—	—	—
	C2: repaglinide 3 x 0.25 mg/day plus BCI			6.2 (1.4)	9.0 (0.9)	6.0 (1.8)	—	—	—
	C3: personalised diet and exercise consultation			6.3 (1.2)	8.8 (0.9)	6.1 (0.9)	—	—	—
	C4: BCI			6.2 (1.7)	8.9 (1.2)	5.8 (0.9)	—	—	—
Zhang 2015	I: pioglitazone 15 mg/day	51	Mean 50.8 ‐ 52.4	6.4 (1.0)	9.8 (0.9)	—	26.3 (0.9)	—	—
Zhang 2015	C: BCI	46	Mean 51.6 ‐ 54.1	6.4 (1.2)	9.8 (0.7)	—	25.6 (0.8)	—	—
Zhao 2009	I: pioglitazone 15 mg/day	47	51 (7.3)	6.1 (0.6)	9.4 (1.1)	—	—	—	—
Zhao 2009	C: BCI	47	52 (6.7)	6.2 (0.7)	9.4 (1.3)	—	—	—	—
— denotes not reported ^aPublication stated statistical variation as x ± s, s was interpreted as standard error (we calculated SD from standard error and number of participants). ^bBaseline values of blood glucose reported according to subgroups of IFG, IGT and IFG plus IGT. All participants were included as prediabetic in this review. Values pooled from the three groups for baseline characteristics. ^cStudy did not specify dosages and which antihypertensive drugs were used. BCI: behaviour‐changing intervention; BMI: body mass index; C: comparator; FPG: fasting plasma glucose; GH: growth hormone; HbA1c: glycosylated haemoglobin A1c; I: intervention; SD: standard deviation

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Appendix 14. Study endpoints and timing of outcome measurement

Study ID	Review's primary and secondary outcomes	Timing of outcome measurement in study
ACT NOW	All‐cause mortality	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	Incidence of T2DM	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	Serious adverse event	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	Non‐fatal myocardial infarction	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	Non‐fatal stroke	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	Non‐serious adverse events	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	Time to progression to T2DM	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	FPG	Baseline, 2, 4, 6, 8, 10, 12 months after randomisation, thereafter every 3 months and at study end
	HbA1c	Baseline and every 6 months post randomisation and at study end
	2‐h glucose	Baseline and every 12 months post randomisation and at study end
Attallah 2007	All‐cause mortality	Baseline and every month
	Incidence of T2DM	—
	Serious adverse event	—
	Non‐serious adverse events	—
	FPG	Baseline and every month
	HbA1c	Baseline and every 3 months
	2‐h glucose	Baseline, 40 weeks and 43‐44 weeks
Bone 2013	All‐cause mortality	Baseline, 12 and 18 months after randomisation
	Incidence of T2DM	Baseline, 12 and 18 months after randomisation
	Serious adverse event	Baseline, 12 and 18 months after randomisation
	Non‐serious adverse events	Baseline, 12 and 18 months after randomisation
	FPG	Baseline, 12 and 18 months after randomisation
	HbA1c	Baseline, 12 and 18 months after randomisation
	2‐h glucose	Baseline, 12 and 18 months after randomisation
Che 2014	All‐cause mortality	—
	Incidence of T2DM	Baseline, 6 months after randomisation
	Serious adverse event	—
	Non‐serious adverse events	—
	FPG	Baseline, 6 months after randomisation
	HbA1c	Baseline, 6 months after randomisation
	2‐h glucose	Baseline, 6 months after randomisation
Chen 2007a	All‐cause mortality	—
	Incidence of T2DM	12 months after randomisation
	Serious adverse event	—
	Non‐serious adverse events	1 week, 2 weeks, 1 month, 12 months after randomisation
	FPG	Baseline, 12 months after randomisation
	2‐h glucose	Baseline, 12 months after randomisation
Chen 2007b	All‐cause mortality	—
	Incidence of T2DM	—
	Serious adverse event	—
	Non‐serious adverse events	—
	2‐h glucose	Baseline, 24 months after randomisation
Deng 2013	All‐cause mortality	—
	Incidence of T2DM	Every 12 months
	Serious adverse event	—
	Non‐serious adverse events	Baseline, every 2 months for 1 year, then every 3 months
	FPG	Baseline, every 2 months for 1 year, then every 3 months
	HbA1c	Baseline, every 6 months
	2‐h glucose	Baseline, every 12 months
Fang 2013	Incidence of T2DM	12 months after randomisation
	Non‐serious adverse events	—
	Hypoglycaemia	—
	FPG	Baseline, 6 months, 12 months after randomisation
	HbA1c	Baseline, 6 months, 12 months after randomisation
	2‐h glucose	Baseline, 6 months, 12 months after randomisation
Gao 2011	Incidence of T2DM	—
	Serious adverse event	—
	Non‐serious adverse events	—
	FPG	—
	HbA1c	—
	2‐h glucose	—
Guo 2009	FPG	Baseline, 6 months after randomisation
	HbA1c	Baseline, 6 months after randomisation
	2‐h glucose	Baseline, 6 months after randomisation
Guo 2010	All‐cause mortality	—
	Incidence of T2DM	—
	Serious adverse event	—
	Non‐serious adverse events	—
	FPG	Baseline, 12 months after randomisation
	HbA1c	Baseline, 12 months after randomisation
	2‐h glucose	Baseline, 12 months after randomisation
Han 2007	FPG	Baseline, 6 months after randomisation
	2‐h glucose	Baseline, 6 months after randomisation
	Non‐serious adverse events	—
IDPP‐2	All‐cause mortality	Baseline, every 6 months, last visit at 36 months
	Incidence of T2DM	Baseline, every 6 months, last visit at 36 months
	Serious adverse event	Baseline, every 6 months, last visit at 36 months
	Cardiovascular mortality	Baseline, every 6 months, last visit at 36 months
	Non‐serious adverse events	Baseline, every 6 months, last visit at 36 months
	Hypoglycemia	Baseline, every 6 months, last visit at 36 months
	Time to progression to T2DM	Baseline, every 6 months, last visit at 36 months
	FPG	Baseline, every 6 months, last visit at 36 months
	HbA1c	Baseline, every 6 months, last visit at 36 months
	2‐h glucose	Baseline, every 6 months, last visit at 36 months
Ke 2006	Incidence of T2DM	Every 2 months
	Non‐serious adverse events	Baseline, every 2 months after randomisation
	FPG	Baseline, every 2 months after randomisation
	HbA1c	Baseline, every 2 months after randomisation
	2‐h glucose	Baseline, every 2 months after randomisation
Li 2017	Incidence of T2DM	—
	Non‐serious adverse events	—
	FPG	Baseline, 6 months after randomisation
	HbA1c	Baseline, 6 months after randomisation
	2‐h glucose	Baseline, 6 months after randomisation
Liang 2004	Incidence of T2DM	—
	Adverse events	Baseline, every month for 6 months, then every 2 months for 6 months
	FPG	Baseline, every month for 6 months, then every 2 months for 6 months
	HbA1c	Baseline, every month for 6 months, then every 2 months for 6 months
	2‐h glucose	Baseline, every month for 6 months, then every 2 months for 6 months
Shi 2014	Incidence of T2DM	10 months after randomisation
	FPG	Baseline, 10 months after randomisation
	HbA1c	Baseline, 10 months after randomisation
	2‐h glucose	Baseline, 10 months after randomisation
Tian 2015	FPG	Baseline, every 2 weeks, last visit at 24 weeks
Tian 2015	2‐h glucose	Baseline, every 2 weeks, last visit at 24 weeks
Wu 2013	Incidence of T2DM	6 months after randomisation
	FPG	Baseline, 6 months after randomisation
	HbA1c	Baseline, 6 months after randomisation
	2‐h glucose	Baseline, 6 months after randomisation
Xiu 2015	Incidence of T2DM	1 year after randomisation
	FPG	Baseline, 4, 24, 48 weeks after randomisation
	2‐h glucose	Baseline, 4, 24, 48 weeks after randomisation
Xu 2011	Incidence of T2DM	48 weeks after randomisation
	FPG	Baseline, 12, 24, 48 weeks after randomisation
	2‐h glucose	Baseline, 12, 24, 48 weeks after randomisation
Yi 2015	Incidence of T2DM	12 months after randomisation
	FPG	Baseline, 12 months after randomisation
	2‐h glucose	Baseline, 12 months after randomisation
Yu 2011	Incidence of T2DM	6 months after randomisation
	FPG	Baseline, every week, last visit at 6 months
	2‐h glucose	Baseline, every week, last visit at 6 months
Zeng 2013	Incidence of T2DM	24 months after randomisation
	FPG	Baseline, 24 months after randomisation
	2‐h glucose	Baseline, 24 months after randomisation
Zhang 2007	Incidence of T2DM	12 months after randomisation
	Adverse events	12 months after randomisation
	FPG	Baseline, every month, last visit at 12 months
	2‐h glucose	Baseline, every month, last visit at 12 months
Zhang 2015	Incidence of T2DM	6 months after randomisation
	Adverse events	3 months, 6 months after randomisation
	FPG	Baseline, every month, last visit at 6 months
	2‐h glucose	Baseline, every month, last visit at 6 months
Zhao 2009	Adverse events	Every month, last visit at 6 months
	FPG	Baseline, every month, last visit at 6 months
	2‐h glucose	Baseline, every month, last visit at 6 months
— denotes not reported d: day(s); FPG: fasting plasma glucose; HbA1c: glycosylated haemoglobin A1c; OGTT: oral glucose tolerance test; T2DM: type 2 diabetes mellitus

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Appendix 15. Matrix of study endpoints (publications and trial documents)

Study ID
ACT NOW	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source:NCT00220961 and protocol Primary outcome measure(s): conversion to T2DM Secondary outcome measure(s): HbA1c, FPG, 2‐h glucose, plasma glucose concentration during OGTT, insulin secretion, insulin sensitivity, blood lipids, adiponectin, blood pressure (including ankle‐arm), ECG, carotid intima thickness, cardiovascular morbidity, body weight, waist circumference, BMD, adipocyte‐derived cytokines, sex steroids, microalbuminuria, creatinine, adverse events, time to progression to T2DM Other outcome measure(s): — Trial results available in trial register: yes
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): conversion to T2DM Secondary outcome measure(s): HbA1c, FPG, plasma glucose concentration during OGTT, insulin secretion, insulin sensitivity, blood lipids, adiponectin, carotid intima thickness, body weight, BMD, adverse events, time to progression to T2DM, low or high age Other outcome measure(s): blood pressure, adipocyte‐derived cytokines, microalbuminuria, liver enzymes
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): conversion to T2DM Secondary outcome measure(s): HbA1c, fasting blood glucose, plasma glucose concentration during OGTT, 2‐h glucose, insulin secretion, insulin sensitivity Other outcome measure(s): blood pressure, carotid intima thickness, blood lipids, body weight, adverse events, beta‐cell function
Attallah 2007	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: NCT00352287 Primary outcome measure(s): VAT, glucose tolerance, insulin sensitivity Secondary outcome measure(s): BMI, anthropometrics, HbA1c, blood lipids Other outcome measure(s): — Trial results available in trial register: no
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): VAT, insulin sensitivity Secondary outcome measure(s): serum IGF‐1, BMI, anthropometrics, HbA1c, glucose metabolism, blood lipids, subcutaneous fat Other outcome measure(s): adverse events
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): VAT, glucose tolerance, insulin sensitivity Secondary outcome measure(s): FPG, BMI, Other outcome measure(s): —
Bone 2013	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: NCT00708175 Primary outcome measure(s): change in BMD in proximal femur by DXA at 12 months Secondary outcome measure(s): change in BMD in proximal femur by DXA at 18 months Other outcome measure(s): — Trial results available in trial register: yes
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): change in BMD in proximal femur by DXA at 12 months Secondary outcome measure(s): change in BMD in proximal femur by DXA at 18 months, bone remodelling markers Other outcome measure(s): glycaemic control, insulin sensitivity, inflammatory markers, sex steroid, adiponectin, IGFBP‐3, BMI, conversion to T2DM
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): BMD Secondary outcome measure(s): — Other outcome measure(s): glycaemic control, insulin sensitivity, conversion to T2DM, adverse events, body fat
Che 2014	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): HbA1c, FPG, 2‐h glucose Other outcome measure(s): blood pressure
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): —
Chen 2007a	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, non‐serious adverse events Other outcome measure(s): FINS, insulin sensitivity index, conversion to NGT, BMI
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): insulin sensitivity index
Chen 2007b	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): all‐cause mortality, incidence of T2DM Secondary outcome measure(s): TG, 2‐h glucose, coronary heart disease, non‐serious adverse events, serious adverse events Other outcome measure(s): blood pressure, FINS, 2hINS, BMI, blood lipids
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): coronary heart disease, TG, 2‐h glucose, Other outcome measure(s): blood pressure, FINS, 2hINS, insuline resistance, blood lipids
Deng 2013	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): all‐cause mortality, incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c, time to progression to T2DM, non‐serious adverse event, serious adverse event Other outcome measure(s): conversion to NGT, insulin resistance, blood pressure, insulin sensitivity, BMI, blood lipids
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c,time to progression to T2DM Other outcome measure(s): conversion to NGT
Fang 2013	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c, non‐serious adverse event, serious adverse event Other outcome measure(s): FINS, HOMA‐IR, conversion to NGT, blood lipids, liver and kidney function, BUN, Cr, ALT, AST
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c, adverse events Other outcome measure(s): FINS, HOMA‐IR, conversion to NGT, blood pressure, liver and kidney function, BMI
Gao 2011	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): 2‐h glucose, serious adverse events, non‐serious adverse events Other outcome measure(s): cardiovascular disease, cerebrovascular disease, blood pressure, TG, 2‐h glucose, FINS, 2hINS, insulin sensitivity, ALT, AST
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): — Other outcome measure(s): cardiovascular disease, cerebrovascular disease, blood pressure
Guo 2009	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): HbA1c, FPG, 2‐h glucose Other outcome measure(s): endothelium‐dependent dilation, blood lipids, hsCRP, HOMA‐IR, BMI, fasting insulin, insulin sensitivity
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): endothelium‐dependent dilation, hsCRP, HOMA‐IR, HbA1c, TG
Guo 2010	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): HbA1c, FPG, 2‐h glucose Other outcome measure(s): blood lipids, hsCRP, HOMA‐IR, CIMT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): blood lipids, hsCRP, HOMA‐IR, CIMT
Han 2007	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): FPG, 2‐h glucose, non‐serious adverse events Other outcome measure(s): fasting insulin, insulin sensitivity, BMI, blood lipids
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): —
IDPP‐2	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: NCT00276497 Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): anthropometric variables, biochemical parameters Other outcome measure(s): — Trial results available in trial register: no
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): HbA1c, FPG, 2‐h glucose Other outcome measure(s): blood lipids, hsCRP, HOMA‐IR, CIMT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): serious adverse events
Ke 2006	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): HbA1c, FPG, 2‐h glucose, non‐serious adverse event Other outcome measure(s): BMI, C‐peptide, blood lipids, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): — Other outcome measure(s): —
Li 2017	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: — Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c, non‐serious adverse events Other outcome measure(s): blood lipids, fasting insulin, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c, non‐serious adverse events Other outcome measure(s): blood lipids, fasting insulin, conversion to NGT
Liang 2004	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c, non‐serious adverse events Other outcome measure(s): blood lipids, FINS, BMI, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, fasting insulin, HOMA‐IR, blood lipids Other outcome measure(s): —
Shi 2014	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c Other outcome measure(s): —
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c Other outcome measure(s): —
Tian 2015	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): CRP, HOMA‐IR, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): CRP, HOMA‐IR, conversion to NGT
Wu 2013	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c Other outcome measure(s): blood lipids, blood pressure, NT‐proBNP
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c Other outcome measure(s): blood lipids, blood pressure, NT‐proBNP
Xiu 2015	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): CRP, insulin resistance, BMI, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): CRP, insulin resistance, BMI
Xu 2011	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): BMI, blood pressure, FINS, HOMA‐IR, measures of insulin, blood lipids, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): FINS, measures of insulin, blood lipids
Yi 2015	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG Other outcome measure(s): NGT, CRP, HOMA‐IR, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG Other outcome measure(s): NGT, CRP, HOMA‐IR, conversion to NGT
Yu 2011	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): CRP, blood lipids, blood cholesterol, endothelin, fibrinogen, BMI, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): CRP, blood lipids, blood cholesterol, endothelin, fibrinogen, BMI
Zeng 2013	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): FINS, BMI, blood pressure, conversion to NGT
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): 2‐h glucose Other outcome measure(s): FINS, BMI, conversion to NGT
Zhang 2007	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, HbA1c, non‐serious adverse events, serious adverse events Other outcome measure(s): BMI, FINS, HOMA‐IR, conversion to NGT, blood lipids, blood cholesterol, blood pressure, serum superoxide dismutase
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose Other outcome measure(s): HOMA‐IR, blood lipids, blood cholesterol, blood pressure, serum superoxide dismutase
Zhang 2015	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): FPG, 2‐h glucose, non‐serious adverse events, serious adverse events Other outcome measure(s): blood pressure, conversion to NGT, blood lipids, ALT, AST
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): incidence of T2DM Secondary outcome measure(s): non‐serious adverse events, serious adverse events Other outcome measure(s): conversion to NGT
Zhao 2009	Endpoints quoted in trial document(s) (ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a,c
	Source: no document available Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): — Trial results available in trial register: —
	Endpoints quoted in publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): FPG, 2‐h glucose, non‐serious adverse events, serious adverse events Other outcome measure(s): blood pressure, blood lipids, HOMA‐IR
	Endpoints quoted in abstract of publication(s)^b,c
	Primary outcome measure(s): — Secondary outcome measure(s): — Other outcome measure(s): —
— denotes not reported ^aTrial document(s) refers to all available information from published design papers and sources other than regular publications (e.g. FDA/EMA documents, manufacturer's websites, trial registers). ^bPublication(s) refers to study information published in scientific journals (primary reference, duplicate publications, companion documents or multiple reports of a primary study). ^cPrimary and secondary outcomes refer to verbatim specifications in publication/records. Unspecified outcome measures refer to all outcomes not described as primary or secondary outcome measures. 2hINS: 2‐h post oral glucose tolerance test insulin; 2‐h glucose: 2‐h post oral glucose tolerance test glucose; AASI: ambulatory arterial stiffness index; ACT NOW: Actos Now for Prevention of Diabetes; BMD: bone mineral density; BMI: body mass index; BUN: blood urea nitrogen; CIMT: carotid intima‐media thickness test; CRP: C‐reactive protein; DXA: dual‐energy X‐ray absorptiometry; ECG: electrocardiography; EMA: European Medicines Agency; FDA: Food and Drug Administration (US); FGF‐21: fibroblast growth factor 21; FINS: fasting insulin; HbA1c: glycosylated haemoglobin A1c; HEP‐IR hepatic insulin resistance; HOMA‐IR: homeostatic model assessment for insulin resistance; hsCRP: high sensitivity C‐reactive protein; IDPP‐2: Indian Diabetes Prevention Programme‐2; IGFBP‐3: insulin‐like growth factor‐binding protein 3; IGF‐1: insulin‐like growth factor 1; NGT: normal glucose tolerance; NT: no trial document available; NT‐proBNP: N‐terminal pro B‐type natriuretic peptide; OGTT: oral glucose tolerance test; PPI: pulse pressure index; T2DM: type 2 diabetes; VAT: visceral adipose tissue

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Appendix 16. High risk of outcome reporting bias according to Outcome Reporting Bias In Trials (ORBIT) classification

Study ID	Outcome	High risk of bias (category A)^a	High risk of bias (category D)^b	High risk of bias (category E)^c	High risk of bias (category G)^d
ACT NOW	Adverse events (serious and non‐serious)	No	No	Yes	No
ACT NOW	Hypoglycaemia	No	No	No	Yes
Attallah 2007	ND
Bone 2013	ND
Che 2014	Adverse events (serious and non‐serious)	No	No	No	Yes
Che 2014	Hypoglcaemia	No	No	No	Yes
Chen 2007a	Hypoglcaemia	No	No	No	Yes
Chen 2007b	Hypoglcaemia	No	No	No	Yes
Chen 2007b	Measures of blood glucose control	Yes	No	No	No
Deng 2013	Hypoglycaemia	No	No	No	Yes
Deng 2013	Measures of blood glucose control	Yes	Yes	No	No
Fang 2013	All‐cause mortality	No	No	No	Yes
Gao 2011	Hypoglycaemia	No	No	No	Yes
Gao 2011	Measures of blood glucose control	No	No	Yes	No
Guo 2009	All‐cause mortality	No	No	No	Yes
	Adverse events (serious and non‐serious)	No	Yes	No	No
	Hypoglycaemia	No	No	No	Yes
Guo 2010	All‐cause mortality	No	No	No	Yes
	Adverse events (serious and non‐serious)	No	Yes	No	No
	Hypoglycaemia	No	No	No	Yes
Han 2007	Incidence of T2DM	No	No	No	Yes
IDPP‐2	ND
Ke 2006	All‐cause mortality	No	No	No	Yes
Ke 2006	Hypoglycaemia	No	No	No	Yes
Li 2017	All‐cause mortality	No	No	No	Yes
Li 2017	Hypoglycaemia	No	No	No	Yes
Liang 2004	ND
Shi 2014	All‐cause mortality	No	No	No	Yes
Shi 2014	Adverse events (serious and non‐serious)	No	No	No	Yes
Tian 2015	Incidence of T2DM	No	No	No	Yes
Tian 2015	Adverse events (serious and non‐serious)	No	Yes	No	No
Wu 2013	Adverse events (serious and non‐serious)	No	No	No	Yes
Xiu 2015	Adverse events (serious and non‐serious)	No	No	Yes	No
Xu 2011	Adverse events (serious and non‐serious)	No	No	Yes	No
Yi 2015	Adverse events (serious and non‐serious)	No	No	No	Yes
Yu 2011	Adverse events (serious and non‐serious)	No	No	No	Yes
Zeng 2013	Adverse events (serious and non‐serious)	No	No	No	Yes
Zhang 2007	All‐cause mortality	No	No	No	Yes
Zhang 2007	Hypoglycaemia	No	No	No	Yes
Zhang 2015	Hypoglycaemia	No	No	No	Yes
Zhao 2009	Incidence of T2DM	No	No	Yes	No
^aClear that outcome was measured and analysed; study report states that outcome was analysed but reports only that result was not significant (Classification 'A', table 2, Kirkham 2010). ^bClear that outcome was measured and analysed; study report states that outcome was analysed but report no results (Classification 'D', table 2, Kirkham 2010). ^cClear that outcome was measured but was not necessarily analysed; judgement says likely to have been analysed but not reported due to non‐significant results (Classification 'E', table 2, Kirkham 2010). ^dUnclear whether outcome was measured; not mentioned, but clinical judgement says likely to have been measured and analysed but not reported on the basis of non‐significant results (Classification 'G', table 2, Kirkham 2010). ND: none detected; T2DM: type 2 diabetes mellitus

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Appendix 17. Definition of endpoint measurements^a

Study ID	Endpoints	Definition
ACT NOW	All‐cause mortality	AO
	Incidence of T2DM	FPG ≥ 7.0 mmol/L or 2‐h glucose > 11.1 mmol/L^b, IO
	Serious adverse events	ND, AO
	Cardiovascular mortality	ND, AO
	Non‐fatal myocardial infarction	ND
	Non‐fatal stroke	ND
	Congestive heart failure	ND
	Non‐serious adverse events	ND
	Time to progression to T2DM	FPG ≥ 7.0 mmol/L or 2‐h glucose > 11.1 mmol/L^b, IO
	Measures of blood glucose control	ND, IO
Attallah 2007	All‐cause mortality	ND
	Incidence of T2DM	FPG ≥ 7.0 mmol/L or 2‐h glucose ≥ 11.1 mmol/L^b, IO
	Serious adverse events	IO
	Non‐serious adverse events	IO
	Hypoglycaemia	ND, assumed SO
	Measures of blood glucose control	ND, IO
Bone 2013	All‐cause mortality	ND, AO
	Incidence of T2DM	Two or more consecutive FPG ≥ 7.0 mmol^b, IO
	Serious adverse events	AO
	Cardiovascular mortality	ND, AO
	Non‐fatal myocardial infarction	AO
	Non‐fatal stroke	AO
	Congestive heart failure	AO
	Amputation of lower extremity	AO
	Blindness or severe vision loss	AO
	End‐stage renal disease	AO
	Non‐serious adverse events	Quote: "defined as an AE with an onset date on or after the first study drug dosing day and within 14 days (30 days for an SAE) after the last dose of study drug, or a continuing AE reported before the first dose of study drug that became worse in intensity after the first dose", IO
	Measures of blood glucose control	ND, IO
Che 2014	Incidence of T2DM	2‐h glucose ≥ 11.1 mmol/L, IO
Che 2014	Measures of blood glucose control	ND, IO
Chen 2007a	All‐cause mortality	ND
	Incidence of T2DM	FPG > 7.8 mmol/L or 2‐h glucose > 11.1 mmol/L, IO
	Serious adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Chen 2007b	All‐cause mortality	ND
	Incidence of T2DM	FPG > 7.8 mmol/L or 2‐h glucose > 11.1 mmol/L, IO
	Serious adverse events	ND, IO
	Non‐serious adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Deng 2013	All‐cause mortality	ND, AO
	Incidence of T2DM	FPG >7.8 mmol/L or 2‐h glucose > 11.1 mmol/L, IO
	Serious adverse events	ND, IO
	Adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Fang 2013	Incidence of T2DM	FPG > 7.8 mmol/L or 2‐h glucose > 11.1 mmol/L, IO
	Adverse events	ND, IO
	Hypoglycaemia	ND, SO
	Measures of blood glucose control	ND, IO
Gao 2011	All‐cause mortality	ND, AO
	Incidence of T2DM	FPG > 7.8 mmol/L or 2‐h glucose > 11.1 mmol/L, IO
	Serious adverse events	ND, IO
	Non‐serious adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Guo 2009	Measures of blood glucose control	ND, IO
Guo 2010	Measures of blood glucose control	ND, IO
Han 2007	Non‐serious adverse events	ND, IO
Han 2007	Measures of blood glucose control	ND, IO
IDPP‐2	All‐cause mortality	AO
	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
	Serious adverse events	ND, AO
	Cardiovascular mortality	AO
	Non‐fatal myocardial infarction	AO
	Non‐fatal stroke	AO
	Congestive heart failure	AO
	Non‐serious adverse events	IO
	Hypoglycaemia	ND, assumed SO
	Time to progression to T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
	Measures of blood glucose control	ND, IO
Ke 2006	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
	Non‐serious adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Li 2017	Incidence of T2DM	ND, IO
	Non‐serious adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Liang 2004	Incidence of T2DM	FPG ≥7.0 and/or 2‐h glucose ≥11.1 mmol/L, IO
	Non‐serious adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Shi 2014	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
Shi 2014	Measures of blood glucose control	ND, IO
Tian 2015	Measures of blood glucose control	ND, IO
Wu 2013	Incidence of T2DM	FPG ≥7.0 and/or 2‐h glucose ≥11.1 mmol/L, IO
Wu 2013	Measures of blood glucose control	ND, IO
Xiu 2015	Incidence of T2DM	FPG ≥7.0 and/or 2‐h glucose ≥11.1 mmol/L, IO
Xiu 2015	Measures of blood glucose control	ND, IO
Xu 2011	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
Xu 2011	Measures of blood glucose control	ND, IO
Yi 2015	Incidence of T2DM	FPG ≥7.0 and/or 2‐h glucose ≥11.1 mmol/L, IO
Yi 2015	Measures of blood glucose control	ND, IO
Yu 2011	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
Yu 2011	Measures of blood glucose control	ND, IO
Zeng 2013	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
Zeng 2013	Measures of blood glucose control	ND, IO
Zhang 2007	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
	Adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Zhang 2015	Incidence of T2DM	FPG ≥ 7.0 and/or 2‐h glucose ≥ 11.1 mmol/L, IO
	Adverse events	ND, IO
	Measures of blood glucose control	ND, IO
Zhao 2009	Adverse events	ND, IO
Zhao 2009	Measures of blood glucose control	ND, IO
^aIn addition to definition of endpoint measurement, description of who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self‐reported outcome measurement). ^bCalculated from mg/dL by dividing by 18. AE: adverse event; FPG: fasting plasma glucose; ND: not defined; SAE: serious adverse event; T2DM: type 2 diabetes mellitus

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Appendix 18. Adverse events (I)

Study ID	Intervention(s) and comparator(s)	Participants included in analysis (N)	Deaths (N)	Deaths (% of participants)	Participants with at least one adverse event (N)	Participants with at least one adverse event (%)	Participants with at least one severe/serious adverse event (N)	Participants with at least one severe/serious adverse event (%)
ACT NOW	I: pioglitazone 45 mg/day titrated up from 30 mg/day after 1 month if no adverse effects plus BCI	303	3	0.9	151	50.0	—^a	—^a
ACT NOW	C: placebo, dose titrated up after 1 month if no adverse effects plus BCI	299	1	0.3	121	40.4	—^a	—^a
Attallah 2007	I: pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks plus GH placebo from 4‐40 weeks	15	0	0	6	40.0	0	0
Attallah 2007	C: pioglitazone placebo plus GH placebo from 4‐40 weeks	16	0	0	1	6.3	0	0
Bone 2013	I: pioglitazone 45 mg/day titrated up from 30 mg once daily plus vitamin D and calcium	78	0	0	49	62.8	3	3.8
Bone 2013	C: matching placebo plus vitamin D and calcium	78	0	0	48	61.5	1	1.3
Che 2014	I: L‐amlodipine 5 mg/day plus pioglitazone 30 mg/day	38	—	—	—	—	—	—
Che 2014	C: L‐amlodipine 5 mg/day	35	—	—	—	—	—	—
Chen 2007a	I: pioglitazone 15 mg/day plus BCI	50	—	—	1	2	0	0
	C1: acarbose 150 mg/day plus BCI	50	—	—	2	4	0	0
	C2: metformin 750 mg/day plus BCI	50	—	—	7	14	0	0
	C3: BCI	50	—	—	0	0	0	0
	C4: no intervention	50	—	—	0	0	0	0
Chen 2007b	I: pioglitazone 15 mg/day plus captopril 50 mg/day and Betaloc 50 mg/day plus BCI	83	5	6.0	0	0	8	9.6
Chen 2007b	C: captopril 50 mg/day and Betaloc 50 mg/day plus BCI	73	4	5.5	0	0	11	15.1
Deng 2013	I: pioglitazone 30 mg/day plus BCI	303	4	1.3	148	48.8	6	2.0
Deng 2013	C: BCI	302	5	1.6	121	40.0	7	2.3
Fang 2013	I: pioglitazone 15 mg/day plus BCI	60	—	—	16	26.7	—	—
Fang 2013	C: BCI	60	—	—	12	20.0	—	—
Gao 2011	I: pioglitazone 30 mg/day, captopril and other antihypertensive drug(s)^b plus BCI	50	2	4	3	6	2	4
Gao 2011	C: captopril and other antihypertensive drug(s)^b plus BCI	50	3	6	9	18	3	6
Guo 2009	I: pioglitazone 30 mg/day plus BCI	30	—	—	—	—	—	—
Guo 2009	C: BCI	30	—	—	—	—	—	—
Guo 2010	I: pioglitazone 30 mg/day plus BCI	32	—	—	—	—	—	—
Guo 2010	C: BCI	32	—	—	—	—	—	—
Han 2007	I: pioglitazone 15 mg/day plus enalapril (dose not reported)	23	—	—	1	4.3	—	—
Han 2007	C: enalapril (dose not reported)	20	—	—	0	0	—	—
IDPP‐2	I: pioglitazone 30 mg once daily titrated up from 15 mg once daily plus BCI	181	2	1.1	—^c	NA	10^c	NA
IDPP‐2	C: placebo in matching doses plus BCI	186	1	0.5	—^c	NA	13^c	NA
Ke 2006	I: pioglitazone 15 mg/day plus BCI	30	—	—	3	10.0	—	—
Ke 2006	C: BCI	28	—	—	0	0	—	—
Li 2017	I: pioglitazone 15 mg/day plus BCI	75	—	—	3	4.0	—	—
Li 2017	C: BCI	75	—	—	0	0	—	—
Liang 2004	I: pioglitazone 15 mg/day plus BCI	29	—	—	7	24.1	—	—
Liang 2004	C: BCI	30	—	—	2	6.7	—	—
Shi 2014	I: pioglitazone 30 mg/day plus BCI	40	—	—	—	—	—	—
Shi 2014	C: placebo in matching doses plus BCI	40	—	—	—	—	—	—
Tian 2015	I: pioglitazone 15 mg/day plus BCI	36	—	—	—	—	—	—
Tian 2015	C: BCI	36	—	—	—	—	—	—
Wu 2013	I: pioglitazone 30 mg/day plus amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	34	—	—	—	—	—	—
Wu 2013	C: amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	33	—	—	—	—	—	—
Xiu 2015	I: pioglitazone 15 mg/day plus BCI	43	—	—	—	—	—	—
Xiu 2015	C: BCI	43	—	—	—	—	—	—
Xu 2011	I: pioglitazone 30 mg/day plus BCI	60	—	—	—	—	—	—
Xu 2011	C: placebo in matching doses plus BCI	59	—	—	—	—	—	—
Yi 2015	I: pioglitazone 15 mg/day plus BCI	35	—	—	—	—	—	—
Yi 2015	C: BCI	35	—	—	—	—	—	—
Yu 2011	I: pioglitazone 4 mg/day plus BCI	60	—	—	—	—	—	—
Yu 2011	C: BCI	60	—	—	—	—	—	—
Zeng 2013	I: pioglitazone 38 mg/day plus BCI	70	—	—	—	—	—	—
	I: metformin 38 mg/day plus BCI	68	—	—	—	—	—	—
	C: BCI	66	—	—	—	—	—	—
Zhang 2007	I: pioglitazone 15 mg/day plus BCI	52	—	—	3	5.8	0	0
	C1: metformin 250 mg/day plus BCI	53	—	—	2	3.8	0	0
	C2: repaglinide 3 x 0.25 mg/day plus BCI	51	—	—	0	0	0	0
	C3: personalised diet and exercise consultation	51	—	—	0	0	0	0
	C4: BCI	56	—	—	0	0	0	0
Zhang 2015	I: pioglitazone 15 mg/day plus BCI	26	—	—	2	7.7	0	0
Zhang 2015	C: BCI	25	—	—	0	0	0	0
Zhao 2009	I: pioglitazone 15 mg/day plus BCI	47	—	—	2	4.3	0	0
Zhao 2009	C: BCI	45	—	—	0	0	0	0
^aStudy did not distinguish between serious and non‐serious adverse events in publication. ^bStudy did not specify dosages and which antihypertensive drugs were used. ^cSerious and non‐serious adverse events reported as events, not as number of participants experiencing an adverse event. — denotes not reported BCI: behaviour‐changing intervention; C: comparator; GH: growth hormone; I: intervention; N: number of participants

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Appendix 19. Adverse events (II)

Study ID	Intervention(s) and comparator(s)	Participants included in analysis (N)	Participants discontinuing study due to an adverse event (N)	Participants discontinuing study due to an adverse event (%)	Participants with at least one hospitalisation (N)	Participants with at least one hospitalisation (%)	Participants with at least one outpatient treatment (N)	Participants with at least one outpatient treatment (%)
ACT NOW	I: pioglitazone 45 mg/day titrated up from 30 mg/day after 1 month if no adverse effects plus BCI	303	14	4.5	—	—	—	—
ACT NOW	C: placebo dose, titrated up after 1 month if no adverse effects plus BCI	299	5	1.7	—	—	—	—
Attallah 2007	I: pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks plus GH placebo from 4‐40 weeks	15	1	6.7	—	—	—	—
Attallah 2007	C: pioglitazone placebo plus GH placebo from 4‐40 weeks	16	0	0	—	—	—	—
Bone 2013	I: pioglitazone 45 mg/day titrated up from 30 mg once daily plus vitamin D and calcium	78	8	10.2	—	—	—	—
Bone 2013	C: matching placebo plus vitamin D and calcium	78	6	7.7	—	—	—	—
Che 2014	I: L‐amlodipine 5 mg/day plus pioglitazone 30 mg/day	—	—	—	—	—	—	—
Che 2014	C: L‐amlodipine 5 mg/day	—	—	—	—	—	—	—
Chen 2007a	I: pioglitazone 15 mg/day plus BCI	50	—	—	—	—	—	—
	C1: acarbose 150 mg/day plus BCI	50	2	4	—	—	—	—
	C2: metformin 750 mg/day plus BCI	50	4	8	—	—	—	—
	C3: BCI	50	—	—	—	—	—	—
	C4: no intervention	50	—	—	—	—	—	—
Chen 2007b	I: pioglitazone 15 mg/day plus captopril 50 mg/day and Betaloc 50 mg/day plus BCI	83	5	6.0	—	—	—	—
Chen 2007b	C: captopril 50 mg/day and Betaloc 50 mg/day plus BCI	73	4	5.5	—	—	—	—
Deng 2013	I: pioglitazone 30 mg/day plus BCI	303	4	1.3	—	—	—	—
Deng 2013	C: BCI	302	5	1.7	—	—	—	—
Fang 2013	I: pioglitazone 15 mg/day plus BCI	60	2	3.3	—	—	1	1.7
Fang 2013	C: BCI	60	0	0	—	—	—	—
Gao 2011	I: pioglitazone 30 mg/day, captopril and other antihypertensive drug(s)^a plus BCI	50	3	6.0	—	—	—	—
Gao 2011	C: captopril and other antihypertensive drug(s)^a plus BCI	50	2	4.0	—	—	—	—
Guo 2009	I: pioglitazone 30 mg/day plus BCI	—	—	—	—	—	—	—
Guo 2009	C: BCI	—	—	—	—	—	—	—
Guo 2010	I: pioglitazone 30 mg/day plus BCI	—	—	—	—	—	—	—
Guo 2010	C: BCI	—	—	—	—	—	—	—
Han 2007	I: pioglitazone 15 mg/day plus enalapril (dose not reported)	23	0	0	—	—	—	—
Han 2007	C: enalapril (dose not reported)	20	0	0	—	—	—	—
IDPP‐2	I: pioglitazone 30 mg once daily titrated up from 15 mg once daily plus BCI	181	—	—	—	—	—	—
IDPP‐2	C: placebo in matching doses plus BCI	186	—	—	—	—	—	—
Ke 2006	I: pioglitazone 15 mg/day plus BCI	30	—	—	—	—	—	—
Ke 2006	C: BCI	28	—	—	—	—	—	—
Li 2017	I: pioglitazone 15 mg/day plus BCI	75	—	—	—	—	—	—
Li 2017	C: BCI	75	—	—	—	—	—	—
Liang 2004	I: pioglitazone 15 mg/day plus BCI	29	1	3.3	—	—	—	—
Liang 2004	C: BCI	30	0	0	—	—	—	—
Shi 2014	I: pioglitazone 30 mg/day plus BCI	40	—	—	—	—	—	—
Shi 2014	C: placebo in matching doses plus BCI	40	—	—	—	—	—	—
Tian 2015	I: pioglitazone 15 mg/day plus BCI	36	—	—	—	—	—	—
Tian 2015	C: BCI	36	—	—	—	—	—	—
Wu 2013	I: pioglitazone 30 mg/day plus amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	34	—	—	—	—	—	—
Wu 2013	C: amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	33	—	—	—	—	—	—
Xiu 2015	I: pioglitazone 15 mg/day plus BCI	34	—	—	—	—	—	—
Xiu 2015	C: BCI	34	—	—	—	—	—	—
Xu 2011	I: pioglitazone 30 mg/day plus BCI	60	—	—	—	—	—	—
Xu 2011	C: placebo in matching doses plus BCI	59	—	—	—	—	—	—
Yi 2015	I: pioglitazone 15 mg/day plus BCI	35	—	—	—	—	—	—
Yi 2015	C: BCI	35	—	—	—	—	—	—
Yu 2011	I: pioglitazone 4 mg/day plus BCI	60	—	—	—	—	—	—
Yu 2011	C: BCI	60	—	—	—	—	—	—
Zeng 2013	I: pioglitazone 38 mg/day plus BCI	70	—	—	—	—	—	—
	I: metformin 38 mg/day plus BCI	68	—	—	—	—	—	—
	C: BCI	66	—	—	—	—	—	—
Zhang 2007	I: pioglitazone 15 mg/day plus BCI	52	—	—	—	—	—	—
	C1: metformin 250 mg/day plus BCI	53	—	—	—	—	—	—
	C2: repaglinide 3 x 0.25 mg/day plus BCI	51	—	—	—	—	—	—
	C3: personalised diet and exercise consultation	51	—	—	—	—	—	—
	C4: BCI	56	—	—	—	—	—	—
Zhang 2015	I: pioglitazone 15 mg/day	26	—	—	—	—	—	—
Zhang 2015	C: BCI	25	—	—	—	—	—	—
Zhao 2009	I: pioglitazone 15 mg/day	47	—	—	—	—	—	—
Zhao 2009	C: BCI	45	—	—	—	—	—	—
— denotes not reported ^aStudy did not specify dosages and which antihypertensive drugs were used. BCI: behaviour‐changing intervention; C: comparator; GH: growth hormone; I: intervention; N: number of participants

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Appendix 20. Adverse events (III)

Study IDR	Intervention(s) and comparator(s)	Participants in analysis (N)	Participants with at least one specific adverse event (N (%))
ACT NOW^a	I: pioglitazone 45 mg/day titrated up from 30 mg/day after 1 month if no adverse effects plus BCI	303	—
ACT NOW^a	C: placebo dose, titrated up after 1 month if no adverse effects plus BCI	299	—
Attallah 2007	I: pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks plus GH placebo from 4‐40 weeks	15	Lower extremity oedema: 2 (13.3)
Attallah 2007	C: pioglitazone placebo plus GH placebo from 4‐40 weeks	16	Lower extremity oedema: 1 (6.3)
Bone 2013^b	I: pioglitazone 45 mg/day titrated up from 30 mg/day plus vitamin D and calcium	78	Oedema: 9 (11.5) UTI: 6 (7.7) Blood PTH increased: 2 (2.6) Weight increased: 4 (5.1) Back pain: 4 (5.1) Fall: 4 (5.1) Nausea: 4 (5.1) Cough: 5 (6.4) Headache: 2 (2.6)
Bone 2013^b	C: matching placebo plus vitamin D and calcium	78	Oedema: 2 (2.6) UTI: 1 (1.3) Blood PTH increased: 1 (1.3) Weight increased: 1 (1.3) Back pain: 5 (6.4) Fall: 1 (1.3) Nausea: 2 (2.6) Cough: 0 (0) Headache: 4 (5.1)
Che 2014	I: L‐amlodipine 5 mg/day plus pioglitazone 30 mg/day	38	—
Che 2014	C: L‐amlodipine 5 mg/day	35	—
Chen 2007a	I: pioglitazone 15 mg/day plus BCI	50	Oedema: 1 (2) Bloating, diarrhoea: 0 (0) Malignancy: 0 (0)
	C1: acarbose 150 mg/day plus BCI	50	Oedema: 0 (0) Bloating, diarrhoea: 2 (4) Malignancy: 0 (0)
	C2: metformin 750 mg/day plus BCI	50	Oedema: 0 (0) Bloating, diarrhoea: 3 (6) Malignancy: 0 (0) Nausea, anorexia: 7 (14)
	C3: BCI	50	Oedema: 0 (0) Bloating, diarrhoea: 0 (0) Malignancy: 0 (0)
	C4: no intervention	50	Oedema: 0 (0) Bloating, diarrhoea: 0 (0) Malignancy: 0 (0)
Chen 2007b	I: pioglitazone 15 mg/day plus captopril 50 mg/day and Betaloc 50 mg/day plus BCI	83	Coronary heart disease: 3 (3.6) Impairment of liver and kidney function: 0 (0) Death: 5 (6)
Chen 2007b	C: captopril 50 mg/day and Betaloc 50 mg/day plus BCI	73	Coronary heart disease: 7 (9.6) Impairment of liver and kidney function: 0 (0) Death: 4 (5.5)
Deng 2013^c	I: pioglitazone 30 mg/day plus BCI	303	Oedema: 141 (46.5) Cardiovascular AEs, NFS: 27 (8.9) Death: 4 (1.3) Heart failure: 2 (0.7)
Deng 2013^c	C: BCI	302	Oedema: 120 (39.7) Cardiovascular AEs, NFS: 23 (7.6) Death: 5 (1.7) Heart failure: 2 (0.7)
Fang 2013	I: pioglitazone 15 mg/day plus BCI	60	Oedema: 3 (5) Gastrointestinal symptoms: 6 (10) Hypoglycaemia: 3 (5) Liver damage: 4 (6.7)
Fang 2013	C: BCI	60	Oedema: 1 (1.7) Gastrointestinal symptoms: 7 (11.7) Hypoglycaemia: 1 (1.7) Liver damage: 3 (5)
Gao 2011^d	I: pioglitazone 30 mg/day, captopril and other antihypertensive drug(s) plus BCI	—	Cardiovascular disease: 2 (4) Cerebrovascular disease: 1 (2) Death: 2 (4) Kidney damage: 0 (0)
Gao 2011^d	C: captopril and other antihypertensive drug(s) plus BCI	—	Cardiovascular disease: 6 (12) Cerebrovascular disease: 3 (6) Death: 3 (6) Kidney damage: 0 (0)
Guo 2009	I: pioglitazone 30 mg/day plus BCI	30	—
Guo 2009	C: BCI	30	—
Guo 2010	I: pioglitazone 30 mg/day plus BCI	32	—
Guo 2010	C: BCI	32	—
Han 2007	I: pioglitazone 15 mg/day plus enalapril (dose not reported)	23	Affected liver enzymes: 1 (4.3) Hypoglycaemia: 0 (0)
Han 2007	C: enalapril (dose not reported)	20	Affected liver enzymes: 0 (0) Hypoglycaemia: 0 (0)
IDPP‐2^a	I: pioglitazone 30 mg once daily titrated up from 15 mg once daily plus BCI	181	—
IDPP‐2^a	C: placebo in matching doses plus BCI	186	—
Ke 2006	I: pioglitazone 15 mg/day plus BCI	30	Dizziness: 2 (6.7) Oedema: 1 (3.3) Hypoglycaemia: 0 (0) Abnormal renal and liver function: 0 (0)
Ke 2006	C: BCI	28	Dizziness: 0 (0) Oedema: 0 (0) Hypoglycaemia: 0 (0) Abnormal renal and liver function: 0 (0)
Li 2017	I: pioglitazone 15 mg/day plus BCI	75	Oedema: 3 (4)
Li 2017	C: BCI	75	Oedema: 0 (0)
Liang 2004	I: pioglitazone 15 mg/day plus BCI	29	Hypoglycaemia: 5 (17.2) Affected liver enzymes: 2 (10.5)
Liang 2004	C: BCI	30	Hypoglycaemia: 2 (6.7) Affected liver enzymes: 0 (0)
Shi 2014	I: pioglitazone 30 mg/day plus BCI	40	—
Shi 2014	C: placebo in matching doses plus BCI	40	—
Tian 2015	I: pioglitazone 15 mg/day plus BCI	36	—
Tian 2015	C: BCI	36	—
Wu 2013	I: pioglitazone 30 mg/day plus amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	34	—
Wu 2013	C: amlodipine 5 mg/day and valsartan 80 mg/day plus BCI	33	—
Xiu 2015	I: pioglitazone 15 mg/day plus BCI	43	—
Xiu 2015	C: BCI	43	—
Xu 2011	I: pioglitazone 30 mg/day plus BCI	60	—
Xu 2011	C: placebo in matching doses plus BCI	59	—
Yi 2015	I: pioglitazone 15 mg/day plus BCI	35	—
Yi 2015	C: BCI	35	—
Yu 2011	I: pioglitazone 4 mg/day plus BCI	60	—
Yu 2011	C: BCI	60	—
Zeng 2013	I: pioglitazone 38 mg/day plus BCI	70	—
	I: metformin 38 mg/day plus BCI	68	—
	C: BCI	66	—
Zhang 2007	I: pioglitazone 15 mg/day plus BCI	52	Gastrointestinal symptoms: 0 (0) Oedema: 3 (5.8)
	C1: metformin 250 mg/day plus BCI	53	Gastrointestinal symptoms: 2 (3.8) Oedema: 0 (0)
	C2: repaglinide 3 x 0.25 mg/day plus BCI	51	Gastrointestinal symptoms: 0 (0) Oedema: 0 (0)
	C3: personalised diet and exercise consultation	51	Gastrointestinal symptoms: 0 (0) Oedema: 0 (0)
	C4: BCI	56	Gastrointestinal symptoms: 0 (0) Oedema: 0 (0)
Zhang 2015	I: pioglitazone 15 mg/day plus BCI	26	Oedema: 2 (7.7)
Zhang 2015	C: BCI	25	Oedema: 0 (0)
Zhao 2009	I: pioglitazone 15 mg/day plus BCI	47	Oedema: 2 (4.3) Hypoglycaemia: 0 (0) Abnormal liver and kidney function: 0 (0)
Zhao 2009	C: BCI	45	Oedema: 0 (0) Hypoglycaemia: 0 (0) Abnormal liver and kidney function: 0 (0)
^aStudies reported number of events, not number of participants experiencing events. ^bFurther adverse events described in supplementary data to article Bone 2013. ^cStudy reported number of participants experiencing Oedema: with various values in the publication. We assumed that 20 and 41 were typos of 120 and 141. ^dStudy did not specify dosages and which antihypertensive drugs were used. — denotes not reported AE: adverse event; BCI: behaviour‐changing intervention; C: comparator; GH: growth hormone; I: intervention; N: number of participants; NFS: not further specified; PTH: parathyroid hormone; UTI: urinary tract infection

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Appendix 21. Survey of study investigators providing information on included studies

Included studies		Date study author contacted	Date study author replied	Date study author was asked for additional information (short summary)	Date study author provided data (short summary)
ACT NOW		11 February 2020	12 February 2020	19 February 2020 (details about SAEs, non‐serious AEs and events of hypoglycaemia. Knowledge about future/ongoing studies, and completeness of our references to the study)	No answer
ACT NOW		19 February	6 March 2020	Contacted Takeda Pharma. Takeda was not able to provide additional data or answer questions	NA
Attallah 2007		13 February 2020	13 February 2020	20 February 2020 (study protocol, events of hypoglycaemia, timing of measurement of OGTT, data‐points in the scope of this review, knowledge about future/ongoing studies.)	20 February 2020 (not able to give additional data, trial protocol or knowledge about studies. Answered questions of hypoglycaemia and timing of OGTT)
Bone 2013		11 February 2020	No reply	NA	NA
Che 2014				No contact information	NA
Chen 2007a				No contact information	NA
Chen 2007b				No contact information	NA
Deng 2013				No contact information	NA
Fang 2013		10 March 2020	No reply	NA	NA
Gao 2011				No contact information	NA
Guo 2009		17 February 2020	No reply	NA	NA
Guo 2010		17 February 2020	No reply	NA	NA
IDPP‐2		12 February 2020	No reply	NA	NA
Ke 2006				No contact information	NA
Li 2017				No contact information	NA
Liang 2004				No contact information	NA
Shi 2014				No contact information	NA
Tian 2015				No contact information	NA
Han 2007				No contact information	NA
Wu 2013		12 March 2020	No reply	NA	NA
Xiu 2015				No contact information	NA
Xu 2011				No contact information	NA
Yi 2015				No contact information	NA
Yu 2011		13 March 2020	No reply	NA	NA
Zeng 2013				No contact information	NA
Zhang 2007				No contact information	NA
Zhang 2015				No contact information	NA
Zhao 2009				No contact information	NA
Studies awaiting assessment	Study completion date	Date study author contacted	Date study author replied	Date study author was asked for additional information (short summary)	Date study author provided data (short summary)
NCT01006018 (terminated) ‐ moved to excluded studies	RT (NCT01006018)	12 February 2020	No reply	NA	NA
Ongoing studies (with an estimated study completion date more than one year in the past)	Study completion date	Date study author contacted	Date study author replied	Date study author was asked for additional information (short summary)	Date study author provided data (short summary)
Beijing prediabetes reversion programme (BPRP)	RT	17 February 2020	18 February 2020	21 February 2020 (expected publishing date of final draft, full trial protocol, knowledge of other studies)	25 February 2020 (English protocol not available, final draft submitted, date of publication not known)
NCT02969798	RT	11 February 2020	12 February 2020	19 February 2020 (knowledge about future/ongoing studies)	No answer
— denotes not reported AE: adverse event; CA: conference abstract; NA: not applicable; OGTT: oral glucose tolerance test; PM: published manuscript; RT: registered trial; SAE: serious adverse event

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Data and analyses

Comparison 1. Pioglitazone versus another glucose‐lowering intervention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Incidence of T2DM (comparator metformin)	3	331	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.40, 2.38]
1.2 Incidence of T2DM by 'prediabetes' criteria (comparator metformin)	3	331	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.40, 2.38]
1.2.1 Only IGT	2	234	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.35, 2.64]
1.2.2 IFG and IGT	1	97	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.15, 6.96]
1.3 Non‐serious adverse events (comparator metformin)	2	201	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.04, 5.51]
1.4 Non‐serious adverse events by 'prediabetes' criteria (comparator metformin)	2	201	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.04, 5.51]
1.4.1 Only IGT	1	96	Risk Ratio (M‐H, Random, 95% CI)	0.13 [0.02, 1.03]
1.4.2 IFG and IGT	1	105	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.27, 8.78]
1.5 Fasting plasma (comparator metformin)	3	339	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.17, 0.23]
1.6 Fasting plasma glucose by 'prediabetes' criteria (comparator metformin)	3	339	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.17, 0.23]
1.6.1 IFG and IGT	1	105	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.90, 0.42]
1.6.2 Only IGT	2	234	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.15, 0.26]
1.7 Fasting plasma glucose by comorbidity (comparator metformin)	3	339	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.17, 0.23]
1.7.1 No comorbidity in inclusion criteria	2	243	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.24, 0.22]
1.7.2 Hypertension	1	96	Mean Difference (IV, Random, 95% CI)	0.15 [‐0.24, 0.54]
1.8 2‐hour blood glucose (comparator metformin)	3	339	Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.43, ‐0.02]
1.9 2‐hour blood glucose by 'prediabetes' criteria (comparator metformin)	3	339	Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.43, ‐0.02]
1.9.1 IFG and IGT	1	105	Mean Difference (IV, Random, 95% CI)	0.16 [‐0.46, 0.78]
1.9.2 Only IGT	2	234	Mean Difference (IV, Random, 95% CI)	‐0.27 [‐0.47, ‐0.08]
1.10 2‐hour blood glucose by comorbidity (comparator metformin)	3	339	Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.43, ‐0.02]
1.10.1 No comorbidity in inclusion criteria	2	243	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.58, 0.25]
1.10.2 Hypertension	1	96	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.63, 0.37]

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Comparison 2. Pioglitazone versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality	4	1156	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.38 [0.54, 10.50]
2.2 All‐cause mortality by subgroup	2	969	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.38 [0.54, 10.50]
2.2.1 Mainly white ethnicity, from USA, commercial funding, IFG and IGT	1	602	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.70 [0.38, 19.23]
2.2.2 Asian Indian ethnicity, from India, non‐commercial funding, only IGT	1	367	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.01 [0.21, 19.44]
2.3 Incidence of T2DM	6	1395	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.17, 0.95]
2.4 Incidence of T2DM by 'prediabetes' criteria	6	1395	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.17, 0.95]
2.4.1 IFG and IGT	3	752	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.18, 0.52]
2.4.2 IFG or IGT	2	236	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.04, 0.77]
2.4.3 Only IGT	1	407	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.71, 1.27]
2.5 Incidence of T2DM by ethnicity	6	1395	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.17, 0.95]
2.5.1 Mixed American	3	789	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.16, 0.48]
2.5.2 Chinese (assumed)	2	199	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.09, 1.21]
2.5.3 Asian Indian	1	407	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.71, 1.27]
2.6 Incidence of T2DM by age	6	1395	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.17, 0.95]
2.6.1 Age ≤ 65 years	5	1276	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.14, 1.07]
2.6.2 Age > 65 years	1	119	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.08, 1.95]
2.7 Incidence of T2DM by sex	6	1395	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.17, 0.95]
2.7.1 Men and women	5	1239	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.19, 1.15]
2.7.2 Women only	1	156	Risk Ratio (M‐H, Random, 95% CI)	0.13 [0.02, 0.98]
2.8 Incidence of T2DM after intervention end, assessed at any time after intervention end	3	468	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.49, 1.60]
2.9 Incidence of T2DM after intervention end, assessed at any time after intervention end by 'prediabetes' criteria	3	468	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.49, 1.60]
2.9.1 IFG and IGT	2	321	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.51, 1.68]
2.9.2 IFG or IGT	1	147	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.01, 7.33]
2.10 Serious adverse events	2	187	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.32, 28.22]
2.11 Cardiovascular mortality	4	1156	Risk Ratio (M‐H, Random, 95% CI)	5.14 [0.25, 106.28]
2.12 Non‐fatal myocardial infarction	3	789	Risk Ratio (M‐H, Random, 95% CI)	1.97 [0.18, 21.65]
2.13 Congestive heart failure	3	789	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.93 [0.20, 18.60]
2.14 Congestive heart failure by 'prediabetes' criteria	3	789	Risk Ratio (M‐H, Random, 95% CI)	1.59 [0.20, 12.86]
2.14.1 IFG and IGT	2	633	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.06, 15.70]
2.14.2 IFG or IGT	1	156	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.12, 72.53]
2.15 Congestive heart failure by sex	3	789	Risk Ratio (M‐H, Random, 95% CI)	1.59 [0.20, 12.86]
2.15.1 Men and women	2	633	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.06, 15.70]
2.15.2 Women only	1	156	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.12, 72.53]
2.16 Non‐serious adverse events	2	187	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.81, 1.31]
2.17 Non‐serious adverse events by 'prediabetes' criterion	2	187	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.81, 1.31]
2.17.1 IFG and IGT	1	31	Risk Ratio (M‐H, Random, 95% CI)	2.13 [0.22, 21.17]
2.17.2 IFG or IGT	1	156	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.80, 1.30]
2.18 Time to progression of T2DM	2		Hazard Ratio (IV, Random, 95% CI)	Subtotals only
2.19 Time to progression of T2DM by subgroup	2	1009	Hazard Ratio (IV, Random, 95% CI)	0.56 [0.15, 2.11]
2.19.1 Mainly white ethnicity, from USA, commercial funding, IFG and IGT	1	602	Hazard Ratio (IV, Random, 95% CI)	0.28 [0.16, 0.49]
2.19.2 Asian Indian ethnicity, from India, non‐commercial funding, only IGT	1	407	Hazard Ratio (IV, Random, 95% CI)	1.08 [0.75, 1.56]
2.20 Fasting plasma glucose	5		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.21 Fasting plasma glucose by 'prediabetes' criteria	5	1125	Mean Difference (IV, Random, 95% CI)	‐0.52 [‐0.97, ‐0.07]
2.21.1 IFG and IGT	2	560	Mean Difference (IV, Random, 95% CI)	‐0.86 [‐1.82, 0.11]
2.21.2 IFG or IGT	2	198	Mean Difference (IV, Random, 95% CI)	‐0.48 [‐0.71, ‐0.25]
2.21.3 Only IGT	1	367	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.17, 0.27]
2.22 Fasting plasma glucose by ethnicity	5	1125	Mean Difference (IV, Random, 95% CI)	‐0.52 [‐0.97, ‐0.07]
2.22.1 Mainly white	2	559	Mean Difference (IV, Random, 95% CI)	‐0.39 [‐0.48, ‐0.29]
2.22.2 Asian Indian	1	367	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.17, 0.27]
2.22.3 Chinese (assumed)	2	199	Mean Difference (IV, Random, 95% CI)	‐0.92 [‐1.83, ‐0.02]
2.23 Fasting plasma glucose by sex	5	1125	Mean Difference (IV, Random, 95% CI)	‐0.52 [‐0.97, ‐0.07]
2.23.1 Men and women	4	1007	Mean Difference (IV, Random, 95% CI)	‐0.53 [‐1.10, 0.05]
2.23.2 Women only	1	118	Mean Difference (IV, Random, 95% CI)	‐0.49 [‐0.74, ‐0.24]
2.24 2‐hour blood glucose	5	1119	Mean Difference (IV, Random, 95% CI)	‐0.89 [‐1.43, ‐0.34]
2.25 2‐hour blood glucose by 'prediabetes' criteria	5	1119	Mean Difference (IV, Random, 95% CI)	‐0.89 [‐1.43, ‐0.34]
2.25.1 IFG and IGT	2	560	Mean Difference (IV, Random, 95% CI)	‐1.44 [‐1.82, ‐1.05]
2.25.2 IFG or IGT	2	192	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.09, ‐0.21]
2.25.3 Only IGT	1	367	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.67, 0.49]
2.26 2‐hour blood glucose by ethnicity	5	1119	Mean Difference (IV, Random, 95% CI)	‐0.89 [‐1.43, ‐0.34]
2.26.1 Mainly white	2	553	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐1.65, ‐0.23]
2.26.2 Asian Indian	1	367	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.67, 0.49]
2.26.3 Chinese (assumed)	2	199	Mean Difference (IV, Random, 95% CI)	‐1.23 [‐2.11, ‐0.35]
2.27 2‐hour blood glucose by sex	5	1119	Mean Difference (IV, Random, 95% CI)	‐0.89 [‐1.43, ‐0.34]
2.27.1 Men and women	4	1007	Mean Difference (IV, Random, 95% CI)	‐0.96 [‐1.59, ‐0.33]
2.27.2 Women only	1	112	Mean Difference (IV, Random, 95% CI)	‐0.53 [‐1.18, 0.12]
2.28 HbA1C	5	1001	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.20, ‐0.07]
2.29 HbA1C by 'prediabetes' criteria	5	1001	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.20, ‐0.07]
2.29.1 IFG and IGT	2	435	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.28, ‐0.13]
2.29.2 IFG or IGT	2	199	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.16, ‐0.01]
2.29.3 Only IGT	1	367	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.26, 0.06]
2.30 HbA1C by ethnicity	5	1001	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.20, ‐0.07]
2.30.1 Mainly white	3	554	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.24, ‐0.05]
2.30.2 Asian Indian	1	367	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.26, 0.06]
2.30.3 Chinese (assumed)	1	80	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.25, 0.13]
2.31 HbA1c by sex	5	1001	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.20, ‐0.07]
2.31.1 Men and women	4	882	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.24, ‐0.09]
2.31.2 Women only	1	119	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.17, ‐0.01]

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Comparison 3. Pioglitazone versus no intervention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 All‐cause mortality	3	866	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.38, 1.91]
3.2 All‐cause mortality by 'prediabetes' criteria	3	866	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.38, 1.91]
3.2.1 IFG or IGT	2	766	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.37, 2.27]
3.2.2 Only IGT	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.82]
3.3 All‐cause mortality by comorbidity	3	866	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.38, 1.91]
3.3.1 No comorbidity in inclusion criteria	2	261	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.32, 2.49]
3.3.2 Hypertension	1	605	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.22, 2.94]
3.4 Incidence of T2DM	16	2053	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.23, 0.40]
3.5 Incidence of T2DM by 'prediabetes' criteria	16	2053	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.23, 0.40]
3.5.1 IFG and IGT	5	445	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.13, 0.50]
3.5.2 IFG or IGT	3	812	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.22, 0.51]
3.5.3 Only IGT	7	676	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.17, 0.44]
3.5.4 Mixed (subpopulations of IFG, IGT, IFG + IGT)	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.16, 1.11]
3.6 Incidence of T2DM by age	16	2053	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.23, 0.40]
3.6.1 Age ≤ 65	15	1986	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.23, 0.40]
3.6.2 Age > 65	1	67	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.08, 1.86]
3.7 Incidence of T2DM by comorbidity	16	2053	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.23, 0.40]
3.7.1 No comorbidity in inclusion criteria	12	1657	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.22, 0.40]
3.7.2 Hypertension	4	396	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.19, 0.72]
3.8 Serious adverse events	7	1211	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.38, 1.32]
3.9 Serious adverse events by 'prediabetes' criteria	3	861	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.38, 1.32]
3.9.1 IFG or IGT	2	761	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.37, 1.40]
3.9.2 Only IGT	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.82]
3.10 Serious adverse events by comorbidity	3	861	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.38, 1.32]
3.10.1 No comorbidity in inclusion criteria	1	605	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.29, 2.51]
3.10.2 Hypertension	2	256	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.30, 1.39]
3.11 Non‐serious adverse events	11	1546	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.81, 1.97]
3.12 Non‐serious adverse events by 'prediabetes' criteria	11	1546	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.81, 1.97]
3.12.1 IFG and IGT	2	135	Risk Ratio (M‐H, Random, 95% CI)	3.59 [0.41, 31.63]
3.12.2 IFG or IGT	4	944	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.83, 1.66]
3.12.3 Only IGT	5	467	Risk Ratio (M‐H, Random, 95% CI)	2.08 [0.50, 8.72]
3.13 Non‐serious adverse events by comorbidity	11	1546	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.81, 1.97]
3.13.1 No comorbidity in inclusion criteria	8	1235	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.07, 1.51]
3.13.2 Hypertension	3	311	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.17, 1.00]
3.14 Participants with events of hypoglycaemia	4	314	Risk Ratio (M‐H, Random, 95% CI)	2.71 [0.76, 9.75]
3.15 Participants with events of hypoglycaemia by 'prediabetes' criteria	2	179	Risk Ratio (M‐H, Random, 95% CI)	2.71 [0.76, 9.75]
3.15.1 Mixed (subpopulations of IFG, IGT, IFG + IGT)	1	120	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.32, 28.03]
3.15.2 Only IGT	1	59	Risk Ratio (M‐H, Random, 95% CI)	2.59 [0.54, 12.29]
3.16 Fasting plasma glucose	18	1533	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.96, ‐0.44]
3.17 Fasting plasma glucose by age	18	1551	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.96, ‐0.44]
3.17.1 Age ≤ 65	15	1360	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.98, ‐0.42]
3.17.2 Age < 65	3	191	Mean Difference (IV, Random, 95% CI)	‐0.69 [‐1.39, 0.01]
3.18 Fasting plasma glucose by 'prediabetes' criteria	18	1551	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.96, ‐0.44]
3.18.1 IFG and IGT	6	560	Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.39, ‐0.31]
3.18.2 IFG or IGT	2	95	Mean Difference (IV, Random, 95% CI)	‐1.12 [‐1.62, ‐0.62]
3.18.3 Only IGT	8	704	Mean Difference (IV, Random, 95% CI)	‐0.64 [‐1.05, ‐0.23]
3.18.4 Mixed (subpopulations of IFG, IGT, IFG + IGT)	1	120	Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.51, ‐0.15]
3.18.5 Unspecified	1	72	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.41, 0.09]
3.19 Fasting plasma glucose by comorbidity	18	1551	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.96, ‐0.44]
3.19.1 No comorbidity in inclusion criteria	15	1368	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐0.89, ‐0.32]
3.19.2 Hypertension	3	183	Mean Difference (IV, Random, 95% CI)	‐1.11 [‐1.26, ‐0.96]
3.20 2‐hour blood glucose	17	1463	Mean Difference (IV, Random, 95% CI)	‐1.58 [‐1.88, ‐1.28]
3.21 2‐hour blood glucose by 'prediabetes' criteria	17	1463	Mean Difference (IV, Random, 95% CI)	‐1.58 [‐1.88, ‐1.28]
3.21.1 IFG and IGT	5	472	Mean Difference (IV, Random, 95% CI)	‐1.76 [‐2.42, ‐1.11]
3.21.2 IFG or IGT	2	95	Mean Difference (IV, Random, 95% CI)	‐2.68 [‐5.10, ‐0.26]
3.21.3 Only IGT	8	704	Mean Difference (IV, Random, 95% CI)	‐1.50 [‐1.69, ‐1.30]
3.21.4 Mixed (subpopulations of IFG, IGT, IFG + IGT)	1	120	Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.31, ‐0.37]
3.21.5 Unspecified	1	72	Mean Difference (IV, Random, 95% CI)	‐0.05 [‐0.86, 0.76]
3.22 2‐hour blood glucose by 'prediabetes' criteria	15	1271	Mean Difference (IV, Random, 95% CI)	‐1.72 [‐2.01, ‐1.42]
3.22.1 IFG and IGT	5	472	Mean Difference (IV, Random, 95% CI)	‐1.76 [‐2.42, ‐1.11]
3.22.2 IFG or IGT	2	95	Mean Difference (IV, Random, 95% CI)	‐2.68 [‐5.10, ‐0.26]
3.22.3 Only IGT	8	704	Mean Difference (IV, Random, 95% CI)	‐1.50 [‐1.69, ‐1.30]
3.23 2‐hour blood glucose by age	17	1463	Mean Difference (IV, Random, 95% CI)	‐1.58 [‐1.88, ‐1.28]
3.23.1 Age ≤ 65	14	1272	Mean Difference (IV, Random, 95% CI)	‐1.51 [‐1.84, ‐1.18]
3.23.2 Age > 65	3	191	Mean Difference (IV, Random, 95% CI)	‐2.06 [‐2.39, ‐1.72]
3.24 2‐hour blood glucose by comorbidity	17	1463	Mean Difference (IV, Random, 95% CI)	‐1.58 [‐1.88, ‐1.28]
3.24.1 No comorbidity in inclusion criteria	14	1280	Mean Difference (IV, Random, 95% CI)	‐1.38 [‐1.67, ‐1.09]
3.24.2 Hypertension	3	183	Mean Difference (IV, Random, 95% CI)	‐2.52 [‐3.54, ‐1.50]
3.25 HbA1C	9	762	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.32, ‐0.23]
3.26 HbA1C by 'prediabetes' criteria	9	762	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.32, ‐0.23]
3.26.1 IFG and IGT	2	174	Mean Difference (IV, Random, 95% CI)	‐0.69 [‐1.18, ‐0.20]
3.26.2 Only IGT	6	468	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐1.46, 0.07]
3.26.3 Unspecified	1	120	Mean Difference (IV, Random, 95% CI)	‐1.43 [‐1.98, ‐0.88]
3.27 HbA1C by age	9	762	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.32, ‐0.23]
3.27.1 Age ≤ 65	6	571	Mean Difference (IV, Random, 95% CI)	‐0.82 [‐1.55, ‐0.10]
3.27.2 Age < 65	3	191	Mean Difference (IV, Random, 95% CI)	‐0.72 [‐1.07, ‐0.37]
3.28 HbA1c by comorbidity	9	762	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.32, ‐0.23]
3.28.1 No comorbidity in inclusion criteria	7	622	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.48, ‐0.13]
3.28.2 Hypertension	2	140	Mean Difference (IV, Random, 95% CI)	‐0.63 [‐1.06, ‐0.20]

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3.22 — Comparison 3: Pioglitazone versus no intervention, Outcome 22: 2‐hour blood glucose by 'prediabetes' criteria

Characteristics of studies

Characteristics of included studies [ordered by study ID]

ACT NOW.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria^a: IFG = FPG ≥ 5.3 and < 7.0 mmol/L and IGT = 2‐h glucose ≥ 7.8 to ≤ 11.1 mmol/L plus at least one other risk factor for T2DM or FPG ≥ 5 and < 7.0 mmol/L and IGT = 2‐h glucose ≥ 9.4 to ≤ 11.1 mmol/L plus at least one other risk factor for T2DM (see Appendix 10), ≥ 18 years of age, BMI > 25 kg/m² Exclusion criteria: T2DM; ever treated with a thiazolidinedione; received metformin within 1 year; treatment within last 3 months or for > 1 week the last year with sulphonylurea, meglitinide or alpha‐glucosidase inhibitor; treatment within last 3 months or for > 1 week in the last year with insulin (excluding pregnancy); cardiovascular disease; renal disease; anaemia; gastrointestinal disease; recent significant abdominal surgery; pulmonary disease; chronic infections; unable to accept treatment assigned by randomisation; participation in another trial; recent major weight loss; pregnancy or childbearing; planning of pregnancy during trial; major psychiatric disorders; acute or chronic alcohol abuse; use of: thiazide diuretics > 25 mg/day, non‐cardioselective systemic beta‐blockers, niacin, systemic glucocorticoids, weight gain or loss medications; thyroid disease with abnormal TSH; other endocrine disorders; fasting plasma triglyceride > 400 mg/dL; history of bladder cancer; untreatable haematuria at screening Diagnostic criteria^a: IFG = FPG ≥ 5.3 and < 7.0 mmol/L and IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L plus at least 1 other risk factor for T2DM or FPG ≥ 5 and < 7.0 mmol/L and IGT = 2‐h glucose ≥ 7.8 to ≤ 11.1 mmol/L plus at least 1 other risk factor for T2DM Setting: outpatients Age group: ≥ 18 years of age Gender distribution: men and women Country/countries where study was performed: USA
Interventions	Intervention(s): pioglitazone 30 mg/day, increased after 1 month pioglitazone 45 mg/day plus BCI Comparator(s): placebo in matching doses plus BCI Duration of intervention: 24 months from last recruitment or until dropout or conversion to T2DM Duration of follow‐up: 24 months after last recruitment or until dropout or conversion to T2DM Run‐in period: no run‐in period Number of study centres: 8
Outcomes	Reported outcome(s) in full text of publication: conversion to T2DM, HbA1c, FPG, plasma glucose concentration during OGTT, 2‐h glucose, insulin secretion, insulin sensitivity, blood lipids, adiponectin, carotid intima thickness, body weight, BMD, AEs, time to progression to T2DM, low or high age, blood pressure, adipocyte‐derived cytokines, microalbuminuria, liver enzymes, bone fractures
Study details	Trial identifier: NCT00220961 Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: English Funding: commercial, funded by Takeda Pharmaceuticals. Non‐commercial by the University of Tennessee Health Science Center, the University of Southern California Keck School of Medicine, the Veterans Affairs institutions in Phoenix and San Diego Publication status: peer‐reviewed journal
Stated aim for study	Quote: "The purpose of this study is to examine whether pioglitazone versus placebo can reduce the conversion rate of impaired glucose tolerance (IGT) to type 2 diabetes mellitus"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... subjects were randomized by center and gender using block randomization to ensure equal distribution." Comment: method of random sequence generation adequately described
Allocation concealment (selection bias)	Low risk	Quote: "When a center identifies a suitable subject, they will call the data coordinating center to obtain the randomization code and they will be informed that the subject will receive either drug A or drug B. A sticker with the subject’s randomization number and drug assignment code (i.e., either A or B) will be placed on the unmarked drug bottles and given to the subject by the site study coordinator. " Comment: method of random allocation concealment adequately described
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed, mortality is unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Quote: "All subjects were followed until they dropped out, reached the primary endpoint of diabetes ..." and "Any IGT subject who developed type 2 diabetes (pioglitazone‐treated or placebo groups) was started on open label pioglitazone (30 mg/day and titrated to 45 mg/day [maximum dose] after one month), but the randomization code was not broken." Comment: patients converting to T2DM did not undergo further follow‐up and randomisation was not revealed, investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) non‐fatal myocardial infarction/stroke/congestive heart failure	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed
Blinding of participants and personnel (performance bias) non‐serious adverse events	Low risk	Quote: "IGT subjects were randomized to receive pioglitazone, 30 mg/day, or placebo and returned 1 month later. If no adverse events were present, the dose of blinded pioglitazone (and placebo) was increased to 45 mg/day ..." and "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: the study is double‐blinded, blinding unlikely to have been broken
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed
Blinding of participants and personnel (performance bias) time to progression to T2DM	Low risk	Quote: "All subjects were followed until they dropped out, reached the primary endpoint of diabetes ..." and "Any IGT subject who developed type 2 diabetes (pioglitazone‐treated or placebo groups) was started on open label pioglitazone (30 mg/day and titrated to 45 mg/day [maximum dose] after one month), but the randomization code was not broken." Comment: participants that converted to T2DM did not undergo further follow‐up and randomisation was not revealed
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed, mortality is unlikely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) non‐fatal myocardial infarction/stroke/congestive heart failure	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: blinding is not likely to influence the outcome assessment of non‐fatal myocardial infarction/stroke/congestive heart failure.
Blinding of outcome assessment (detection bias) non‐serious adverse events	Low risk	Quote: "IGT subjects were randomized to receive pioglitazone, 30 mg/day, or placebo and returned 1 month later. If no adverse events were present, the dose of blinded pioglitazone (and placebo) was increased to 45 mg/day ..." Comment: blinding unlikely to have been broken
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed, blinding not likely to influence SAEs.
Blinding of outcome assessment (detection bias) time to progression to T2DM	Low risk	Quote: "The study is a prospective, randomized, double‐blind placebo controlled trial ..." Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	Unclear risk	Quote: "A total of 161 patients did not complete the study (71 in the placebo group and 90 in the pioglitazone group). The median follow‐up time for these patients was 7.6 months. Baseline characteristics of the patients who did not complete the study were similar to those of the 441 patients who completed the study" and "Two approaches were used to assess whether patients who completed the study differed from those who withdrew. The first approach involved a withdrawal‐free survival analysis of time to withdrawal, with the final study visit used as the censoring variable. Data for patients who underwent an oral glucose‐tolerance test at the end‐of study visit were censored at 3 years. All other patients were counted as having withdrawn as of the last study visit. On the basis of this analysis, the hazard ratio for withdrawal in the pioglitazone group as compared with the placebo group was 1.125 (P = 0.42). In the second approach, missing data (for the two study groups combined) were assessed for each continuous measure with analysis of variance, stratified according to whether the measure was missing at each subsequent visit. Since neither approach produced statistically significant evidence of bias due to missing data, the primary and secondary analyses were performed without data imputation" Comment: 29.7% (N = 90/303) of pioglitazone group and 23.7% (N = 71/299) of placebo group dropped out of the study. Unknown whether mortality status was investigated in the participants lost to follow‐up
Incomplete outcome data (attrition bias) incidence of T2DM	High risk	Quote: "A total of 161 patients did not complete the study (71 in the placebo group and 90 in the pioglitazone group). The median follow‐up time for these patients was 7.6 months. Baseline characteristics of the patients who did not complete the study were similar to those of the 441 patients who completed the study" and "Two approaches were used to assess whether patients who completed the study differed from those who withdrew. The first approach involved a withdrawal‐free survival analysis of time to withdrawal, with the final study visit used as the censoring variable. Data for patients who underwent an oral glucose‐tolerance test at the end‐of study visit were censored at 3 years. All other patients were counted as having withdrawn as of the last study visit. On the basis of this analysis, the hazard ratio for withdrawal in the pioglitazone group as compared with the placebo group was 1.125 (P = 0.42). In the second approach, missing data (for the two study groups combined) were assessed for each continuous measure with analysis of variance, stratified according to whether the measure was missing at each subsequent visit. Since neither approach produced statistically significant evidence of bias due to missing data, the primary and secondary analyses were performed without data imputation" Comment: 29.7% (N = 90/303) of pioglitazone group and 23.7% (N = 71/299) of placebo group dropped out of the study. Analysis performed without data imputation. PP analysis. Number of dropouts between intervention groups balanced, however 9 left study in the pioglitazone due to weight gain and 5 due to AEs, for the placebo group these numbers were 3 due to weight gain and 3 due to AEs
Incomplete outcome data (attrition bias) measures of blood glucose control	High risk	Quote: "A total of 161 patients did not complete the study (71 in the placebo group and 90 in the pioglitazone group). The median follow‐up time for these patients was 7.6 months. Baseline characteristics of the patients who did not complete the study were similar to those of the 441 patients who completed the study." Comment: 29.7% (N = 90/303) of pioglitazone group and 23.7% (N = 71/299) of placebo group dropped out of the study. PP analysis. Number of dropouts between intervention groups balanced, however 9 left study in the pioglitazone due to weight gain and 5 due to AEs, for the placebo group these numbers were 3 due to weight gain and 3 due to AEs.
Incomplete outcome data (attrition bias) non‐fatal myocardial infarction/stroke/congestive heart failure	High risk	Comment: 29.7% (N = 90/303) of pioglitazone group and 23.7% (N = 71/299) of placebo group dropped out of the study.
Incomplete outcome data (attrition bias) non‐serious adverse events	High risk	Comment: 29.7% (N = 90/303) of pioglitazone group and 23.7% (N = 71/299) of placebo group dropped out of the study.
Incomplete outcome data (attrition bias) serious adverse events	High risk	Comment: 29.7% (N = 90/303) of pioglitazone group and 23.7% (N = 71/299) of placebo group dropped out of the study.
Incomplete outcome data (attrition bias) time to progression to T2DM	High risk	Quote: "A total of 161 patients did not complete the study (71 in the placebo group and 90 in the pioglitazone group). The median follow‐up time for these patients was 7.6 months. Baseline characteristics of the patients who did not complete the study were similar to those of the 441 patients who completed the study." and "Two approaches were used to assess whether patients who completed the study differed from those who withdrew. The first approach involved a withdrawal‐free survival analysis of time to withdrawal, with the final study visit used as the censoring variable. Data for patients who underwent an oral glucose‐tolerance test at the end‐of study visit were censored at 3 years. All other patients were counted as having withdrawn as of the last study visit. On the basis of this analysis, the hazard ratio for withdrawal in the pioglitazone group as compared with the placebo group was 1.125 (P = 0.42). In the second approach, missing data (for the two study groups combined) were assessed for each continuous measure with analysis of variance, stratified according to whether the measure was missing at each subsequent visit. Since neither approach produced statistically significant evidence of bias due to missing data, the primary and secondary analyses were performed without data imputation." Comment: 29.7% (N =90/303) of pioglitazone group and 23.7% (N =71/299) of placebo group dropped out of the study.
Selective reporting (reporting bias)	High risk	Comment: all of the trial's prespecified (primary and secondary) outcomes that are of interest in the review have been reported. However, SAEs are recorded according to protocol but not sufficiently reported or analysed in publications. Only deaths are listed as SAEs in publications as well as ClinicalTrials.gov. Author and sponsoring company were not able to elaborate on details.
Other bias	Unclear risk	Quote: "To preserve study power, the recruitment period was lengthened 3 months to a total of 24 months to allow recruitment of the targeted number of participants with a commensurate increase in the total study duration for a follow up time of 4 years, starting from the time that the first IGT subject was recruited." Comment: recruitment period was extended from 21 months to 24 months to allow recruitment of targeted number of participants. Not likely to induce bias on outcomes Quote: "During the course of recruitment, the investigators agreed to modify the glycaemic inclusion criteria to allow enrolment of persons with fasting glucose of 90–125 mg/dL as long as the 2‐hour plasma glucose concentration was 170–199 mg/dL, in recognition of the high risk of diabetes in such persons." Comment: a change of 5 mg/dL in the lower interval of the fasting glucose during recruitment. Not likely to induce bias. Quote: "Takeda Pharmaceuticals provided financial support for the study but had no access to the data." Comment: study was sponsored by a pharmaceutical company.

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Attallah 2007.

*Study characteristics*
Methods	Study design: 2 x 2 factorial RCT
Participants	Inclusion criteria: IGT and IFG, age = 40 ‐ 75, BMI ≥ 27 kg/m², WC > 100 cm for men and > 88 cm for women Exclusion criteria: known diabetes; history of malignancy, congestive heart failure, recent treatment with weight‐reducing medications or corticosteroids in doses exceeding standard replacement; pregnant or breastfeeding; declining contraception throughout the treatment period; history of acromegaly, cardiac, pulmonary, hepatic or renal disease; ALT > 3 times above the upper normal limit; uncontrolled hypertension Diagnostic criteria^a: IFG = FPG < 6.9 mmol/L; IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: USA
Interventions	Intervention(s): pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks and recombinant human GH placebo Comparator(s): pioglitazone placebo plus GH placebo Duration of intervention: 40 weeks Duration of follow‐up: 43‐44 weeks Run‐in period: 4 weeks Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: VAT, insulin sensitivity, serum IGF‐1, glucose metabolism, lipids, BMI, anthropometrics
Study details	Trial identifier: NCT00352287 Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: English Funding: commercial funding by Genentech Center for Clinical Research in Endocrinology, Pfizer Pharmaceuticals; non‐commercial funding by an F‐32 National Research Service Award from the National Institutes of Health, Research Service of the Department of Veterans Affairs Publication status: peer‐reviewed journal
Stated aim for study	Quote: "Recombinant human growth hormone (GH) and pioglitazone (PIO) in abdominally obese adults with impaired glucose tolerance were evaluated under the hypothesis that the combination attenuates GH‐induced increases in glucose concentrations, reduces visceral adipose tissue (VAT), and improves insulin sensitivity over time"
Notes	The trial had a total of 4 intervention groups, however, we included only two of these in our review. The 2 intervention arms not included were; (1) pioglitazone placebo and recombinant human GH 8μg/kg/day and (2) pioglitazone 30 mg/day titrated up from 15 mg/day after 4 weeks and recombinant human GH 8μg/kg/day
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Generation of the randomization sequence was performed at the office of a third‐party investigator not affiliated with the study. Permuted blocks and stratification by BMI, gender, 2‐h postprandial glucose (after 75‐g oral glucose challenge), and oestrogen repletion status of women were used." Comment: random sequence generation adequately described
Allocation concealment (selection bias)	Low risk	Quote: "The randomization list generated in the office of the third party investigator was forwarded to an investigational pharmacist, who dispensed medications. All randomization assignments were sequentially numbered and placed in sealed opaque envelopes. Assignment codes were fully concealed until after all recruitment, testing, and data analyses were complete." Comment: allocation concealment adequately described
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: adjudicated, mortality unlikely to induce bias by lack of blinding
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: investigator‐assessed, laboratory indexes unlikely to induce bias by lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: investigator‐assessed, laboratory indexes unlikely to induce bias by lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	Low risk	Quote: "Participants were followed monthly as outpatients and had a complete physical examination at each visit. Each participant was examined for treatment‐related side effects, including peripheral edema or other fluid retention symptoms" Comment: investigator‐assessed, blinding adequately described
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: blinding adequately described, SAEs unlikely to induce bias by lack of blinding
Blinding of participants and personnel (performance bias) time to progression to T2DM	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: investigator‐assessed, laboratory indexes unlikely to induce bias by lack of blinding
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: blinding adequately described, mortality unlikely to induce bias by lack of blinding. No deaths reported, mode of assessment not specified
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: investigator‐assessed, laboratory indexes unlikely to induce bias by lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: investigator‐assessed, laboratory indexes unlikely to induce bias by lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: investigator‐assessed. Blinding adequately described
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: blinding adequately described, mortality unlikely to induce bias by lack of blinding. No SAEs reported, mode of assessment not specified
Blinding of outcome assessment (detection bias) time to progression to T2DM	Low risk	Quote: "Given the double‐blind, placebo‐controlled nature of the study, all participants and investigators were blinded to group assignment until after the study was completed and data were analyzed. The manufacturers of recombinant human GH and PIO provided matching placebos that were indistinguishable from the active medications. Medication seals, labels, and containers were utilized in a uniform fashion to preserve the study blind." Comment: investigator‐assessed, laboratory indexes unlikely to induce bias by lack of blinding
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	High risk	Quote: "The last available postrandomization value obtained prior to a missing measurement was carried forward for the missing data." and "A total of 19 withdrew or were lost to follow‐up, and postrandomization measures of visceral fat and insulin sensitivity after a confirmed overnight fast were not obtained." Comment: reported and reasons explained, ITT‐analysis on participants finishing study, dropouts not included in analysis. 15.8% of placebo group were lost to follow‐up post‐randomisation (N = 3/19) and 31.8% in the pioglitazone group (N = 7/22).
Incomplete outcome data (attrition bias) incidence of T2DM	High risk	Quote: "The last available postrandomization value obtained prior to a missing measurement was carried forward for the missing data." and "A total of 19 withdrew or were lost to follow‐up, and postrandomization measures of visceral fat and insulin sensitivity after a confirmed overnight fast were not obtained." Comment: reported and reasons explained, ITT‐analysis on participants finishing the study, dropouts not included in analysis. 15.8% of placebo group were lost to follow‐up (N =3/19) and 31.8% in the pioglitazone group (N = 7/22).
Incomplete outcome data (attrition bias) measures of blood glucose control	High risk	Quote: "The last available postrandomization value obtained prior to a missing measurement was carried forward for the missing data." and "A total of 19 withdrew or were lost to follow‐up, and postrandomization measures of visceral fat and insulin sensitivity after a confirmed overnight fast were not obtained." Comment: reported and reasons explained, ITT‐analysis on participants finishing the study, dropouts not included in analysis. 15.8% of placebo group were lost to follow‐up (N = 3/19) and 31.8% in the pioglitazone group (N = 7/22)
Incomplete outcome data (attrition bias) non‐serious adverse events	High risk	Quote: "The last available postrandomization value obtained prior to a missing measurement was carried forward for the missing data." and "A total of 19 withdrew or were lost to follow‐up, and postrandomization measures of visceral fat and insulin sensitivity after a confirmed overnight fast were not obtained." Comment: reported and reasons explained, ITT‐analysis on participants finishing the study, dropouts not included in analysis. 15.8% of placebo group were lost to follow‐up (N = 3/19) and 31.8% in the pioglitazone group (N = 7/22).
Incomplete outcome data (attrition bias) serious adverse events	High risk	Quote: "The last available postrandomization value obtained prior to a missing measurement was carried forward for the missing data." and "A total of 19 withdrew or were lost to follow‐up, and postrandomization measures of visceral fat and insulin sensitivity after a confirmed overnight fast were not obtained." Comment: reported and reasons explained, ITT‐analysis on participants finishing the study, dropouts not included in analysis. 15.8% of placebo group were lost to follow‐up (N = 3/19) and 31.8% in the pioglitazone group (N = 7/22).
Incomplete outcome data (attrition bias) time to progression to T2DM	High risk	Quote: "The last available postrandomization value obtained prior to a missing measurement was carried forward for the missing data." and "A total of 19 withdrew or were lost to follow‐up, and postrandomization measures of visceral fat and insulin sensitivity after a confirmed overnight fast were not obtained." Comment: reported and reasons explained, ITT‐analysis on participants finishing the study, dropouts not included in analysis. 15.8% of placebo group were lost to follow‐up (N = 3/19) and 31.8% in the pioglitazone group (N = 7/22).
Selective reporting (reporting bias)	Low risk	Quote: "During follow‐up, no significant change in ALT was seen in any group (unpublished data)." and "Although lipid testing was not prespecified in the protocol, measurement of lipids was performed using available stored serum samples" Comment: not of special interest in this review. Measures of blood glucose control (fasting blood glucose and 2‐h blood glucose) reported in a way not available for meta‐analysis in this review, but still analysed completely.
Other bias	Unclear risk	Quote: "In addition to unrestricted grants from the Genentech Center for Clinical Research in Endocrinology and Pfizer Pharmaceuticals, the study was supported by an F‐32 National Research Service Award from the National Institutes of Health (NIH) for Hamdee Attallah and by the Research Service of the Department of Veterans Affairs. None of the funding sources (Genentech, Pfizer, or the NIH) were involved in designing the protocol or in providing statistical support or in gathering or analysing data. In addition, the companies were not involved in the preparation of the manuscript or the decision to submit it for publication." Comment: study funded by pharmaceutical companies

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Bone 2013.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG or IGT, female, age ≤ 70 years, no menses for at least 5 years, BMI ≥ 16 and ≤ 40 kg/m² and weight < 136 kg, agreeing to take daily supplements of vitamin D and calcium during the trial, clinical laboratory evaluations normal deemed by a physician at screening Exclusion criteria: fasting triglyceride level > 500 mg/dL; haemoglobinopathy causing anaemia or interfering with HbA1c assays; ALT ≥ 2.5 times the upper limit of normal or active liver disease; jaundice; vitamin D (25‐OH‐D) < 20 ng/mL; BMD with T‐score < −2.0 at the total hip, spine, or femoral neck based on white reference values; unexplained haematuria confirmed by repeated testing; following disorders: rheumatoid arthritis, thyroid, parathyroid, pituitary, nutritional, inflammatory, gastrointestinal, autoimmune, renal, diseases known to affect bone metabolism; history of kidney stones; clinical history of wrist, hip, or leg fractures after age 45; history of > 1 asymptomatic vertebral deformity or any vertebral deformity attributed to osteoporosis; history of drug abuse; history of alcohol abuse within 2 years of screening; signs and/or symptoms of heart failure; taking any of the protocol‐specified excluded medication; not capable of understanding and/or complying with protocol requirements; unable to understand the approved consent form; currently participating in another investigational study or had participated in an investigational study within the past 30 days or 5 half lives of the investigational product; other serious condition making it difficult to follow protocol; history of cancer, other than basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin that had not been in remission for ≥ 5 years; taking or ever had taken pioglitazone hydrochloride or other thiazolidinediones; study site employees or immediate family member of a study site employee; received or donated blood or blood products within 30 days preceding the screening visit or planned to donate blood during the study Diagnostic criteria^a: IFG = FPG ≥ 5.6 mmol/L and < 7 mmol/L or IGT = 2‐h glucose ≥ 7.8 and ≤ 11.1 mmol/L Setting: outpatient Age group: adults/elderly Gender distribution: women Country/countries where study was performed: USA
Interventions	Intervention(s): pioglitazone 45 mg/day, increased from 30 mg/day after 4 weeks (N = 78) Comparator(s): placebo in matching doses (N = 78) Duration of intervention: 12 months Duration of follow‐up: 18 months Run‐in period: no run‐in period Number of study centres: 31
Outcomes	Reported outcome(s) in full text of publication: DXA‐scans measures, conversion to T2DM, FPG, HbA1c, FFA, C‐peptide, adiponectin, inflammatory markers, IGF, estradiol
Study details	Trial identifier: NCT00708175 Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: English Funding: commercial funding: Takeda Global Research and Development Center Publication status: peer‐reviewed journal
Stated aim for study	Quote: "We designed the present study to further investigate the potential effects of pioglitazone on BMD and markers of bone remodeling after longer‐term (12 months) treatment"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Eligible participants were randomly assigned in a 1:1 ratio to receive either pioglitazone 30 mg or matching placebo once daily (QD), increased to 45 mg QD after 1 month, according to a computer‐generated randomization schedule with no stratification (block size of four)." Comment: randomisation sequence adequately described
Allocation concealment (selection bias)	Low risk	Quote: "...according to a computer‐generated randomization schedule with no stratification (block size of four)." Comment: allocation concealment adequately described
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Quote: "Twenty‐five sites (in the United States) enrolled participants in this randomized, double‐blind, placebo‐controlled study." Comment: investigator‐assessed, mortality unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Quote: "This randomized, double‐blind, placebo‐controlled, multicenter study enrolled participants at 25 sites in the United States." Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Quote: "This randomized, double‐blind, placebo‐controlled, multicenter study enrolled participants at 25 sites in the United States." Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) non‐fatal myocardial infarction/stroke/congestive heart failure	Low risk	Quote: "AEs of special interest were all suspected or confirmed bone fractures; these events were adjudicated by an independent Clinical Adjudication Committee in a blinded manner." and Comment: adjudicated, no events reported
Blinding of participants and personnel (performance bias) non‐serious adverse events	Low risk	Quote: "Twenty‐five sites (in the United States) enrolled participants in this randomized, double‐blind, placebo‐controlled study." Comment: blinding described
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Quote: "AEs of special interest were all suspected or confirmed bone fractures; these events were adjudicated by an independent Clinical Adjudication Committee in a blinded manner." Comment: adjudicated
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Quote: "Twenty‐five sites (in the United States) enrolled participants in this randomized, double‐blind, placebo‐controlled study." Comment: investigator‐assessed, mortality unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Quote: "This randomized, double‐blind, placebo‐controlled, multicenter study enrolled participants at 25 sites in the United States." Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) non‐fatal myocardial infarction/stroke/congestive heart failure	Low risk	Quote: "AEs of special interest were all suspected or confirmed bone fractures; these events were adjudicated by an independent Clinical Adjudication Committee in a blinded manner." Comment: adjudicated blinded
Blinding of outcome assessment (detection bias) non‐serious adverse events	Low risk	Quote: "This randomized, double‐blind, placebo‐controlled, multicenter study enrolled participants at 25 sites in the United States." Comment: mode assessment not specified, unlikely to induce bias based on lack of blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Quote: "AEs of special interest were all suspected or confirmed bone fractures; these events were adjudicated by an independent Clinical Adjudication Committee in a blinded manner." Comment: independently adjudicated, not likely to induce bias
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	Unclear risk	Quote: "The safety analysis set and the full analysis set both consisted of all participants who were randomly assigned and took at least one dose of study drug." Comment: not clear whether dropouts were followed for mortality status
Incomplete outcome data (attrition bias) incidence of T2DM	High risk	Quote: "Overall, 117 women (75.0%) completed the study: 57 women in the pioglitazone group (73.1%) and 60 in the placebo group (76.9%)" and "All prespecified analyses were performed using observed values only." Comment: reported and reasons explained, no statistical evaluation regarding participants not completing study. Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. Reasons for discontinuation due to AEs 6.4% (N = 5/78) in pioglitazone versus 5.1% (N = 4/78) in placebo group, due to BMD loss > 7% was 3.8% in pioglitazone group (N = 3/78) versus 2.6% in placebo group (N = 2/78). The proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in the intervention effect estimate.
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Quote: "Overall, 117 women (75.0%) completed the study: 57 women in the pioglitazone group (73.1%) and 60 in the placebo group (76.9%)" and "All prespecified analyses were performed using observed values only." Comment: reported and reasons explained, no statistical evaluation regarding participants not completing study. Missing outcome data balanced in numbers across groups, with similar reasons for missing data. Reasons for discontinuation due to AEs 6.4% (N = 5/78) in pioglitazone versus 5.1% (N = 4/78) in placebo group, due to BMD loss > 7% was 3.8% in pioglitazone group (N = 3/78) versus 2.6% in placebo group (N = 2/78). High dropout, but plausible effect size (mean difference or standardised mean difference) among missing outcomes not likely enough to induce clinically relevant bias in observed effect size
Incomplete outcome data (attrition bias) non‐fatal myocardial infarction/stroke/congestive heart failure	High risk	Quote: "Overall, 117 women (75.0%) completed the study: 57 women in the pioglitazone group (73.1%) and 60 in the placebo group (76.9%)" and "All prespecified analyses were performed using observed values only." Comment: high dropout, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in the intervention effect estimate.
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Quote: "The safety analysis set and the full analysis set both consisted of all participants who were randomly assigned and took at least one dose of study drug." and "Overall, 117 women (75.0%) completed the study: 57 women in the pioglitazone group (73.1%) and 60 in the placebo group (76.9%)" Comment: high dropout, but the proportion of missing outcomes compared with observed events risk not enough to induce clinically relevant bias in the intervention effect estimate
Incomplete outcome data (attrition bias) serious adverse events	Unclear risk	Quote: "The safety analysis set and the full analysis set both consisted of all participants who were randomly assigned and took at least one dose of study drug." Comment: not clear whether dropouts were followed for SAEs
Selective reporting (reporting bias)	Unclear risk	Comment: clinicaltrials.gov only lists change in BMD in proximal femur by DXA at 12 months and change in BMD in proximal femur by DXA at 18 months as outcomes. These were reported as prespecified. Full‐length protocol was not available. Study did not report on events of hypoglycaemia, which we expected.
Other bias	Unclear risk	Quote: "Twenty‐five sites (in the United States) enrolled participants in this randomized, double‐blind, placebo‐controlled study." Comment: 31 sites screened and 25 sites enrolled 156 participants. No information regarding enrolment at different sites, and the distribution of incomplete data among sites. Quote: "This work (financial support for the conduct of this study and for data analysis) was supported by Takeda Global Research and Development Center, Inc (Deerfield, Illinois)." Comment: funded by a pharmaceutical company

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Che 2014.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT, hypertension Exclusion criteria: none reported Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L; hypertension not defined Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): L‐amlodipine 5 mg/day plus pioglitazone 30 mg/day Comparator(s): L‐amlodipine 5 mg/day Duration of intervention: 6 months Duration of follow‐up: 6 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, HbA1c, FPG, 2‐h glucose, blood pressure
Study details	Trial identifier: none Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not specified Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe the effect of pioglitazone dispersible tablets on glucose tolerance of essential hypertension"
Notes	No report on dropouts or loss to follow‐up No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: no reporting on missing data or handling of missing data
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: no reporting on missing data or handling of missing data
Selective reporting (reporting bias)	High risk	Comment: no protocol available, study does not report on SAEs or non‐serious AEs which are likely to have been assessed
Other bias	Unclear risk	Comment: no reporting on funding. No report on dropouts or loss to follow‐up

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Chen 2007a.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT, age > 25 years Exclusion criteria: hyperthyroidism, hypercortisolaemia, acromegaly, chronic pancreatitis, secondary diabetes, fever, acute infection, trauma, surgery, other stress factors Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): comparator 1: acarbose 150 mg/day plus BCI comparator 2: metformin 750 mg/day plus BCI comparator 3: exercise plus BCI comparator 4: no intervention Duration of intervention: 1 year Duration of follow‐up: 1 year Run‐in period: none reported Number of study centres: not specified
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, FINS, BMI, non‐serious AEs, insulin sensitivity index, conversion to NGT
Study details	Trial identifier: none reported Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not reported Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To compare the effect of pharmacological and non‐pharmacological intervention on the incidence of diabetes in impaired glucose tolerance (IGT) patients and observe the effect of pioglitazone on IGT patients"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators, non‐serious adverse are likely to induce bias because lack of blinding
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Comment: no blinding of participants or investigators, SAEs are unlikely to induce bias because lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors, non‐serious adverse are likely to induce bias because lack of blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Comment: no blinding of outcome assessors, SAEs are unlikely to induce bias because lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	High risk	Comment: no imputation or evaluation of missing data was performed. No dropout in pioglitazone, intensive BCI or no intervention arms. Dropout of 8 % (N = 4/50) in both metformin and acarbose groups. Dropout likely to induce bias in comparison of pioglitazone with other glucose‐lowering drugs.
Incomplete outcome data (attrition bias) measures of blood glucose control	High risk	Comment: no imputation or evaluation of missing data was performed. No dropout in pioglitazone, intensive BCI or no intervention arms. Dropout of 8 % (N = 4/50) in both metformin and acarbose groups. Dropout likely to induce bias in comparison of pioglitazone with other glucose‐lowering drugs.
Incomplete outcome data (attrition bias) non‐serious adverse events	High risk	Comment: no imputation or evaluation of missing data was performed. No dropout in pioglitazone, intensive BCI or no intervention arms. Dropout of 8 % (N = 4/50) in both metformin and acarbose groups. Dropout likely to induce bias in comparison of pioglitazone with other glucose‐lowering drugs.
Incomplete outcome data (attrition bias) serious adverse events	High risk	Comment: no imputation or evaluation of missing data was performed. No dropout in pioglitazone, intensive BCI or no intervention arms. Dropout of 8 % (N = 4/50) in both metformin and acarbose groups. Dropout likely to induce bias in comparison of pioglitazone with other glucose‐lowering drugs.
Selective reporting (reporting bias)	High risk	Comment: outcomes in the scope of this review were not reported or reported insufficiently (measures of blood glucose control and AEs)
Other bias	Unclear risk	Comment: no reporting on funding

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Chen 2007b.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT, hypertension Exclusion criteria: none reported Diagnostic criteria: hypertension: prior hypertension diagnosis, taking antihypertensive drugs, systolic ≥ 140 mmHg and diastolic ≥ 90 mmHg; IGT not defined Setting: outpatients Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day, captopril 50 mg/day, Betaloc 50 mg/day Comparator(s): captopril 50 mg/day, Betaloc 50 mg/day Duration of intervention: 2 years Duration of follow‐up: 2 years Run‐in period: none reported Number of study centres: not reported
Outcomes	Reported outcome(s) in full text of publication: all‐cause mortality, incidence of T2DM, coronary heart disease, blood pressure, insuline resistance, TG, 2‐h glucose, FINS, 2hINS, SAEs, non‐serious AEs, BMI, blood lipids
Study details	Trial identifier: none Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not specified Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To investigate the therapeutic effect of pioglitazone on patients with essential hypertension with glucose tolerance disorder (IGT), in order to explore whether it can reduce blood pressure, delay type 2 diabetes and cardiovascular disease while increasing insulin sensitivity"
Notes	Secondary reference Gong 2018 with identical population and results. None of the publications lists a link to each other. 80 participants randomised to the control group. Study reports 4 deaths and 2 lost to follow‐up and reports 73 finishing study. The last participant is not accounted for
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of participants or investigators described, mortality status is unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, AEs are likely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Comment: no blinding of participants or investigators described, SAEs are unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of outcome assessors, mortality is unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors described, AEs are likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Comment: no blinding of outcome assessors described, SAEs are unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	High risk	Comment: no imputation or evaluation of missing data was performed. Dropout in pioglitazone group of 5.7% (N = 83/88) compared with 8.7% in no‐intervention group (N = 73/80), reasons for dropout not explained.
Incomplete outcome data (attrition bias) incidence of T2DM	High risk	Comment: no imputation or evaluation of missing data was performed. Dropout in pioglitazone group of 5.7% (N = 83/88) compared with 8.7% in no‐intervention group (N = 73/80), reasons for dropout not explained.
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: no imputation or evaluation of missing data was performed. Dropout in pioglitazone group of 5.7% (N = 83/88) compared with 8.7% in no‐intervention group (N = 73/80), reasons for dropout not explained.
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: no imputation or evaluation of missing data was performed. Dropout in pioglitazone group of 5.7% (N = 83/88) compared with 8.7% in no‐intervention group (N = 73/80), reasons for dropout not explained.
Incomplete outcome data (attrition bias) serious adverse events	Unclear risk	Comment: no imputation or evaluation of missing data was performed. Dropout in pioglitazone group of 5.7% (N = 83/88) compared with 8.7% in no‐intervention group (N = 73/80), reasons for dropout not explained.
Selective reporting (reporting bias)	High risk	Comment: outcomes in the scope of this review were not reported or reported insufficiently (SAEs and non‐serious AEs and measures of blood glucose). Protocol not available. Study does not account for all randomised participants, see notes
Other bias	Unclear risk	Comment: no reporting on funding. Identical results and population as Gong 2018 (listed as secondary reference). No mention of cross referencing of publications.

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Deng 2013.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: age > 18 years, IGT or IFG, have > 1 risk factor for development of T2DM, BMI ≥ 25 kg/m² Exclusion criteria: none reported Diagnostic criteria: IFG = FPG > 5.3 mmol/L and < 6.9 mmol/L, IGT = 2‐h glucose > 7.8 mmol/L and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 30 mg/day plus BCI Comparator(s): BCI Duration of intervention: median of 2.5 years, mean of 2.2 years Duration of follow‐up: median of 2.5 years, mean of 2.2 years Run‐in period: none reported Number of study centres: not reported
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, time to progression to T2DM, non‐serious AE, SAE, insulin resistance, FPG, HbA1c, BMI, conversion to NGT, blood lipids
Study details	Trial identifier: none reported Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not specified Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe the effect of pioglitazone on the prevention of conversion to type 2 diabetes in patients with impaired glucose tolerance"
Notes	Study reports number of participants experiencing oedema with different values in different sections of publication No report on dropouts or loss to follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of participants or investigators described, mortality status is unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators, non‐serious AEs are likely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Comment: no blinding of participants or investigators, SAEs are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of outcome assessors described, mortality status is unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors, non‐serious AEs are likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Comment: no blinding of outcome assessors, SAEs are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	Unclear risk	Comment: no report on missing data
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: no report on missing data
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: no report on missing data
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: no report on missing data
Incomplete outcome data (attrition bias) serious adverse events	Unclear risk	Comment: no report on missing data
Selective reporting (reporting bias)	High risk	Comment: outcomes in the scope of this review were not reported or reported insufficiently (measures of blood glucose control and AEs)
Other bias	Unclear risk	Comment: no reporting on funding. No report on dropouts or loss to follow‐up

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Fang 2013.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG or IGT or IFG and IGT, age 40‐70 years, blood pressure < 160/95 mmHg, hypertensive drugs used unchanged within last month Exclusion criteria: secondary reason for elevated blood glucose; severe cerebrovascular or cardiovascular disease; gastrointestinal disease; abnormal liver function; use of blood glucose‐altering drugs within last 2 months; history of family bladder malignancy; pregnancy or currently lactating; mental disorders; deemed ineligible by study physicians Diagnostic criteria: IFG = FPG > 5.3 mmol/L and < 6.9 mmol/L, IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 12 months Duration of follow‐up: 12 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, FINS, HbA1c, HOMA‐IR, SAEs, non‐serious AEs, conversion to NGT, liver and kidney function, TC, TG, HDL, LDL, BUN, Cr, ALT, AST
Study details	Trial identifier: none reported Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: non‐commercial: Pudong New Area Health Bureau of Shanghai Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To observe the efficacy and safety of pioglitazone for the intervention therapy of impaired glucose regulation"
Notes	Statistical variation on continuous data not clearly explained. Interpreted variation for HbA1c measurements as SEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of participants or investigators described, mortality status is unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators, non‐serious AEs are likely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Comment: no blinding of participants or investigators, SAEs are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of outcome assessors described, mortality status is unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors, non‐serious AEs are likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Comment: no blinding of outcome assessors, SAEs are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	Unclear risk	Comment: no imputation or evaluation of missing data was performed. Dropout was 8.3% (N = 5/60) in the pioglitazone group compared with 6,7% (N = 4/60) in the control group. Reasons for dropout not explained. Unclear whether dropout could affect effect estimate
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: no imputation or evaluation of missing data was performed. Dropout was 8.3% (N = 5/60) in the pioglitazone group compared with 6,7% (N = 4/60) in the control group. Reasons for dropout not explained. Unclear whether dropout could affect effect estimate
Incomplete outcome data (attrition bias) measures of blood glucose control	Low risk	Comment: no imputation or evaluation of missing data was performed. Dropout was 8.3% (N = 5/60) in the pioglitazone group compared with 6,7% (N = 4/60) in the control group. Reasons for dropout not explained. Unclear whether dropout could affect effect estimate
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: no imputation or evaluation of missing data was performed. Dropout was 8.3% (N = 5/60) in the pioglitazone group compared with 6,7% (N = 4/60) in the control group. Reasons for dropout not explained. Unclear whether dropout could affect effect estimate
Incomplete outcome data (attrition bias) serious adverse events	Unclear risk	Comment: no imputation or evaluation of missing data was performed. Dropout was 8.3% (N = 5/60) in the pioglitazone group compared with 6,7% (N = 4/60) in the control group. Reasons for dropout not explained. Unclear whether dropout could affect effect estimate
Selective reporting (reporting bias)	High risk	Comment: outcomes in the scope of this review were not reported or reported insufficiently (measures of blood glucose and all‐cause mortality)

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Gao 2011.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT, hypertension Exclusion criteria: none described Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L; hypertension = prior diagnosis of hypertension, in pharmacological treatment for hypertension or blood pressure > 140/90 mmHg Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 30 mg/day, antihypertensive drugs (captopril and other)^b plus BCI Comparator(s): antihypertensive drugs (captopril and others)^b plus BCI Duration of intervention: 18 months Duration of follow‐up: 18 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, cardiovascular disease, cerebrovascular disease, non‐serious AEs, SAEs, blood pressure, TG, 2‐h glucose, FINS, 2hINS, insulin sensitivity, liver proteins
Study details	Trial identifier: none reported Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not reported Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To observe and assess the curative effect of Pioglitazone for treating hypertension with impaired glucose tolerance"
Notes	Publication does not list the dosages and kind of antihypertensive drugs used (besides captopril). Does state that the medication was identical in both intervention and comparator groups
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of participants or investigators described, mortality status is unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding, open‐label study
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Comment: no blinding, open‐label study. SAEs are unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Comment: no blinding of outcome assessors described, mortality status is unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors, non‐serious AEs are likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Comment: no blinding of outcome assessors, SAEs are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	Unclear risk	Comment: no imputation or evaluation of missing data was performed
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: no imputation or evaluation of missing data was performed
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: no imputation or evaluation of missing data was performed
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: no imputation or evaluation of missing data was performed.
Incomplete outcome data (attrition bias) serious adverse events	Unclear risk	Comment: no imputation or evaluation of missing data was performed
Selective reporting (reporting bias)	High risk	Comment: outcomes with relevance of this review were not reported or reported insufficiently (mortality, SAEs and non‐serious AEs, measures of blood glucose)
Other bias	Unclear risk	Comment: no details on funding

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Guo 2009.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: elderly, IGT Exclusion criteria: blood pressure < 150/90 mmHg; smoking; creatinine > 115 mmol/L; vascular disease; liver disease; severe infectious disease; heart failure Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 mmol/L and < 11.0 mmol/L Setting: outpatient Age group: elderly people Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 30 mg/day plus BCI Comparator(s): BCI Duration of intervention: 6 months Duration of follow‐up: 6 months Run‐in period: none reported Number of study centres: not reported
Outcomes	Reported outcome(s) in full text of publication: FPG, 2‐h glucose, HbA1c, endothelium‐dependent dilation, hsCRP, HOMA‐IR, fasting insulin, insulin sensitivity, blood lipids
Study details	Trial identifier: none available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not reported Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To investigate the effects of pioglitazone on endothelial function in elderly patients with impaired glucose tolerance (IGT)"
Notes	No report on dropouts or loss to follow‐up. No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available, trial does not report key outcomes for review as AEs and incidence of T2DM
Other bias	Unclear risk	Comment: no details on funding. No report on dropouts or loss to follow‐up

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Guo 2010.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: older individuals with IGT, blood pressure < 150/90 mmHg, creatinine < 115 mmol/L, not smoking or given up smoking for > 5 years Exclusion criteria: blood disease; liver insufficiency; severe infectious diseases; heart failure Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 mmol/L and < 11.0 mmol/L Setting: hospital Age group: elderly people Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 30 mg/day plus BCI Comparator(s): BCI Duration of intervention: 12 months Duration of follow‐up: 12 months Run‐in period: not reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: blood lipids, FPG, 2‐h glucose, HbA1c, hsCRP, HOMA‐IR, CIMT
Study details	Trial identifier: not reported Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not reported Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To investigate the effects of pioglitazone on carotid atherosclerosis in old‐aged impaired glucose tolerance (IGT) patient"
Notes	No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available, study does not report outcomes that are likely to have been assessed (such as AEs and incidence of T2DM), which are in the scope for this review
Other bias	Unclear risk	Comment: did not report on AEs

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Han 2007.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT, hypertension Exclusion criteria: secondary hypertension; diabetes; liver or kidney disease Diagnostic criteria: hypertension > 140/90 mmHg; IFG = FPG < 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 mmol/L and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus enalapril (dose not reported) Comparator(s): enalapril (dose not reported) Duration of intervention: 24 weeks Duration of follow‐up: 24 weeks Run‐in period: none reported Number of study centres: not reported
Outcomes	Reported outcome(s) in full text of publication: FPG, 2‐h glucose, non‐serious AEs, fasting insulin, insulin sensitivity, BMI, blood lipids
Study details	Trial identifier: none available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not reported Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe the effects of pioglitazone hydrochloride on glucose metabolism, insulin sensitivity, lipid metabolism and body mass index in patients with essential hypertension (EH) and IGT"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, AEs are likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors described, non‐serious AEs are likely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available, study does not report on incidence of T2DM, which is a key outcome for this review
Other bias	Unclear risk	Comment: did not report on funding

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IDPP‐2.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT, age 35‐55 years Exclusion criteria: known coronary artery disease; history of stroke; major Q wave abnormalities; liver disorders; kidney disorders Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 mmol/L and 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: India
Interventions	Intervention(s): pioglitazone 15 mg/day for 6 months, titrated to 30 mg/day for the next 30 months. 10 participants were titrated up to 45 mg/day plus BCI Comparator(s): placebo in matching doses plus BCI Duration of intervention: 36 months Duration of follow‐up: 36 months Run‐in period: no run‐in period Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, HbA1c, cholesterol, blood pressure
Study details	Trial identifier: NCT00276497 Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: English Funding: non‐commercial funding: India Diabetes Research Foundation Publication status: peer‐reviewed journal
Stated aim for study	Quote: "The objective oft his prevention programme was to study whether combining pioglitazone with lifestyle modification would enhance the efficacy of lifestyle modification in preventing type 2 diabetes in Asian Indians with impaired glucose tolerance"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants with persistent IGT were assigned to group A (tablet A) and B (tablet B) in sequential order." Comment: randomisation sequence adequately described. Inadequate sequence generation. Groups appear similar at baseline for all important prognostic variables
Allocation concealment (selection bias)	Low risk	Quote: "Participants with persistent IGT were assigned to group A (tablet A) and B (tablet B) in sequential order." and "The bottles were labelled with the individually alloted number and participants name" Comment: allocation concealment not adequately described. Groups appear similar at baseline for all important prognostic variables
Blinding of participants and personnel (performance bias) all‐cause/cardiovascular mortality	Low risk	Quote: "The participants and investigators were blinded to the group allocation." and "The causes of death were verified from medical records and death certificates" Comment: adjudicated, mortality is unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) hypoglycaemia	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: mode of assessment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) non‐fatal myocardial infarction/stroke/congestive heart failure	Low risk	Quote: "Any serious adverse reactions or events were reviewed and appropriate remedial measures were taken by the internal safety committee, which comprised an administrator and a consultant physician." Comment: adjudicated, not likely to induce bias
Blinding of participants and personnel (performance bias) non‐serious adverse events	Low risk	Quote: "The participants and investigators were blinded to the group allocation." Comment: mode of assessment not adequately described
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Quote: "Any serious adverse reactions or events were reviewed and appropriate remedial measures were taken by the internal safety committee, which comprised an administrator and a consultant physician." Comment: adjudicated, not likely to induce bias
Blinding of participants and personnel (performance bias) time to progression to T2DM	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Quote: "The participants and investigators were blinded to the group allocation." and "The causes of death were verified from medical records and death certificates" Comment: adjudicated, mortality is unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) hypoglycaemia	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: mode of assessment not described
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) non‐fatal myocardial infarction/stroke/congestive heart failure	Low risk	Quote: "Any serious adverse reactions or events were reviewed and appropriate remedial measures were taken by the internal safety committee, which comprised an administrator and a consultant physician." Comment: adjudicated, not likely to induce bias by lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	Unclear risk	Comment: mode of assessment not adequately described
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Quote: "Any serious adverse reactions or events were reviewed and appropriate remedial measures were taken by the internal safety committee, which comprised an administrator and a consultant physician." Comment: adjudicated, not likely to induce bias by lack of blinding
Blinding of outcome assessment (detection bias) time to progression to T2DM	Low risk	Quote: "The participants and investigators were blinded to the group allocation" Comment: investigator‐assessed, laboratory indexes are unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (N = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Incomplete outcome data (attrition bias) hypoglycaemia	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (N = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (N = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (N = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Incomplete outcome data (attrition bias) non‐fatal myocardial infarction/stroke/congestive heart failure	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (N = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (N = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Incomplete outcome data (attrition bias) serious adverse events	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (n = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Incomplete outcome data (attrition bias) time to progression to T2DM	Unclear risk	Quote: "At year 3, the overall response rate was 90.2% (N = 367): 88.7% (N = 181) in the pioglitazone group and 91.6% (n = 186) in the placebo group." Comment: reasons for missing data and ways of handling missing data not described. Dropout similar across groups, reasons for dropout not reported.
Selective reporting (reporting bias)	Low risk	Comment: protocol only lists 3 outcomes. These 3 outcomes are all addressed.
Other bias	Unclear risk	Quote: "The dose was increased to 45 mg/day in ten participants in each group. In both groups, more than 60% complained of giddiness or weakness. Hence, the 30 mg/day dose was continued." Comment: not likely to induce bias

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Ke 2006.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT Exclusion criteria: not reported Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 12 months Duration of follow‐up: 12 months Run‐in period: none reported Number of study centres: not reported
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, HbA1c, non‐serious AE, BMI, C‐peptide, blood lipids, conversion to NGT
Study details	Trial identifier: none available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not specified Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To observe the therapeutic effect of pioglitazone hydrochloride on impaired glucose tolerance (IGT)"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, AEs are likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors described, AEs are likely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: details on missing data or handling of missing data not reported. Dropout of 6.2% (N = 2/32) participants in the pioglitazone group and 6.7% (N = 2/30) in the comparator group, reasons not explained
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: details on missing data or handling of missing data not reported. Dropout of 6.2% (N = 2/32) participants in the pioglitazone group and 6.7% (N = 2/30) in the comparator group, reasons not explained
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: details on missing data or handling of missing data not reported. Dropout of 6.2% (N = 2/32) participants in the pioglitazone group and 6.7% (N = 2/30) in the comparator group, reasons not explained
Selective reporting (reporting bias)	High risk	Comment: no protocol available, trial does not report key outcomes for review (SAEs and non‐serious AEs, mortality)
Other bias	Unclear risk	Comment: funding not reported

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Li 2017.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT Exclusion criteria: thyroid, heart, liver, kidney or heart disease; secondary reason for intermediate hyperglycaemia Diagnostic criteria: not reported Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 6 months Duration of follow‐up: 6 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, HbA1c, blood lipids, fasting insulin, non‐serious AEs, conversion to NGT
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not specified Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To explore the value of pioglitazone in the treatment of patients with impaired glucose tolerance (IGT)"
Notes	No report on dropouts or loss to follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomisation by random alphabet method
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, AEs are likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors described, AEs are likely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: handling of missing data not reported, dropout of 2 among 75 participants in intervention group versus 3 among 75 participants in control group (2.7% vs 4%). Reasons for dropout not explained. Unclear whether dropout could affect effect estimate.
Incomplete outcome data (attrition bias) measures of blood glucose control	Low risk	Comment: handling of missing data not reported, dropout of 2 among 75 participants in intervention group versus 3 among 75 participants in control group (2.7% vs 4%). Reasons for dropout not explained. Unlikely dropout could affect effect estimate.
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: handling of missing data not reported, dropout of 2 among 75 participants in intervention group versus 3 among 75 participants in control group (2.7% vs 4%). Reasons for dropout not explained. Unclear whether dropout could affect effect estimate.
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on hypoglycaemia or mortality, which are key outcomes for this review and we had expected for this kind of study
Other bias	Unclear risk	Comment: funding not reported. No report on dropouts or loss to follow‐up

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Liang 2004.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT, age 25‐60 years Exclusion criteria: none Diagnostic criteria: IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 12 months Duration of follow‐up: 12 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, HbA1c, blood lipids, FINS, BMI, non‐serious AEs, conversion to NGT
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not reported Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To investigate the interventive effect of pioglitazone hydrochloride on the subjects with impaired glucose tolerance (IGT)"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomisation sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) hypoglycaemia	Unclear risk	Comment: no blinding of outcome assessors described, definition or assessment of hypoglycaemia not defined
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, AEs are likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) hypoglycaemia	Unclear risk	Comment: no blinding of outcome assessors described, definition or assessment of hypoglycaemia not defined
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors described, non‐serious AEs are likely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) hypoglycaemia	Unclear risk	Comment: handling of missing data not described, drop out of 0 among 30 participants in intervention group versus 1 among 30 participants in control group (0% vs 3.3%) reason for dropout not explained. Unclear whether dropout could affect effect estimate
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: handling of missing data not described, drop out of 0 among 30 participants in intervention group versus 1 among 30 participants in control group (0% vs 3.3%) reason for dropout not explained. Unclear whether dropout could affect effect estimate
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: handling of missing data not described, drop out of 0 among 30 participants in intervention group versus 1 among 30 participants in control group (0% vs 3.3%) reason for dropout not explained. Unclear whether dropout could affect effect estimate
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: handling of missing data not described, drop out of 0 among 30 participants in intervention group versus 1 among 30 participants in control group (0% vs 3.3%) reason for dropout not explained. Unclear whether dropout could affect effect estimate
Selective reporting (reporting bias)	Unclear risk	Comment: no protocol available
Other bias	Unclear risk	Comment: funding not reported

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Shi 2014.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and/or IGT Exclusion criteria: known diabetes; severe heart, liver or kidney disease; prior usage of glucocorticoids in large doses; pregnancy; women breastfeeding Diagnostic criteria: IFG = FPG > 5.6 mmol/L and < 6.9 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 30 mg/day plus BCI Comparator(s): placebo in matching doses plus BCI Duration of intervention: 10 months Duration of follow‐up: 10 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: FPG, 2‐h glucose, HbA1c, incidence of T2DM
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not reported Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To observe the therapeutic effect of pioglitazone on patients with impaired fasting glucose regulation and impaired glucose tolerance in pre‐diabetes"
Notes	No report on dropouts or loss to follow‐up. No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomisation sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: missing data or handling of these not reported
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of these not reported
Selective reporting (reporting bias)	High risk	Comment: no protocol available. No reporting on SAEs and non‐serious AEs or mortality, which we expected for this type of study
Other bias	Unclear risk	Comment: funding not reported. No report on dropouts or loss to follow‐up

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Tian 2015.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: prediabetes (not defined) Exclusion criteria: medical disease; mental disease; allergy; secondary reason for elevated blood glucose Diagnostic criteria: IFG = FPG < 6.1 and > 7.0 mmol/L; IGT = 2‐h glucose ≥ 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 24 weeks Duration of follow‐up: 24 weeks Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: CRP, FPG, 2‐h glucose, HOMA‐IR, conversion to NGT
Study details	Trial identifier: none available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no report on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To investigate the effect of pioglitazone treatment in pre‐diabetes and its improvement on C‐reactive protein (CRP)"
Notes	No report on dropouts or loss to follow‐up No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on incidence of T2DM, SAEs and non‐serious AEs, which we expected for this kind of study
Other bias	Unclear risk	Comment: funding not reported. No report on dropouts or loss to follow‐up

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Wu 2013.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT, age > 65 years, essential hypertension Exclusion criteria: liver disease; hypertensive crisis; secondary hypertension; multi‐organ failure; mental disorders; diabetes; cardial or renal insufficiency Diagnostic criteria: IFG = FPG > 5.6 and < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: inpatient Age group: elderly people Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 30 mg/day plus amlodipine 5 mg/day and valsartan 80 mg/day plus BCI Comparator(s): amlodipine 5 mg/day and valsartan 80 mg/day plus BCI Duration of intervention: 6 months Duration of follow‐up: 6 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, HbA1c, blood lipids, blood pressure, NT‐proBNP
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: non‐commercial funding: Science and Technology Project of Wuhan Municipal Health Bureau Publication status: peer‐reviewed journal
Stated aim for study	Quote: "To observe the effect of pioglitazone on blood glucose, blood lipid, dynamic pulse pressure index (PPI) and Effects of arteriosclerosis index (ASI) and plasma amino‐terminal brain natriuretic peptide precursor (NT‐proBNP)"
Notes	No report on dropouts or loss to follow‐up. No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: missing data or handling of missing data not described
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on SAEs and non‐serious AEs, which we had expected for this type of study
Other bias	Unclear risk	Comment: no report on dropouts or loss to follow‐up

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Xiu 2015.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT Exclusion criteria: secondary hyperglycaemia; severe heart, liver or kidney disease; other major disease; taking glucose‐lowering drugs within last 3 months prior to randomisation Diagnostic criteria: IFG = FPG < 6.1 and > 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 48 weeks Duration of follow‐up: 48 weeks Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, CRP, insulin resistance, BMI, conversion to NGT
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: not specified Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe the effect of pioglitazone on the treatment of prediabetic patients and the effect of C reactive protein"
Notes	No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on SAEs and non‐serious AEs even though they are prespecified in methods section
Other bias	Unclear risk	Comment: does not report on funding

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Xu 2011.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT after 1 month of lifestyle intervention Exclusion criteria: secondary reasons for elevated blood glucose; microvascular complications; severe heart, liver or kidney disease; other serious organic disease Diagnostic criteria: IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: elderly people Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 30 mg/day plus BCI Comparator(s): placebo in matching doses plus BCI Duration of intervention: 12 months Duration of follow‐up: 12 months Run‐in period: 1 month Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, BMI, blood pressure, FPG, 2‐h glucose, FINS, HOMA‐IR, measures of insulin, blood lipids, conversion to NGT
Study details	Trial identifier: none available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no report on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe the therapeutic effect of pioglitazone on patients with impaired glucose tolerance"
Notes	No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on SAEs and non‐serious AEs even though they are prespecified in methods section
Other bias	Unclear risk	Comment: does not report on funding

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Yi 2015.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT Exclusion criteria: secondary hyperglycaemia; heart, liver or kidney disease; use of glucose‐lowering drugs within last 3 months prior to randomisation Diagnostic criteria: IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 1 year Duration of follow‐up: 1 year Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, CRP, HOMA‐IR, conversion to NGT
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no details on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To analyze and explore the effect of pioglitazone on pre‐diabetic patients and the effect of C‐reactive protein (CRP)"
Notes	No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: missing data or handling of missing data not described
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on SAEs and non‐serious AEs
Other bias	Unclear risk	Comment: does not report on funding

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Yu 2011.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT Exclusion criteria: diabetes; acute or chronic pancreatitis; severe heart, lung, liver or kidney disease; use of glucose‐altering drugs; hyperthyroid disease; acute or chronic pancreatitis; recent infection; recent trauma Diagnostic criteria: IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 4 mg/day plus BCI Comparator(s): BCI Duration of intervention: 6 months Duration of follow‐up: 6 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, CRP, blood lipids, blood cholesterol, endothelin, fibrinogen, BMI, conversion to NGT
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no details on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe the changes of plasma endothelin (ET), C‐reactive protein (CRP) and fibrinogen (Fg) in IGT patients before and after pioglitazone intervention"
Notes	Participants in both groups experienced extreme weight reduction during 6‐month intervention period. No report on dropouts or loss to follow‐up. No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not adequately described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: missing data or handling of missing data not described
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on SAEs and non‐serious AEs
Other bias	Unclear risk	Comment: does not report on funding. No report on dropouts or loss to follow‐up

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Zeng 2013.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IGT Exclusion criteria: liver or kidney disease; cardiovascular disease; cerebrovascular disease Diagnostic criteria: IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 38 mg/day plus BCI metformin 38 mg/day plus BCI Comparator(s): lifestyle modifications (BCI) Duration of intervention: 24 months Duration of follow‐up: 24 months Run‐in period: no run‐in period reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, FINS, BMI, blood pressure, conversion to NGT
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no details on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To explore the clinical effects of different intervention methods in impaired glucose regulation (IGR) population"
Notes	No report on AEs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: random sequence was generated using random number table
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: missing data or handling of missing data not described
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on SAEs and non‐serious AEs
Other bias	Unclear risk	Comment: does not report on funding

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Zhang 2007.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT Exclusion criteria: secondary reasons for elevated blood glucose; recent history of glucocorticoid usage; heart, liver, kidney disease Diagnostic criteria: IFG = FPG > 5.6 and < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI metformin 250 mg/day plus BCI repaglinide 0.75 mg/day plus BCI intensive BCI Comparator(s): BCI Duration of intervention: 12 months Duration of follow‐up: 12 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, HbA1c, BMI, FINS, HOMA‐IR, conversion to NGT, SAEs, non‐serious AEs, blood lipids, blood cholesterol, blood pressure, serum superoxide dismutase
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no details on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To evaluate the effects of pharmacological and non‐pharmacological interventions on patients with impaired glucose regulation (IGR)"
Notes	Study states dropout in analysis of conversion to T2DM. All other analyses indicate ITT‐population (all randomised participants) according to tables. Study does list all participants as part of analysis for other outcomes. Publication text does not evaluate handling of the participants lost to follow up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, non‐serious AEs likely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Comment: no blinding, open‐label study, SAEs are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors described, non‐serious AEs likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Comment: no blinding of outcome assessors described, SAEs are unlikely to induce bias because lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Low risk	Comment: the number of participants in the tables indicate only participants finishing study in analysis for incidence of T2DM. Dropout in pioglitazone group was 7.7% (N = 4/52), metformin group 7.5% (N = 5/53), repaglinide 5.9% (N = 3/51), intensive lifestyle modifications 5.9% (N = 3/51) and control group 3.6% (N = 2/56). Reasons not explained, dropout is < 10% and comparable among the groups
Incomplete outcome data (attrition bias) measures of blood glucose control	Low risk	Comment: handling of missing data or imputation not described. Number of participants in analysis unclear. Dropout in pioglitazone group was 7.7% (N = 4/52), metformin group 7.5% (N = 5/53), repaglinide 5.9% (N = 3/51), intensive lifestyle modifications 5.9% (N = 3/51) and control group 3.6% (N = 2/56). Reasons not explained, dropout is < 10% and comparable among the groups
Incomplete outcome data (attrition bias) non‐serious adverse events	Low risk	Comment: handling of missing data or imputation not described. Number of participants in analysis unclear. Dropout in pioglitazone group was 7.7% (N = 4/52), metformin group 7.5% (N = 5/53), repaglinide 5.9% (N = 3/51), intensive lifestyle modifications 5.9% (N = 3/51) and control group 3.6% (N = 2/56). Reasons not explained, dropout is < 10% and comparable among the groups
Incomplete outcome data (attrition bias) serious adverse events	Low risk	Comment: handling of missing data or imputation not described. Number of participants in analysis unclear. Dropout in pioglitazone group was 7.7% (N = 4/52), metformin group 7.5% (N = 5/53), repaglinide 5.9% (N = 3/51), intensive lifestyle modifications 5.9% (N = 3/51) and control group 3.6% (N = 2/56). Reasons not explained, dropout is < 10% and comparable among the groups
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on all‐cause mortality or events of hypoglycaemia
Other bias	Unclear risk	Comment: does not report on funding

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Zhang 2015.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG, IGT, or IFG and IGT Exclusion criteria: — Diagnostic criteria: IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 6 months Duration of follow‐up: 6 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: incidence of T2DM, FPG, 2‐h glucose, blood pressure, SAEs, non‐serious AEs, conversion to NGT, blood lipids, liver enzymes
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no details on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe and analyze the clinical effects of pioglitazone hydrochloride intervention therapy on impaired glucose regulation"
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, non‐serious AEs likely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Comment: no blinding, open‐label study. SAEs are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of outcome assessors described, non‐serious AEs are likely to induce bias because of the lack of blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Comment: no blinding of outcome assessors described. SAEs are likely to induce bias because of the lack of blinding
Incomplete outcome data (attrition bias) incidence of T2DM	Unclear risk	Comment: statistical handling of missing data not described. There were no dropouts in the pioglitazone group and 1 (3.8%) in the control group (N = 1/26). Dropout could affect the effect estimate
Incomplete outcome data (attrition bias) measures of blood glucose control	Low risk	Comment: statistical handling of missing data not described. There were no dropouts in the pioglitazone group and 1 (3.8%) in the control group (N = 1/26). Dropout not likely to affect effect estimate
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: statistical handling of missing data not described. There were no dropouts in the pioglitazone group and 1 (3.8%) in the control group (N = 1/26). Dropout could affect effect estimate
Incomplete outcome data (attrition bias) serious adverse events	Unclear risk	Comment: statistical handling of missing data not described. There were no dropouts in the pioglitazone group and 1 (3.8%) in the control group (N = 1/26). Dropout could affect effect estimate
Selective reporting (reporting bias)	Unclear risk	Comment: no protocol available
Other bias	Unclear risk	Comment: does not report on funding

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Zhao 2009.

*Study characteristics*
Methods	Study design: parallel RCT
Participants	Inclusion criteria: IFG and IGT Exclusion criteria: heart or lung disease; abnormal liver and kidney function Diagnostic criteria: IFG = FPG > 6.1 and < 7.0 mmol/L; IGT = 2‐h glucose > 7.8 and < 11.1 mmol/L Setting: outpatient Age group: adults Gender distribution: men and women Country/countries where study was performed: China
Interventions	Intervention(s): pioglitazone 15 mg/day plus BCI Comparator(s): BCI Duration of intervention: 6 months Duration of follow‐up: 6 months Run‐in period: none reported Number of study centres: 1
Outcomes	Reported outcome(s) in full text of publication: FPG, 2‐h glucose, blood pressure, SAEs, non‐serious AEs, blood lipids, HOMA‐IR
Study details	Trial identifier: not available Study terminated early (for benefit/because of AEs): no
Publication details	Language of publication: Chinese Funding: no details on funding Publication status: peer‐reviewed journal
Stated aim for study	Quote (translated): "To observe the effect of lifestyle adjustment plus pioglitazone on the intervention of patients with impaired glucose tolerance"
Notes	No report on dropouts or loss to follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Comment: no blinding of participants or investigators described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of participants and personnel (performance bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, non‐serious AEs likely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Comment: no blinding of outcome assessors described, laboratory indexes are unlikely to induce bias because of lack of blinding
Blinding of outcome assessment (detection bias) non‐serious adverse events	High risk	Comment: no blinding of participants or investigators described, non‐serious AEs likely to induce bias because of lack of blinding
Incomplete outcome data (attrition bias) measures of blood glucose control	Unclear risk	Comment: missing data or handling of missing data not described
Incomplete outcome data (attrition bias) non‐serious adverse events	Unclear risk	Comment: missing data or handling of missing data not described
Selective reporting (reporting bias)	High risk	Comment: no protocol available. Study does not report on incidence of T2DM even though measures of blood glucose control is an outcome for the study.
Other bias	Unclear risk	Comment: does not report on funding. No report on dropouts or losses to follow‐up

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Note: where the judgement is 'Unclear' and the description is blank, the study did not report that particular outcome.

^aUnit of measurement for glucose reported as mg/dL. Values converted to mmol/L by dividing by 18. ^bStudy reports use of captopril and other unspecified antihypertensive drugs. Doses or which drugs used is not further specified. Study reports that the antihypertensive drugs are identical in both groups.

2hINS: 2‐hour post oral glucose tolerance test insulin; 2‐h glucose: 2‐hour post oral glucose tolerance test glucose; AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AV: atrioventricular; BCI: behaviour‐changing intervention; BMD: bone mineral density; BMI: body mass index; BUN: blood urea nitrogen; CIMT: carotid intima‐media thickness test; CRP: C‐reactive protein; DXA: dual‐energy X‐ray absorptiometry; FFA: free fatty acids; FINS: fasting insulin; FPG: fasting plasma glucose; GH: growth hormone; HbA1c: glycosylated haemoglobin A1c; HDL: high‐density lipoprotein; HOMA‐IR: homeostatic model assessment of insulin resistance; hsCRP: high sensitivity C‐reactive protein; IFG: impaired fasting glucose; IGF: insulin‐like growth factor; IGT: impaired glucose tolerance; IS: insulin sensitivity; ITT: intention‐to‐treat; LBBB: left bundle branch block; LDL: low‐density lipoprotein; NGT: normal glucose tolerance; NT‐proBNP: N‐terminal pro B‐type Natriuretic Peptide; NYHA: New York Heart Association; OGTT: oral glucose tolerance test; PCOS: polycystic ovary syndrome; PIO: pioglitazone; PP: per‐protocol; RCT: randomised controlled trial; SAE: serious adverse event; SE: standard error; T2DM: type 2 diabetes; TC: total cholesterol; TG: total glycerides; TSH: thyroid stimulating hormone; VAT: visceral adipose tissue; WC: waist circumference.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Belfort 2006	Wrong population (NASH as comorbidity)
ChiCTR‐TRC‐08000099	Wrong population (metabolic syndrome)
ChiCTR‐TRC‐08000111	Wrong population (metabolic syndrome)
Cusi 2016	Wrong population (NASH as comorbidity)
Durbin 2004	Wrong intervention (intervention with rosiglitazone which was changed to pioglitazone after a mean of 10 months after rosiglitazone intervention start)
EudraCT2005‐004421‐26	Wrong comparison (compares pioglitazone to simvastatin)
EudraCT2006‐002084‐49	Intervention < 24 weeks
IRIS 2016	Wrong population (prior stroke as comorbidity)
J‐SPIRIT 2015	Wrong population (prior stroke as comorbidity)
Karim 2016	Wrong comparison (compares pioglitazone to pentoxifylline)
Kawamori 1996	Not a RCT
Kobayashi 2005	Not a RCT
Lan 2012	Not a RCT
Li 2009	Wrong population (coronary heart disease as comorbidity)
Liu 2015	Intervention less than 24 weeks
Nam 2013	Wrong population (T2DM)
NCT00015626	Wrong population (T2DM)
NCT00306826	Wrong comparison and population (compares pioglitazone to simvastatin and includes people with T1DM and T2DM)
NCT00470262	Intervention < 24 weeks
NCT00633282	Intervention < 24 weeks
NCT00722631	Wrong population (T2DM)
NCT01006018	Terminated early, enrolled 3 participants
Norris 2007	Not a RCT
UMIN000001035	Wrong population (NASH as comorbidity)
Wu 2008	Wrong population (CHF as comorbidity)
Yang 2012	Wrong population (coronary atherosclerosis as comorbidity)
Yokoyama 2007	Wrong population (prior AMI as comorbidity)
Zhang 2014	Wrong population (T2DM)
Zhao 2011	Wrong population (coronary lesions as comorbidity)
Zhou 2006	Wrong comparison (compares metformin plus pioglitazone treatment with pioglitazone treatment)

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AMI: acute myocardial infarction; CHF: chronic heart failure; NASH: non‐alcoholic steatohepatitis; RCT: randomised controlled trial; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus.

Characteristics of ongoing studies [ordered by study ID]

Beijing prediabetes reversion programme (BPRP).

Study name	Beijing prediabetes reversion programme
Methods	Type of trial: efficacy trial Allocation: randomised Intervention model: 2 x 2 factorial assignment Masking: double‐blinded Primary purpose: treatment
Participants	Condition: prediabetes Enrollment: 1954 Inclusion criteria: voluntary participation and signing participant’s informed consent form, prediabetic patients, age 25‐70 years, 22 kg/m² ≤ BMI < 35 kg/m² Exclusion criteria: diabetes; previous use of hypoglycaemic agents (except gestational diabetes); coronary heart disease; NYHA III‐IV; LBBB, 3rd‐degree AV‐block; severe arrhythmia; uncontrolled hypertension; severe cardiovascular or cerebrovascular disease; severe pulmonary diseases; recent or major abdominal surgery; gastrointestinal diseases; liver disease or ALT/AST 2.5 times upper limit of normal range; urological diseases; anaemia; thyroid disease; endocrine disease; fasting triglycerides > 6.77 mmol/L; cancer; physical function disease; tuberculosis or in treatment for tuberculosis; allergy to pioglitazone or its components; pregnant or breastfeeding; planning pregnancy during trial; newly major weight loss; use of drugs including loop diuretics, thiazides, β‐receptor blocker, nicotinic acid, systemic glucocorticoids, weight‐reducing agents (including last 3 months); member of household entering study, or member of household from staff member of study; travel plans or other limitations deemed unable to follow study protocol by principal investigator
Interventions	Intervention(s): pioglitazone 30 mg once daily plus conventional lifestyle intervention Comparator(s): placebo plus conventional lifestyle intervention
Outcomes	Primary outcome(s): conversion to T2DM, blood glucose metabolism Secondary outcome measure(s): incidence of cardiovascular and cerebrovascular disease, all‐cause mortality, hypertension, blood lipids, fasting insulin, hsCRP, adiponectin, glucose regulation after wash‐out, incidence of metabolic syndrome, body weight and waistline, safety issues Other outcome(s): — Relevant proposed outcome measures for SoF table: conversion to T2DM, cardiovascular disease and cerebrovascular disease, all‐cause mortality, safety issues
Starting date	Trial start date: March 2007 Trial completion date: March 2011
Contact information	Responsible party/principal investigator: Ji Linong, +86 010 88324108, jlin@bjmu.edu.cn
Study identifier	Trial identifier: ChiCTR-PRC-06000005
Official title	Pre‐diabetes reversion program in Beijing
Stated purpose of study	Quote: "The study hypothesis was that intensive lifestyle intervention and/or pioglitazone 30 mg/day would increase the conversion rate of patients with prediabetes to normal glycaemia, compared to conventional lifestyle intervention only"
Notes

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NCT02969798.

Study name	Pre‐diabetes in subject with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)
Methods	Type of trial: efficacy trial Allocation: randomised Intervention model: parallel assignment Masking: open‐label Primary purpose: treatment
Participants	Condition: IGT, IFG or IGT and IFG Enrollment: estimated 700 Inclusion criteria: protocol not available as of 17 February 2020 Exclusion criteria: protocol not available as of 17 February 2020
Interventions	Intervention(s): dapagliflozin 10 mg once daily, saxagliptin 5 mg once daily, pioglitazone 15 mg once daily increased to 30 mg once daily after 2 months, metformin 1000 mg once daily increased to 2000 mg once daily after 2 months Comparator(s): placebo
Outcomes	Primary outcome(s): beta cell function, insulin sensitivity, glucose tolerance status Secondary outcome(s): — Other outcome(s): — Relevant proposed outcome measures for SoF table: none
Starting date	Trial start date: January 2014 Trial completion date: July 2022
Contact information	Responsible party/principal investigator: Ralph A DeFronzo, 210‐567‐6691, defronzo@uthscsa.edu
Study identifier	NCT number: NCT02969798
Official title	Preservation of beta cell function in pre‐diabetes in subject with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)
Stated purpose of study	Quote: "To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with isolated impaired glucose tolerance (IGT): (i) treatment with the renal Sodium‐glucose co‐transporter 2 (SGLT2) inhibitor inhibitor, dapagliflozin; (ii) treatment with the inhibitors of dipeptidyl peptidase 4, also DPP4, saxagliptin ; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin. To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with isolated impaired fasting glucose (IFG): (i) treatment with the renal SGLT2 inhibitor, dapagliflozin; (ii) treatment with the DPP4 inhibitor, saxagliptin; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin. To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with combined impaired glucose tolerance (IGT) plus impaired fasting glucose (IFG): i) treatment with the renal SGLT2 inhibitor, dapagliflozin; (ii) treatment with the DPP4 inhibitor, saxagliptin; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin"
Notes	Study will compare 4 interventions groups to healthy NGT participants by matching. This comparison not relevant for this review. Comparison between the different intervention groups will be of interest for this review.

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ALT: alanine aminotransferase; AST: aspartate aminotransferase; AV: atrioventricular; BCI: behaviour‐changing intervention; BMI: body mass index; hsCRP: high sensitivity C‐reactive protein; IFG: impaired fasting glucose; IGT: impaired glucose tolerance; LBBB: left bundle branch block; NGT: normal glucose tolerance; NYHA: New York Heart Association; SoF: 'Summary of findings'; T2DM: type 2 diabetes.

Differences between protocol and review

We added the following Chinese databases to our electronic searches:

China Network Knowledge Infrastructure (CNKI) (www.cnki.net)
Chinese Scientific Journals Database (VIP) (www.cqvip.com)
Wan Fang data (www.wanfangdata.com.cn/index.html)
SinoMed (www.sinomed.ac.cn)

Abstract screening was done independently by authors EI and BH instead of BR and BH.

YC was added as an author. For the Chinese databases, YC developed the search strategy, screened abstracts/titles and acquired Chinese studies. EI and YC independently extracted data from Chinese studies.

Contributions of authors

All review authors contributed to, read and approved the final review draft.

Emil Ørskov Ipsen (EI): acquiring study reports, study selection, data extraction, data analysis, data interpretation, review drafts and will be involved in future review updates

Kasper Staberg Madsen (KM): study selection, data extraction and review of drafts

Yuan Chi (YC): Chinese search strategy development, acquiring Chinese study reports, Chinese study selection, Chinese study data extraction and review of drafts

Ulrik Pedersen‐Bjergaard (UP): review of drafts

Bernd Richter (BR): protocol, search strategy development, data analysis, data interpretation and review of drafts

Maria‐Inti Metzendorf (MIM): search strategy development and review of drafts

Bianca Hemmingsen (BH): protocol, search strategy development, study selection, data extraction, data analysis, data interpretation, review of drafts

Declarations of interest

Emil Ørskov Ipsen (EI): had an inadvertent conflict of interest because he had owned a small number of shares with Novo Nordisk A/S before registering the title. Without prompting EI amended the situation by selling the shares on 11 June 2019. The Cochrane Metabolic and Endocrine Disorders group contacted the Cochrane Funding Arbiter for guidance, who agreed to allow the review to proceed with EI as a first author, providing that this issue was clearly explained in the declarations of interest. EI also received a students allowance from the Danish government. The allowance is granted for every full‐time student at universities regardless of field of studies or topic of the master thesis. The review was written as part of his masters' thesis.

Kasper Madsen (KM): none known

Yuan Chi (YC): none known

Ulrik Pedersen‐Bjerregaard (UP): has served on advisory panels for Novo Nordisk and Sanofi Aventis and his institution received an unrestricted research grant from Novo Nordisk.

Bernd Richter (BR): none known

Maria‐Inti Metzendorf (MIM): none known

Bianca Hemmingsen (BH): none known

New

References

References to studies included in this review

ACT NOW {published data only}

Alonzo R, Chavez-Velazquez A, Martinez R, Velez-Garza J, Carreon M, Musi N, et al. Increase in serum fibroblast growth factor-21 (FGF-21) predicts development of diabetes in IGT subjects and pioglitazone attenuates the increase in FGF-21 and reduces conversion of IGT to T2DM. Diabetes 2016;65:A482. [DOI: 10.2337/db16-1771-2041] [DOI] [Google Scholar]
Anonymous. Pioglitazone reduces the risk of converting impaired glucose tolerance to type 2 diabetes. Australian Journal of Pharmacy 2011;92(1095):82. [Google Scholar]
Bray GA, Smith SR, Banerji MA, Tripathy D, Clement SC, Buchanan TA, et al. Effect of pioglitazone on body composition and bone density in subjects with prediabetes in the ACT NOW trial. Diabetes, Obesity & Metabolism 2013;15(10):931-7. [DOI: 10.1111/dom.12099] [DOI] [PubMed] [Google Scholar]
Defronzo RA, Banerji M, Bray GA, Buchanan TA, Clement S, Henry RR, et al. Actos now for the prevention of diabetes (ACT NOW) study. BMC Endocrine Disorders 2009;9:17. [DOI] [PMC free article] [PubMed] [Google Scholar]
Defronzo RA, Tripathy D, Abdul-Ghani M, Musi N, Gastaldelli A. The disposition index does not reflect beta-cell function in IGT subjects treated with pioglitazone. Journal of Clinical Endocrinology and Metabolism 2014;99(10):3774-81. [DOI: 10.1210/jc.2014-1515] [DOI] [PubMed] [Google Scholar]
DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. New England Journal of Medicine 2011;364(12):1104-15. [DOI: 10.1056/NEJMoa1010949] [DOI] [PubMed] [Google Scholar]
Defronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates. Diabetes 2013;62(11):3920-6. [EMBASE: 10.2337/db13-0265] [DOI] [PMC free article] [PubMed] [Google Scholar]
Espinoza S, Wang C, Reaven P, DeFronzo R, Tripathy D, Musi N. Pioglitazone is equally effective for preventing diabetes in older compared to younger pre-diabetic adults. Journal of the American Geriatrics Society 2015;63:S100. [DOI: 10.1111/jgs.13439] [DOI] [Google Scholar]
Espinoza S, Wang CP, Clement S, Schwenke D, Banerjee MA, Bray G, et al. Pioglitazone is equally effective for diabetes prevention in older compared with younger prediabetic adults. Diabetes 2015;64:A308-9. [DOI: 10.2337/db159321471] [DOI] [Google Scholar]
Espinoza SE, Wang CP, Tripathy D, Clement SC, Schwenke DC, Banerji MA, et al. Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance. Age 2016;38(5-6):485-93. [DOI: 10.1007/s11357-016-9946-6] [DOI] [PMC free article] [PubMed] [Google Scholar]
Gall W, Musi N, DeFronzo R, Tripathy D. Novel index of insulin sensitivity from fasting biomarkers: validation in the ACT NOW study. Diabetologia 2012;55:S234. [DOI: 10.1007/s00125-012-2688-9] [DOI] [Google Scholar]
Gastaldelli A, Tripathy D, Gaggini M, Musi N, DeFronzo RA. Improvement in hepatic metabolism is associated with reduced conversion to diabetes in IGT subjects treated with pioglitazone (ACT NOW study). Diabetologia 2015;58 Suppl1 1:S164. [DOI: 10.1007/s00125-015-3687-4] [DOI] [Google Scholar]
Gastaldelli A, Tripathy D, Gall W, DeFronzo RA. Pioglitazone decreases hepatic insulin resistance index and improves hepatic metabolic biomarkers in IGT subjects: the ACTNOW study. Diabetologia 2012;55 Suppl 1:S234. [DOI: 10.1007/s00125-012-2688-9] [DOI] [Google Scholar]
Hu X, Reaven P, Saremi A, Liu H, et al, ACT NOW Study Investigators. Machine learning to predict rapid progression of carotid atherosclerosis in patients with impaired glucose tolerance. EURASIP Journal on Bioinformatics and Systems Biology 2016;2016:14. [DOI] [PMC free article] [PubMed] [Google Scholar]
NCT00220961. Actos now for prevention of diabetes (ACT NOW). clinicaltrials.gov/show/NCT00220961 (first received January 2004).
Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, et al. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arteriosclerosis, Thrombosis, and Vascular Biology 2013;33(2):393-9. [DOI: 10.1161/ATVBAHA.112.300346] [DOI] [PMC free article] [PubMed] [Google Scholar]
Tripathy D, Alonzo RP, Chavez-Velazquez A, Martinez R, Musi N, Defronzo R. Fibroblast growth factor-21 (FGF-21) predicts development of diabetes and pioglitazone attenuates the increase in FGF-21 in subjects with IGT: results from the ACTNOW study. Diabetologia 2016;59(1):S164. [DOI: 10.1007/s00125-016-4046-9] [DOI] [Google Scholar]
Tripathy D, Banerji MA, Bray GA, Buchanan TA, Clement S, Henry RR, et al. Effect of pioglitazone on beta cell function in impaired glucose tolerance: results form ACTNOW. https://professional.diabetes.org/abstract/effect-pioglitazone-beta-cell-function-impaired-glucose-tolerance-results-form-actnow (assessed 11 November 2020).
Tripathy D, Banerji MA, Bray GA, Buchanan TA, Clement S, Henry RR, et al. Pioglitazone improves adipocyte insulin resistance in subjects with impaired glucose tolerance: results from ACT NOW. https://professional.diabetes.org/abstract/pioglitazone-improves-adipocyte-insulin-resistance-subjects-impaired-glucose-tolerance (accessed 11 November 2020).
Tripathy D, Clement SC, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Baseline adiponectin levels do not influence the response to pioglitazone in ACT NOW. Diabetes Care 2014;37(6):1706-11. [DOI: 10.2337/dc13-1745] [DOI] [PMC free article] [PubMed] [Google Scholar]
Tripathy D, Cobb JE, Gall W, Adam KP, George T, Schwenke DC, et al. A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study. Journal of Clinical Endocrinology and Metabolism 2015;100(5):1855-62. [DOI: 10.1210/jc.2014-3824] [DOI] [PMC free article] [PubMed] [Google Scholar]
Tripathy D, Gall W, Adam KP, Schwenke D, Gastaldelli A, Musi N, et al. Pioglitazone improves insulin sensitivity by modulating novel biomarkers in impaired glucose tolerance. Diabetes 2012;61:A305. [DOI: 10.2337/db12-836-1328] [DOI] [Google Scholar]
Tripathy D, Gall WE, Adam KP, Schwenke DC, Banerji M, Bray GA, et al. Pioglitazone improves insulin sensitivity by modulating novel biomarkers: results from the ACTNOW study. Diabetologia 2011;54 Suppl 1:S30. [DOI: 10.1007/s00125-011-2276-4] [DOI] [Google Scholar]
Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Diabetes incidence and glucose tolerance 1 year after termination of pioglitazone therapy: Results from ACT now. Diabetes 2014;63:A292. [DOI: 10.2337/db14-833-1316] [DOI] [PMC free article] [PubMed] [Google Scholar]
Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Diabetes incidence and glucose tolerance after termination of pioglitazone therapy: results from ACT NOW. Journal of Clinical Endocrinology and Metabolism 2016;101(5):2056-62. [DOI: 10.1210/jc.2015-4202] [DOI] [PMC free article] [PubMed] [Google Scholar]
Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Effect of pioglitazone on adipocytokines and insulin sensitivity in subjects with impaired glucose tolerance: results from ACT now. Diabetes 2011;60:A435. [DOI: 10.2337/db11-1487-1624] [DOI] [Google Scholar]
Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Inadequate plasma adiponectin response characterises nonresponsiveness to pioglitazone in individuals with impaired glucose tolerance: results from the ACT NOW study. Diabetologia 2013;56 Suppl 1:S106. [DOI: 10.1007/s00125-013-3012-z] [DOI] [Google Scholar]
Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Reduced beta cell function and inadequate rise in plasma adiponectin characterizes non-responsiveness to pioglitazone in individuals with impaired glucose tolerance in ACT NOW. Diabetes 2013;62:A277. [DOI: 10.2337/db13-859-1394] [DOI] [Google Scholar]
Velez-Garza JA, Giuseppe DA, Alonzo R, Martinez R, Bruder J, Musi N, et al. Pioglitazone does not modulate plasma sclerostin levels in subjects with impaired glucose tolerance (IGT): results from the ACT NOW study. Diabetes. Conference: 76th scientific sessions of the American Diabetes Association, ADA 2016. United states 2016;65 Suppl 1:A291-2. [DOI: 10.2337/db16-861-1374] [DOI] [Google Scholar]

Attallah 2007 {published data only}

Attallah H, Friedlander AL, Nino-Murcia M, Hoffman AR. Effects of growth hormone and pioglitazone in viscerally obese adults with impaired glucose tolerance: a factorial clinical trial. PLoS Clinical Trials 2007;2(5):e21. [EMBASE: 10.1371/journal.pctr.0020021] [DOI] [PMC free article] [PubMed] [Google Scholar]
NCT00352287. Study to determine the effects of human growth hormone and pioglitazone in overweight, prediabetic adults [Effects of GH and pioglitazone in viscerally obese adults with IGT]. clinicaltrials.gov/show/NCT00352287 (first received 14 July 2006).

Bone 2013 {published data only}

Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Spanheimer RG. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism 2013;98(12):4691-701. [DOI: 10.1210/jc.2012-4096] [DOI] [PubMed] [Google Scholar]
NCT00708175. Efficacy of pioglitazone on bone metabolism in postmenopausal women with impaired fasting glucose [A phase 4, randomized, double-blind, placebo-controlled study to evaluate the effect of pioglitazone compared to placebo on bone metabolism in impaired fasting glucose, postmenopausal women for one year of treatment]. clinicaltrials.gov/show/NCT00708175 (first received 2 July 2008).

Che 2014 {published data only}

Che CJ, Zhao QH. Clinical analysis of pioglitazone dispersible tablets in 38 patients with abnormal glucose tolerance in essential hypertension [吡格列酮分散片对原发性高血压糖耐量异常38例临床分析]. Journal of Medical Theory and Practice [医学理论与实践] 2014;(17):2290-1. [Google Scholar]

Chen 2007a {published data only}

Chen JH, Wu JN, Su YR, Liu AY, Xu SZ, Huang XY. Intervention study on effects of pioglitazone on patients with impaired glucose tolerance [吡格列酮对糖耐量受损患者的干预治疗研究]. Hainan Medical Journal [海南医学] 2007;18(12):15-7. [DOI: 10.3969/j.issn.1003-6350.2007.12.009] [DOI] [Google Scholar]

Chen 2007b {published data only}

Chen RJ. Effect of pioglitazone on hypertension patients with abnormal glucose tolerance [吡格列酮对高血压合并糖耐量异常患者疗效观察]. Shenzhen Journal of Integrated Traditional Chinese and Western Medicine [深圳中西医结合杂志] 2007;17(6):379-80. [10.3969/j.issn.1007-0893.2007.06.017] [Google Scholar]
Gong XY. 吡格列酮在高血压病合并糖耐量异常患者中的应用. Chinese Journal of Clinical Medicine [中国现代临床医学] 2008;7(9):9-11. [Google Scholar]

Deng 2013 {published data only}

Deng CR, Fan HW. Pioglitazone prevents conversion to diabetes in patients with impaired glucose tolerance [吡格列酮预防糖耐量受损患者向糖尿病转化]. Guide of China Medicine [中国医药指南] 2013;11(10):205-7. [DOI: 10.3969/j.issn.1671-8194.2013.10.159] [DOI] [Google Scholar]

Fang 2013 {published data only}

Fang Q, Fang MX, Yao Y, Feng SY, Yang YP, Xue L, et al. Efficacy and safety of pioglitazone for intervention therapy of impaired glucose regulation [吡格列酮干预糖调节受损的疗效和安全性]. Journal of Clinical Research [医学临床研究] 2013;30(2):239-42. [DOI: 10.3969/j.issn.1671-7171.2013.02.012] [DOI] [Google Scholar]

Gao 2011 {published data only}

Gao WX. Curative effect analysis on pioglitazone for treating hypertension with impaired glucose tolerance [吡格列酮对高血压合并糖耐量异常的疗效分析]. Good Health for All [大家健康（中旬版）] 2011;5(5):2-4. [Google Scholar]

Guo 2009 {published data only}

Guo Y, Li W, Bao H, Fan CH, Zhang XW. Effect of pioglitazone on endothelial function in elderly patients with impaired glucose tolerance [吡格列酮对老年糖耐量低减患者内皮功能的影响]. Chinese Journal of New Drugs [中国新药杂志] 2009;18(24):2323-6. [Google Scholar]

Guo 2010 {published data only}

Guo Y, Bao H, Li W, Su L, Zhang QW, Miao YD. Effect of pioglitazone on carotid atherosclerosis in old-aged impaired glucose tolerance patients [吡格列酮对老年糖耐量低减患者颈动脉硬化的影响]. Chinese Pharmaceutical Journal [中国药学杂志] 2010;45(10):764-7. [Google Scholar]

Han 2007 {published data only}

Han SX. Efficacy of pioglitazone in patients with primary hypertension with impaired glucose tolerance [吡格列酮对原发性高血压伴糖耐量减低患者的疗效观察]. Hebei Medical Journal [河北医药] 2007;29(6):595. [DOI: 10.3969/j.issn.1002-7386.2007.06.040] [DOI] [Google Scholar]

IDPP‐2 {published data only}

NCT00276497. Role of pioglitazone in preventing diabetes. clinicaltrials.gov/show/NCT00276497 (first received 13 January 2006).
Ramachandran A, Arun N, Shetty AS, Snehalatha C. Efficacy of primary prevention interventions when fasting and postglucose dysglycemia coexist: analysis of the Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2). Diabetes Care 2010;33(10):2164-8. [DOI: 10.2337/dc09-1150] [DOI] [PMC free article] [PubMed] [Google Scholar]
Ramachandran A, Snehalatha C, Mary S, Selvam S, Kumar CK, Seeli AC, et al. Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian Diabetes Prevention Programme-2 (IDPP-2). Diabetologia 2009;52(6):1019-26. [DOI: 10.1007/s00125-009-1315-x] [DOI] [PubMed] [Google Scholar]

Ke 2006 {published data only}

Ke XH, Tang LH, Tan ML, Huang YZ. Results of intervention of subsidence of glucose tolerance by using rosiglitazone [糖耐量减退吡格列酮干预治疗的研究]. China Tropical Medicine [中国热带医学] 2006;6(9):1622-31. [DOI: 10.3969/j.issn.1009-9727.2006.09.047] [DOI] [Google Scholar]

Li 2017 {published data only}

Li Y. The value of pioglitazone in the treatment of patients with impaired glucose tolerance [吡格列酮在葡萄糖耐量受损患者治疗中应用的价值]. The Journal of Medical Theory and Practice [医学理论与实践] 2017;30(11):1609-11. [Google Scholar]

Liang 2004 {published data only}

Liang ZQ, Tang L. Observation on the interventive effect of pioglitazone hydrochloride on the IGT population of diabetes mellitus [盐酸吡格列酮干预治疗糖耐量减退的疗效观察]. Journal of Guangxi Medical University [广西医科大学学报] 2004;21(2):165-7. [DOI: 10.3969/j.issn.1005-930X.2004.02.004] [DOI] [Google Scholar]

Shi 2014 {published data only}

Shi J. Intervention of pioglitazone in the development of pre-diabetes [吡格列酮对糖尿病前期病情演变的干预]. Chinese Journal of Trauma and Disability Medicine [中国伤残医学] 2014;22(23):117. [DOI: 10.13214/j.cnki.cjotadm.2014.23.099] [DOI] [Google Scholar]

Tian 2015 {published data only}

Tian F. Effect of pioglitazone on the treatment effect and C-reactive protein of prediabetic patients [探讨吡格列酮对糖尿病前期患者的治疗效果及C反应蛋白的影响]. World Latest Medicine Information [世界最新医学信息文摘] 2015;15(24):131-2. [DOI: 10.3969/j.issn.1671-3141.2015.24.102] [DOI] [Google Scholar]

Wu 2013 {published data only}

Wu YX, Wu TY, Li XJ, Wang W, Zhang Q, Xiong HL, et al. Effects of pioglitazone on ambulatory pulse pressure index in patients with elderly essential hypertension and impaired glucose tolerance [吡格列酮对老年原发性高血压伴糖耐量异常患者动态脉压指数的影响]. Journal of Clinical Cardiology [临床心血管病杂志] 2013;29(6):443-5. [Google Scholar]

Xiu 2015 {published data only}

Xiu SL, Wang L. Effect of pioglitazone on intervention and C-reactive protein in prediabetic patients [吡格列酮对糖尿病前期患者的干预及C反应蛋白的影响]. Chinese Journal of Medicine [中国医刊] 2015;(1):65-7. [DOI: 10.3969/j.issn.1008-1070.2015.01.021] [DOI] [Google Scholar]

Xu 2011 {published data only}

Xu HS, Lei MX, Kong DM, Xiang H, Xie XY. Intervention of pioglitazone in patients with glucose tolerance disorder [吡格列酮对糖耐量异常患者的干预作用]. Chinese Journal of Gerontology [中国老年学杂志] 2011;31(14):2640-1. [DOI: 10.3969/j.issn.1005-9202.2011.14.013] [DOI] [Google Scholar]

Yi 2015 {published data only}

Yi FS, Li F, Shen LL, Li WJ. Effect of pioglitazone on the treatment effect and C-reactive protein of prediabetic patients [探讨吡格列酮对糖尿病前期患者的治疗效果及C反应蛋白的影响]. Journal of Frontiers of Medicine [医药前沿] 2015;(25):39-40. [DOI: 10.3969/j.issn.2095-1752.2015.25.038] [DOI] [Google Scholar]

Yu 2011 {published data only}

Yu XD, Qian ZM, Ge CL. Effects of pioglitazone on endothelin, C-reactive protein and fibrinogen in patients with impaired glucose tolerance [吡格列酮对糖耐量减低患者内皮素、C反应蛋白、纤维蛋白原的影响]. 中国医师进修杂志 [Chinese Journal of Postgraduates of Medicine] 2011;34(18):62-3. [Google Scholar]

Zeng 2013 {published data only}

Zeng ZH, Cai F, Qiu JF, Liu YQ, Zhou WZ, Weng LH. The effects of different interventions on impaired glucose regulation [糖调节受损人群不同干预方法的临床效果观察]. Health Research [健康研究] 2013;33(5):370-2, 375. [DOI: 10.3969/j.issn.1674-6449.2013.05.016] [DOI] [Google Scholar]

Zhang 2007 {published data only}

Zhang AH, Li PX, Cao WH, Wei AF, Huang LH. Clinical intervention in patients with IGR [糖调节受损者的临床干预研究]. Acta Academiae Medicinae Weifang [潍坊医学院学报] 2007;29(5):394-7. [Google Scholar]

Zhang 2015 {published data only}

Zhang FY, Zhao XJ, An YL. Study of pioglitazone intervention effect on impaired glucose regulation [盐酸吡格列酮对葡萄糖调节受损的干预治疗作用]. Journal of Shanxi Medical College for Continuing Education [山西职工医学院学报] 2015;25(1):9-11. [Google Scholar]

Zhao 2009 {published data only}

Zhao JK. Observation on the effect of pioglitazone intervention in the treatment of glucose tolerance reduction [吡格列酮干预治疗糖耐量减低疗效观察]. 中国实用乡村医生杂志 [Chinese Practical Journal of Rural Doctor] 2009;16(4):32-3. [DOI: 10.3969/j.issn.1672-7185.2009.04.018] [DOI] [Google Scholar]

References to studies excluded from this review

Belfort 2006 {published data only}

Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. New England Journal of Medicine 2006;355(22):2297-307. [DOI] [PubMed] [Google Scholar]
Serfaty L. Pioglitazone: the beginning of a new era for NASH? Journal of Hepatology 2007;47(1):160-2. [DOI: 10.1016/j.jhep.2007.03.002] [DOI] [PubMed] [Google Scholar]

ChiCTR‐TRC‐08000099 {published data only}

ChiCTR-TRC-08000099. Multicenter research of early intervention for adult metabolic syndrome in Beijing region. www.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-TRC-08000099 (first received 14 august 2008).

ChiCTR‐TRC‐08000111 {published data only}

ChiCTR-TRC-08000111. A multicenter study of effects of early prevention on adult metabolic syndrome in Beijing region. www.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-TRC-08000111 (first received 14 april 2008).

Cusi 2016 {published data only}

Anonymous. Pioglitazone for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes. Annals of Internal Medicine 2016;165(5):I15. [DOI: 10.7326/P16-9018] [DOI] [PubMed] [Google Scholar]
Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clinical Gastroenterology and Hepatology 2018;16(4):558-66. [DOI: 10.1016/j.cgh.2017.12.001] [DOI] [PubMed] [Google Scholar]
Bril F, Lomonaco R, Orsak B, Finch J, Ortiz-Lopez C, Darland C, et al. Safety of statin therapy in patients with prediabetes or T2DM and NASH: a long-term prospective study. Diabetes 2013;62:A164. [DOI: 10.2337/db13-388-679] [DOI] [Google Scholar]
Bril F, Lomonaco R, Orsak B, Hecht J, Ortiz-Lopez C, Hardies J. Predictors of response after extended pioglitazone treatment in patients with prediabetes or T2DM and nonalcoholic steatohepatitis (NASH). Hepatology (Baltimore, Md.) 2013;58(4 Suppl 1):513A-4A. [DOI: ] [Google Scholar]
Bril F, Lomonaco R, Orsak B, Hecht J, Tio F, Cusi K. Is treatment of nonalcoholic steatohepatitis with pioglitazone equally effective in patients with prediabetes compared with type 2 diabetes (T2DM)? American Diabetes Association 2017;66:A64. [Google Scholar]
Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Hecht J, Tio F, et al. Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial. Journal of Clinical Endocrinology and Metabolism 2017;102(8):2950–61. [DOI: 10.1210/jc.2017-00867] [DOI] [PMC free article] [PubMed] [Google Scholar]
Cases MM. Pioglitazone improves the biological and histological markers of nonalcoholic hepatic steatosis in patients with type 2 diabetes or glucose intolerance [Pioglitazona mejora los marcadores biológicos e histológicos de la esteatosis hepática no alcohólica en pacientes con diabetes tipo 2 o intolerancia a la glucosa]. FMC Formacion Medica continuada en Atencion Primaria 2007;14(5):285. [DOI: 10.1016/S1134-2072(07)71636-5] [DOI] [Google Scholar]
Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long- term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Annals of Internal Medicine 2016;165(5):305-15. [DOI: 10.7326/M15-1774] [DOI] [PubMed] [Google Scholar]
Cusi K, Orsak B, Lomonaco R, Bril F, Ortiz-Lopez C, Hecht J, et al. Extended treatment with pioglitazone improves liver histology in patients with prediabetes or type 2 diabetes mellitus and NASH. Hepatology (Baltimore, Md.) 2013;58(4):248A. [DOI: 10.1002/hep.26804] [DOI] [Google Scholar]
Cusi K, Orsak B, Lomonaco R, Finch J, Ortiz-Lopez C, Bril F, et al. Safety and efficacy of long-term pioglitazone treatment for patients with prediabetes or T2DM and NASH. Diabetes 2013;62:A309. [DOI: 10.2337/db13-859-1394] [DOI] [Google Scholar]
Kawaguchi-Suzuki M, Bril F, Cusi K, Langaee T, Gong Y, Frye R. Role of genetic polymorphisms on the improvement of liver histology after pioglitazone treatment in patients with nonalcoholic fatty liver disease (NAFLD). Hepatology (Baltimore, Md.) 2014;60:591A. [DOI: ] [Google Scholar]
Portillo-Sanchez P, Bril F, Lomonaco R, Barb D, Orsak B, Bruder JM, et al. Effect of pioglitazone on bone mineral density in patients with nonalcoholic steatohepatitis: a 36-month clinical trial. Journal of Diabetes 2019;11(3):223-31. [DOI: 10.1111/1753-0407.12833] [DOI] [PubMed] [Google Scholar]
Portillo Sanchez P, Bril F, Lomonaco R, Maximos M, Bruder J, Orsak B, et al. Effects of extended pioglitazone treatment (PIO) on bone metabolism in patients with prediabetes and type 2 diabetes mellitus (T2DM). Diabetes 2014;63:A293-4. [DOI: ] [Google Scholar]
Sunny N, Bril F, Kalavalapalli S, Sanchez PP, Maximos M, Biernacki D, et al. Pioglitazone therapy improves insulin suppression of branched chain amino acids in patients with prediabetes or T2DM and NAFLD. Diabetes 2015;64:A341. [DOI: ] [Google Scholar]

Durbin 2004 {published data only}

Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes, Obesity & Metabolism 2004;6(4):280-5. [DOI: 10.1111/j.1462-8902.2004.0348.x] [DOI] [PubMed] [Google Scholar]

EudraCT2005‐004421‐26 {published data only}

EudraCT2005-004421-26. Effect of pioglitazone on intima media thickness, endothelial function and heart rate variability in patients with impaired glucose tolerance. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-004421-26 (first received 18 July 2006).

EudraCT2006‐002084‐49 {published data only}

EudraCT2006-002084-49. Vascular function in impaired glucose tolerance - effect of pioglitazone. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-002084-49 (first received 13 September 2006).

IRIS 2016 {published data only}

Inzucchi SE, Viscoli CM, Young LH, Furie KL, Gorman M, Lovejoy A, et al. Diabetes prevention with pioglitazone in insulin resistant patients with cerebrovascular disease. American Diabetes Association 2016;Conference: 76th Scientific Sessions of the American Diabetes Association, ADA 2016. United States. 65(Suppl 1):A99. [Google Scholar]
Inzucchi SE, Viscoli CM, Young LH, Furie KL, Gorman M, Lovejoy AM, et al. Pioglitazone prevents diabetes in patients with insulin resistance and cerebrovascular disease. Diabetes Care 2016;39(10):1684-92. [DOI: 10.2337/dc16-0798] [DOI] [PMC free article] [PubMed] [Google Scholar]
Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. New England Journal of Medicine 2016;374(14):1321-31. [DOI: 10.1056/NEJMoa1506930] [DOI] [PMC free article] [PubMed] [Google Scholar]
Mayor S. Pioglitazone may reduce cardiovascular events in high risk patients with prediabetes. BMJ (Clinical Research Ed.) 2016;352:i1029. [DOI] [PubMed]
Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, et al. Correction: pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial (Journal of Physical Chemistry (2019). JAMA Neurology. [DOI: 10.1001/jamaneurol.2019.0475] [DOI] [PMC free article] [PubMed]
Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, et al. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurology 2019;76(5):526-35. [DOI] [PMC free article] [PubMed] [Google Scholar]
Treating insulin resistance in patient after stroke for prevention of stroke and myocardial infarction after ischemic stroke and transient ischemic attack. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2008-005546-23-DE.
Young LH, Viscoli CM, Schwartz GG, Inzucchi SE, Curtis JP, Gorman MJ, et al. Heart failure after ischemic stroke or transient ischemic attack in insulin-resistant patients without diabetes mellitus treated with pioglitazone. Circulation 2018;138(12):1210-20. [DOI] [PMC free article] [PubMed] [Google Scholar]

J‐SPIRIT 2015 {published data only}

Tanaka R, Okuma Y, Miyamoto N, Tanaka Y, Yamashiro K, Watada H, et al. Effects of pioglitazone in patients with impaired glucose tolerance after stroke; progress report from J-SPIRIT study. International Journal of Stroke 2010;5 Suppl 2:195.
Tanaka R, Yamashiro K, Okuma Y, Shimura H, Nakamura S, Ueno Y, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT study. Journal of Atherosclerosis and Thrombosis 2015;22(12):1305-16. [DOI] [PubMed] [Google Scholar]
Tanaka R, Yamashiro K, Tanaka Y, Miyamoto N, Ueno Y, Watanabe M, et al. Effects of pioglitazone in patients with abnormal glucose metabolism after stroke: the J-SPIRIT study. Cerebrovascular Diseases 2013;36 Suppl 2:32 (P59). [DOI: 10.1159/000356197] [DOI]
Tanaka R, Yamashiro K, Tanaka Y, Miyamoto N, Ueno Y, Watanabe M, et al. Effects of pioglitazone in patients with abnormal glucose metabolism after stroke. The J-SPIRIT study. Stroke; a Journal of Cerebral Circulation 2013;44(2):Abst.ATP416.
UMINR000015768. Juntendo the stroke prevention study in insulin resistance and impaired glucose tolerance (J-SPIRIT study). upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015768 (first received 1 December 2005).

Karim 2016 {published data only}

Karim MR, Ahmed H, Paul RK, Chowdhury M, Alam MS, Saha A. Comparative study between pentoxifylline and pioglitazone in the treatment of non-alcoholic fatty liver disease among newly detected glucose intolerant patients. Mymensingh Medical Journal : MMJ 2016;25(2):198-204. [PubMed] [Google Scholar]

Kawamori 1996 {published data only}

Kawamori R, Yoshii H. Drug therapy in subjects with impaired glucose tolerance. Nippon Rinsho - Japanese Journal of Clinical Medicine 1996;54(10):2750-3. [PubMed] [Google Scholar]

Kobayashi 2005 {published data only}

Kobayashi M. Effect of pioglitazone, one of TZDs, on IGT-patients. Nippon Rinsho - Japanese Journal of Clinical Medicine 2005;63 Suppl 2:462-70. [PubMed] [Google Scholar]

Lan 2012 {published data only}

Lan C, Ruan DF. Pioglitazone in the treatment of 60 patients with glucose tolerance reduction [吡格列酮治疗糖耐量减退60例]. China Pharmaceuticals [中国药业] 2012;21(13):80-1. [DOI: 10.3969/j.issn.1006-4931.2012.13.052] [DOI] [Google Scholar]

Li 2009 {published data only}

Li RJ, Li SH, Wu K. Effects of pioglitazone on stent restenosis in coronary heart disease patients with impaired glucose tolerance [吡格列酮对冠心病合并糖耐量异常患者冠脉支架内再狭窄的影响]. Journal of Guangdong Medical College [广东医学院学报] 2009;27(6):620-3. [DOI: 10.3969/j.issn.1005-4057.2009.06.006] [DOI] [Google Scholar]

Liu 2015 {published data only}

Liu MH. The early intervention effect of pioglitazone in IGT patients [吡格列酮对IGT患者早期干预效果的探究]. Guide of China Medicine [中国医药指南] 2015;13(17):158-9. [Google Scholar]

Nam 2013 {published data only}

Cheon J, Sun Nam J, Kim J, Kim S, Kyung C, Baek H, et al. Additional benefits of pioglitazone to lifestyle modification in patients at increased risk for diabetes and newly developed diabetes. American Diabetes Association 2014;63:A289. [Google Scholar]
Nam JS, Kim JW, Kang SA, Park JS, Ahn CW, Cha BS, et al. Additional benefits of pioglitazone to lifestyle modification in patients at increased risk for diabetes and newly developed diabetes. American Diabetes Association 2013;62:A596. [Google Scholar]

NCT00015626 {published data only}

NCT00015626. A clinical trial to prevent the complications of insulin resistance (including type-2 diabetes). ClinicalTrials.gov/show/NCT00015626 (first received 26 april 2001).

NCT00306826 {published data only}

NCT00306826. Pioglitazone in impaired glucose tolerance. clinicaltrials.gov/show/NCT00306826 (first received 24 May 2006).

NCT00470262 {published data only}

NCT00470262. Effects of PPAR ligands on ectopic fat accumulation and inflammation. clinicaltrials.gov/show/NCT00470262 (first received 7 May 2007).

NCT00633282 {published data only}

NCT00633282. Role of pioglitazone and berberine in treatment of non-alcoholic fatty liver disease [Role of pioglitazone and berberine in treatment of non-alcoholic fatty liver disease (NAFLD) patients with impaired glucose regulation or type 2 diabetes mellitus]. clinicaltrials.gov/show/NCT00633282 2008.

NCT00722631 {published data only}

NCT00722631. Anti-inflammatory effects of pioglitazone [Detection of plaque inflammation and visualization of anti-inflammatory effects of pioglitazone on plaque inflammation in subjects with impaired glucose tolerance and type 2 diabetes mellitus by FDG-PET/CT]. clinicaltrials.gov/ct2/show/NCT00722631 2007.

NCT01006018 {published data only}

NCT01006018. DPP-4 inhibition and TZD for DM prevention (DInT DM). clinicaltrials.gov/show/NCT01006018 (first received 7 june 2013).

Norris 2007 {published data only}

Norris SL, Carson S, Roberts C. Comparative effectiveness of pioglitazone and rosiglitazone in type 2 diabetes, prediabetes, and the metabolic syndrome: a meta-analysis. Current Diabetes Reviews 2007;3(2):127-40. [DOI: 10.2174/157339907780598216] [DOI] [PubMed] [Google Scholar]

UMIN000001035 {published data only}

UMIN000001035. Therapeutic efficacy of pioglitazone for non-alcoholic fatty liver desease(NAFLD) patients with impaired glucose tolerance or type 2 diabetes. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000001215 2008.

Wu 2008 {published data only}

Wu FM. Clinical study of pioglitazone on chronic heart failure and urinary albumin in prediabetic patients [瑞彤对糖尿病前期慢性心衰及尿白蛋白的临床研究]. 实用糖尿病杂志 [Journal of Practical Diabetology] 2008;4(3):46-8. [DOI: 10.3969/j.issn.1673-9191.2008.03.038] [DOI] [Google Scholar]

Yang 2012 {published data only}

Yang HB, Zhao XY, Zhang JY, Du YY, Wang XF. Pioglitazone induces regression and stabilization of coronary atherosclerotic plaques in patients with impaired glucose tolerance. Diabetic Medicine 2012;29(3):359-65. [DOI] [PubMed] [Google Scholar]

Yokoyama 2007 {published data only}

UMINC000000230. Effects of pioglitazone on coronary atherosclerotic plaques of patients with impaired glucose tolerance or type 2 diabetes mellitus:a randomized,open rabelled,prospective study [Effects of pioglitazone on coronary atherosclerotic plaques:a randomized,open rabelled,prospective study of pioglitazone intervention on coronary atherosclerosis (PIGEON) using intravascular ultrasound]. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000000230 2010.
Yokoyama J, Sutoh N, Higuma T, Horiuchi D, Katoh C, Yokota T, et al. Efficacy and safety of low-dose pioglitazone after primary coronary angioplasty with the use of bare metal stent in patients with acute myocardial infarction and with type 2 diabetes mellitus or impaired glucose tolerance. Heart and Vessels 2007;22(3):146-51. [DOI] [PubMed] [Google Scholar]

Zhang 2014 {published data only}

Zhang QX. Clinical effect of pioglitazone on hypertension with diabetes mellitus with abnormal glucose tolerance [吡格列酮对高血压合并糖尿病糖耐量异常的临床疗效分析]. Diabetes New World [糖尿病新世界] 2014;34(10):9. [Google Scholar]

Zhao 2011 {published data only}

Zhao XY, Zhang JY, Yang HB, Li L, Du YY, Wang XF. Pioglitazone regresses coronary plaques in patients of impaired glucose tolerance combined with coronary borderline lesions [吡格列酮缩小糖耐量异常患者冠状动脉斑块面积的临床研究]. Chinese Circulation Journal [中国循环杂志] 2011;26(6):418-21. [DOI: 10.3969/j.issn.1000-3614.2011.06.006] [DOI] [Google Scholar]

Zhou 2006 {published data only}

Zhou WD. The intervention study on impaired glucose tolerance [糖耐量减低的干预研究]. Journal of Clinical Research [医学临床研究] 2006;23(5):714-6. [Google Scholar]

References to ongoing studies

Beijing prediabetes reversion programme (BPRP) {published data only}

ChiCTR-PRC-06000005. Beijing prediabetes reversion program [Pre-diabetes reversion program in Beijing]. www.chictr.org.cn/showproj.aspx?proj=9520 (first received March 2007).
Duan W, Luo Y, Wang H, Ji L. A compliance evaluation model of lifestyle intervention in prediabetes. American Diabetes Association 2014;63:A208. [DOI: 10.2337/db14-665-832] [DOI] [Google Scholar]
Luo Y, Paul SK, Zhou X, Chang C, Chen W, Guo X, et al. Rationale, design, and baseline characteristics of Beijing Prediabetes Reversion Program: a randomized controlled clinical trial to evaluate the efficacy of lifestyle intervention and/or pioglitazone in reversion to normal glucose tolerance in prediabetes. Journal of Diabetes Research 2017;2017:7602408. [DOI: 10.1155/2017/7602408] [DOI] [PMC free article] [PubMed] [Google Scholar]
Luo Y, Zhou X, Wang H, Ji L. Study design and baseline characteristics of Beijing Pre-diabetes Reversion Program (BPRP). American Diabetes Association 2012;61:A626. [DOI: 10.2337/db12-2323-2568] [DOI] [Google Scholar]

NCT02969798 {published data only}

NCT02969798. Pre-diabetes in subject with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) [Preservation of beta cell function in pre-diabetes in subject with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)]. clinicaltrials.gov/ct2/show/nct02969798 (first received 21 November 2016).

Additional references

Abdul‐Ghani 2006

Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 2006;55(5):1430-5. [PMID: ] [DOI] [PubMed] [Google Scholar]

ADA 1997

American Diabetes Association. Report on the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183-97. [DOI] [PubMed] [Google Scholar]

ADA 2003

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S5-20. [DOI] [PubMed] [Google Scholar]

ADA 2008

American Diabetes Association. Standards of medical care in diabetes - 2008. Diabetes Care 2008;31 Suppl 1:S12-54. [PMID: ] [DOI] [PubMed] [Google Scholar]

ADA 2010

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 Suppl 1:S62-9. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

ADA 2015

American Diabetes Association. Standards of medical care in diabetes - 2015. Diabetes Care 2015;38 Suppl 1:S1-93. [PMID: ] [PubMed] [Google Scholar]

ADA 2017

American Diabetes Association (ADA). Standards of medical care in diabetes - 2017. Diabetes Care 2017;40 Suppl 1:S 11-33. [Google Scholar]

Altman 2003

Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ 2003;326(7382):219. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Babai 2018

Babai S, Auclert L, Le-Louet H. Safety data and withdrawal of hepatotoxic drugs. Therapie 2018;S0040-5957(18):30036-2. [DOI: 10.1016/j.therap.2018.02.004] [PMID: ] [DOI] [PubMed] [Google Scholar]

Bell 2013

Bell ML, McKenzie JE. Designing psycho-oncology randomised trials and cluster randomised trials: variance components and intra-cluster correlation of commonly used psychosocial measures. Psycho-oncology 2013;22:1738-47. [DOI] [PubMed] [Google Scholar]

Borenstein 2017a

Borenstein M, Higgins JP, Hedges LV, Rothstein HR. Basics of meta-analysis: I² is not an absolute measure of heterogeneity. Research Synthesis Methods 2017;8(1):5-18. [DOI] [PubMed] [Google Scholar]

Borenstein 2017b

Borenstein M. Prediction intervals. www.meta-analysis.com/prediction (accessed 1 September 2019).

Boutron 2014

Boutron I, Altman DG, Hopewell S, Vera-Badillo F, Tannock I, Ravaud P. Impact of spin in the abstracts of articles reporting results of randomized controlled trials in the field of cancer: the SPIIN randomized controlled trial. Journal of Clinical Oncology 2014;32(36):4120-6. [DOI] [PubMed] [Google Scholar]

Buch 2011

Buch MH, Aletaha D, Emery P, Smolen JS. Reporting of long-term extension studies: lack of consistency calls for consensus. Annals of the Rheumatic Diseases 2011;70(6):886-90. [DOI] [PubMed] [Google Scholar]

CDC 2015

Centers for Disease Control and Prevention. 2014 National Diabetes Statistics Report. www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html (accessed 15 October 2015).

Cheng 2006

Cheng C, Kushner H, Falkner BE. The utility of fasting glucose for detection of prediabetes. Metabolism: Clinical and Experimental 2006;55(4):434-8. [PMID: ] [DOI] [PubMed] [Google Scholar]

ClinicalTrials.gov

Search terms: prediabetes drugs. clinicaltrials.gov/ct2/results?term=prediabetes+drugs&Search=Search (accessed 7 June 2019).

Cochrane 2018

Cochrane. CENTRAL creation details. www.cochranelibrary.com/central/central-creation (accessed 21 August 2018).

Cohen 2010

Cohen D. Rosiglitazone: what went wrong? BMJ (Clinical Research Ed.) 2010;341:c4848. [PMID: ] [DOI] [PubMed] [Google Scholar]

CONSORT 2018

Consolidated Standards of Reporting Trials (CONSORT). The CONSORT statement. www.consort-statement.org (accessed 7 June 2019).

Cooper 2019

Cooper C, Varley-Campbell J, Carter P. Established search filters may miss studies when identifying randomized controlled trials. Journal of Clinical Epidemiology 2019;112(Aug):12-9. [DOI: 10.1016/j.jclinepi.2019.04.002] [PMID: ] [DOI] [PubMed] [Google Scholar]

Corbett 2014

Corbett MS, Higgins JP, Woolacott NF. Assessing baseline imbalance in randomised trials: implications for the Cochrane risk of bias tool. Research Synthesis Methods 2014;5(1):79-85. [DOI] [PubMed] [Google Scholar]

Davies 2019

Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Correction to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2019;62(5):873. [PMID: ] [DOI] [PubMed]

Deeks 2019

Deeks JJ, Higgins JP, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

DeFronzo 1989

DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism: Clinical and Experimental 1989;38(4):387-95. [PMID: ] [DOI] [PubMed] [Google Scholar]

Diabetes Prevention Program 2002

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 2002;346(6):393-403. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Diabetes Prevention Program 2009

Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374(9702):1677-86. [DOI] [PMC free article] [PubMed]

Diabetes Prevention Program FU 2009

Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374(9702):1677-86. [DOI: 10.1016/S0140-6736(09)61457-4] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Dunkley 2014

Dunkley AJ, Bodicoat DH, Greaves CJ, Russell C, Yates T, Davies MJ, et al. Diabetes prevention in the real world: effectiveness of pragmatic lifestyle interventions for the prevention of type 2 diabetes and of the impact of adherence to guideline recommendations: a systematic review and meta-analysis. Diabetes Care 2014;37(4):922-33. [PMID: ] [DOI] [PubMed] [Google Scholar]

Finnish Diabetes Prevention Study Group 2001

Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 2001;344(18):1343-50. [PMID: ] [DOI] [PubMed] [Google Scholar]

Gosmanov 2014

Gosmanov AR, Wan J. Low positive predictive value of hemoglobin A1c for diagnosis of prediabetes in clinical practice. American Journal of the Medical Sciences 2014;348(3):191-4. [PMID: ] [DOI] [PubMed] [Google Scholar]

GRADEproGDT [Computer program]

McMaster University (developed by Evidence Prime) GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), accessed 7 June 2019. Available at gradepro.org.

Hart 2012

Hart B, Lundh A, Bero L. Effect of reporting bias on meta-analyses of drug trials: reanalysis of meta-analyses. BMJ 2012;344:d7202. [DOI: 10.1136/bmj.d7202] [DOI] [PubMed] [Google Scholar]

Haw 2017

Haw JS, Galaviz KI, Straus AN, Kowalski AJ, Magee MJ, Weber MB, et al. Long-term sustainability of diabetes prevention approaches: a systematic review and meta-analysis of randomized clinical trials. JAMA Internal Medicine 2017;177(12):1808-17. [DOI] [PMC free article] [PubMed] [Google Scholar]

Hemmingsen 2016a

Hemmingsen B, Sonne DP, Metzendorf MI, Richter B. Insulin secretagogues for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No: CD012151. [DOI: 10.1002/14651858.CD012151.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

Hemmingsen 2016b

Hemmingsen B, Krogh J, Metzendorf MI, Richter B. Sodium-glucose cotransporter (SGLT) 2 inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No: CD012106. [DOI: 10.1002/14651858.CD012106.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

Hemmingsen 2017

Hemmingsen B, Sonne DP, Metzendorf MI, Richter B. Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No: CD012204. [DOI: 10.1002/14651858.CD012204.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

Higgins 2002

Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539-58. [DOI] [PubMed] [Google Scholar]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327(7414):557-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

Higgins 2009

Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. Journal of the Royal Statistical Society: Series A (Statistics in Society) 2009;172(1):137-59. [DOI] [PMC free article] [PubMed] [Google Scholar]

Higgins 2019a

Higgins JP, Li T, Deeks JJ (editors). Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

Higgins 2019b

Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

Hoffmann 2014

Hoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ 2014;348:g1687. [DOI] [PubMed] [Google Scholar]

Hoffmann 2017

Hoffmann TC, Oxman AD, Ioannidis JP, Moher D, Lasserson TJ, Tovey DI, et al. Enhancing the usability of systematic reviews by improving the consideration and description of interventions. BMJ 2017;358:j2998. [DOI] [PubMed] [Google Scholar]

Hozo 2005

Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Medical Research Methodology 2005;5:13. [DOI: 10.1186/1471-2288-5-13] [DOI] [PMC free article] [PubMed] [Google Scholar]

Hróbjartsson 2013

Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, et al. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. Canadian Medical Association Journal 2013;185(4):E201-11. [DOI] [PMC free article] [PubMed] [Google Scholar]

ICH 1997

International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice //1997 CFR & ICH Guidelines. In: PA 19063-2043. USA: Barnett International/PAREXEL, 1997.

IDF 2013

International Diabetes Federation (IDF). IDF Diabetes Atlas. 6th edition. Brussels: International Diabetes Federation, 2013. [Google Scholar]

IEC 2009

International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32(7):1327-34. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Inzucchi 2012

Inzucchi SE. Clinical practice. Diagnosis of diabetes. New England Journal of Medicine 2012;367(6):542-50. [PMID: ] [DOI] [PubMed] [Google Scholar]

Jones 2015

Jones CW, Keil LG, Holland WC, Caughey MC, Platts-Mills TF. Comparison of registered and published outcomes in randomized controlled trials: a systematic review. BMC Medicine 2015;13:282. [DOI: 10.1186/s12916-015-0520-3] [DOI] [PMC free article] [PubMed] [Google Scholar]

Kirkham 2010

Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ 2010;340:c365. [DOI: 10.1136/bmj.c365] [DOI] [PubMed] [Google Scholar]

Liao 2017

Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open 2017;7(1):e013927. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Liberati 2009

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic and meta-analyses of studies that evaluate interventions: explanation and elaboration. PLoS Medicine 2009;6(7):e1000100. [DOI: 10.1371/journal.pmed.1000100] [DOI] [PMC free article] [PubMed] [Google Scholar]

Lundh 2017

Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No: MR000033. [DOI: 10.1002/14651858.MR000033.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]

Marshall 2018

Marshall IJ, Noel-Storr AH, Kuiper J, Thomas J, Wallace BC. Machine learning for identifying randomized controlled trials: an evaluation and practitioner’s guide. Research Synthesis Methods 2018;9(4):602-14. [DOI: 10.1002/jrsm.1287 ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Mathieu 2009

Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 2009;302:977-84. [DOI] [PubMed] [Google Scholar]

McDonald 2017

McDonald S, Noel-Storr AH, Thomas J. Harnessing the efficiencies of machine learning and Cochrane Crowd to identify randomised trials for individual Cochrane reviews. Global Evidence Summit, Cape Town, South Africa 13-16 Semptember 2017.

Meader 2014

Meader N, King K, Llewellyn A, Norman G, Brown J, Rodgers M, et al. A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation. Systematic Reviews 2014;3:82. [DOI] [PMC free article] [PubMed] [Google Scholar]

Megan 2012

Megan B, Pickering RM, Weatherall M. Design, objectives, execution and reporting of published open-label extension studies. Journal of Evaluation in Clinical Practice 2012;18(2):209-15. [DOI] [PubMed] [Google Scholar]

Merlotti 2014

Merlotti C, Morabito A, Pontiroli AE. Prevention of type 2 diabetes; a systematic review and meta-analysis of different intervention strategies. Diabetes, Obesity & Metabolism 2014;16(8):719-27. [DOI] [PubMed] [Google Scholar]

Morris 2013

Morris DH, Khunti K, Achana F, Srinivasan B, Gray LJ, Davies MJ, et al. Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis. Diabetologia 2013;56(7):1489-93. [PMID: ] [DOI] [PubMed] [Google Scholar]

NDDG 1979

National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039-57. [DOI] [PubMed] [Google Scholar]

Ninomiya 2016

Ninomiya H, Hirata A, Kozawa J, Nakata S, Kimura T, Kitamura T, et al. Treatment of mitochondrial diabetes with a peroxisome proliferator-activated receptor (PPAR)-gamma agonist. Internal Medicine (Tokyo, Japan) 2016;55(9):1143-7. [PMID: ] [DOI] [PubMed] [Google Scholar]

Noel‐Storr 2018

Noel-Storr AH, the Project Transform team. Cochrane Crowd: new ways of working together to produce health evidence. Evidence Live 2018, Oxford, UK 18–20 June 2018.

Pang 2018

Pang B, Zhao L-H, Li X-L, Song J, Li Q-W, Liao X, et al. Different intervention strategies for preventing type 2 diabetes mellitus in China: a systematic review and network meta-analysis of randomized controlled trials. Diabetes, Obesity & Metabolism 2018;20(3):718-22. [DOI] [PubMed] [Google Scholar]

Pi‐Sunyer 2015

Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine 2015;373(1):11-22. [DOI] [PubMed]

Review Manager 2020 [Computer program]

The Cochrane Collaboration Review Manager 5 (RevMan 5). Version 5.4. Copenhagen: The Cochrane Collaboration, 2020.

Richter 2006

Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No: CD006060. [DOI: 10.1002/14651858.CD006060.pub2] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Richter 2018

Richter B, Hemmingsen B, Metzendorf MI, Takwoingi Y. Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia. Cochrane Database of Systematic Reviews 2018, Issue 10. Art. No: CD012661. [DOI: 10.1002/14651858.CD012661.pub2] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Riley 2013

Riley RD, Kauser I, Bland M, Thijs L, Staessen JA, Wang J, et al. Meta-analysis of randomised trials with a continuous outcome according to baseline imbalance and availability of individual participant data. Statistics in Medicine 2013;32(16):2747-66. [DOI] [PubMed] [Google Scholar]

Schernthaner 2013

Schernthaner G, Currie CJ, Schernthaner GH. Do we still need pioglitazone for the treatment of type 2 diabetes? A risk-benefit critique in 2013. Diabetes Care 2013;36 Suppl 2:S155-61. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Schroll 2015

Schroll JB, Bero L. Regulatory agencies hold the key to improving Cochrane Reviews of drugs [editorial]. Cochrane Database of Systematic Reviews 2015;4:10.1002/14651858.ED000098. [DOI] [PMC free article] [PubMed]

Schünemann 2019

Schünemann HJ, Higgins JP, Vist GE, Glasziou P, Akl EA, Skoetz N, et al. Chapter 14: Completing ‘Summary of findings’ tables and grading the confidence in or quality of the evidence. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors), Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

Selvin 2011

Selvin E, Steffes MW, Ballantyne CM, Hoogeveen RC, Coresh J, Brancati FL. Racial differences in glycemic markers: a cross-sectional analysis of community-based data. Annals of Internal Medicine 2011;154(5):303-9. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Thomas 2017

Thomas J, Noel-Storr AH, Marshall I, Wallace B, McDonald S, Mavergames C, et al. Living systematic review network. Living systematic reviews: 2. combining human and machine effort. Journal of Clinical Epidemiology 2017;S0895-4356(17):30604-2. [DOI] [PubMed] [Google Scholar]

Viera 2011

Viera AJ. Predisease: when does it make sense? Epidemiologic Reviews 2011;33:122-34. [DOI] [PubMed] [Google Scholar]

WHO/IDF 2006

World Health Organization/International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: report of a WHO/IDF consultation. www.who.int/diabetes/publications/Definition%20and%20diagnosis%20of%20diabetes_new.pdf 2006;(accessed 17 March 2017).

WHO 1998

Alberti KM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Medicine 1998;15(7):539-53. [DOI] [PubMed] [Google Scholar]

WHO 1999

World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. In: Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, Switzerland: World Health Organization, 1999:1-59. [Google Scholar]

Wood 2008

Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008;336(7644):601-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

Yudkin 2014

Yudkin JS, Montori VM. The epidemic of pre-diabetes: the medicine and the politics. BMJ 2014;349:g4485. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0001] Alonzo R, Chavez-Velazquez A, Martinez R, Velez-Garza J, Carreon M, Musi N, et al. Increase in serum fibroblast growth factor-21 (FGF-21) predicts development of diabetes in IGT subjects and pioglitazone attenuates the increase in FGF-21 and reduces conversion of IGT to T2DM. Diabetes 2016;65:A482. [DOI: 10.2337/db16-1771-2041] [DOI] [Google Scholar]

[CD013516-bib-0002] Anonymous. Pioglitazone reduces the risk of converting impaired glucose tolerance to type 2 diabetes. Australian Journal of Pharmacy 2011;92(1095):82. [Google Scholar]

[CD013516-bib-0003] Bray GA, Smith SR, Banerji MA, Tripathy D, Clement SC, Buchanan TA, et al. Effect of pioglitazone on body composition and bone density in subjects with prediabetes in the ACT NOW trial. Diabetes, Obesity & Metabolism 2013;15(10):931-7. [DOI: 10.1111/dom.12099] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0004] Defronzo RA, Banerji M, Bray GA, Buchanan TA, Clement S, Henry RR, et al. Actos now for the prevention of diabetes (ACT NOW) study. BMC Endocrine Disorders 2009;9:17. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0005] Defronzo RA, Tripathy D, Abdul-Ghani M, Musi N, Gastaldelli A. The disposition index does not reflect beta-cell function in IGT subjects treated with pioglitazone. Journal of Clinical Endocrinology and Metabolism 2014;99(10):3774-81. [DOI: 10.1210/jc.2014-1515] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0006] DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. New England Journal of Medicine 2011;364(12):1104-15. [DOI: 10.1056/NEJMoa1010949] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0007] Defronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates. Diabetes 2013;62(11):3920-6. [EMBASE: 10.2337/db13-0265] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0008] Espinoza S, Wang C, Reaven P, DeFronzo R, Tripathy D, Musi N. Pioglitazone is equally effective for preventing diabetes in older compared to younger pre-diabetic adults. Journal of the American Geriatrics Society 2015;63:S100. [DOI: 10.1111/jgs.13439] [DOI] [Google Scholar]

[CD013516-bib-0009] Espinoza S, Wang CP, Clement S, Schwenke D, Banerjee MA, Bray G, et al. Pioglitazone is equally effective for diabetes prevention in older compared with younger prediabetic adults. Diabetes 2015;64:A308-9. [DOI: 10.2337/db159321471] [DOI] [Google Scholar]

[CD013516-bib-0010] Espinoza SE, Wang CP, Tripathy D, Clement SC, Schwenke DC, Banerji MA, et al. Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance. Age 2016;38(5-6):485-93. [DOI: 10.1007/s11357-016-9946-6] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0011] Gall W, Musi N, DeFronzo R, Tripathy D. Novel index of insulin sensitivity from fasting biomarkers: validation in the ACT NOW study. Diabetologia 2012;55:S234. [DOI: 10.1007/s00125-012-2688-9] [DOI] [Google Scholar]

[CD013516-bib-0012] Gastaldelli A, Tripathy D, Gaggini M, Musi N, DeFronzo RA. Improvement in hepatic metabolism is associated with reduced conversion to diabetes in IGT subjects treated with pioglitazone (ACT NOW study). Diabetologia 2015;58 Suppl1 1:S164. [DOI: 10.1007/s00125-015-3687-4] [DOI] [Google Scholar]

[CD013516-bib-0013] Gastaldelli A, Tripathy D, Gall W, DeFronzo RA. Pioglitazone decreases hepatic insulin resistance index and improves hepatic metabolic biomarkers in IGT subjects: the ACTNOW study. Diabetologia 2012;55 Suppl 1:S234. [DOI: 10.1007/s00125-012-2688-9] [DOI] [Google Scholar]

[CD013516-bib-0014] Hu X, Reaven P, Saremi A, Liu H, et al, ACT NOW Study Investigators. Machine learning to predict rapid progression of carotid atherosclerosis in patients with impaired glucose tolerance. EURASIP Journal on Bioinformatics and Systems Biology 2016;2016:14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0015] NCT00220961. Actos now for prevention of diabetes (ACT NOW). clinicaltrials.gov/show/NCT00220961 (first received January 2004).

[CD013516-bib-0016] Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, et al. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arteriosclerosis, Thrombosis, and Vascular Biology 2013;33(2):393-9. [DOI: 10.1161/ATVBAHA.112.300346] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0017] Tripathy D, Alonzo RP, Chavez-Velazquez A, Martinez R, Musi N, Defronzo R. Fibroblast growth factor-21 (FGF-21) predicts development of diabetes and pioglitazone attenuates the increase in FGF-21 in subjects with IGT: results from the ACTNOW study. Diabetologia 2016;59(1):S164. [DOI: 10.1007/s00125-016-4046-9] [DOI] [Google Scholar]

[CD013516-bib-0018] Tripathy D, Banerji MA, Bray GA, Buchanan TA, Clement S, Henry RR, et al. Effect of pioglitazone on beta cell function in impaired glucose tolerance: results form ACTNOW. https://professional.diabetes.org/abstract/effect-pioglitazone-beta-cell-function-impaired-glucose-tolerance-results-form-actnow (assessed 11 November 2020).

[CD013516-bib-0019] Tripathy D, Banerji MA, Bray GA, Buchanan TA, Clement S, Henry RR, et al. Pioglitazone improves adipocyte insulin resistance in subjects with impaired glucose tolerance: results from ACT NOW. https://professional.diabetes.org/abstract/pioglitazone-improves-adipocyte-insulin-resistance-subjects-impaired-glucose-tolerance (accessed 11 November 2020).

[CD013516-bib-0020] Tripathy D, Clement SC, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Baseline adiponectin levels do not influence the response to pioglitazone in ACT NOW. Diabetes Care 2014;37(6):1706-11. [DOI: 10.2337/dc13-1745] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0021] Tripathy D, Cobb JE, Gall W, Adam KP, George T, Schwenke DC, et al. A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study. Journal of Clinical Endocrinology and Metabolism 2015;100(5):1855-62. [DOI: 10.1210/jc.2014-3824] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0022] Tripathy D, Gall W, Adam KP, Schwenke D, Gastaldelli A, Musi N, et al. Pioglitazone improves insulin sensitivity by modulating novel biomarkers in impaired glucose tolerance. Diabetes 2012;61:A305. [DOI: 10.2337/db12-836-1328] [DOI] [Google Scholar]

[CD013516-bib-0023] Tripathy D, Gall WE, Adam KP, Schwenke DC, Banerji M, Bray GA, et al. Pioglitazone improves insulin sensitivity by modulating novel biomarkers: results from the ACTNOW study. Diabetologia 2011;54 Suppl 1:S30. [DOI: 10.1007/s00125-011-2276-4] [DOI] [Google Scholar]

[CD013516-bib-0024] Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Diabetes incidence and glucose tolerance 1 year after termination of pioglitazone therapy: Results from ACT now. Diabetes 2014;63:A292. [DOI: 10.2337/db14-833-1316] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0025] Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Diabetes incidence and glucose tolerance after termination of pioglitazone therapy: results from ACT NOW. Journal of Clinical Endocrinology and Metabolism 2016;101(5):2056-62. [DOI: 10.1210/jc.2015-4202] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0026] Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Effect of pioglitazone on adipocytokines and insulin sensitivity in subjects with impaired glucose tolerance: results from ACT now. Diabetes 2011;60:A435. [DOI: 10.2337/db11-1487-1624] [DOI] [Google Scholar]

[CD013516-bib-0027] Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Inadequate plasma adiponectin response characterises nonresponsiveness to pioglitazone in individuals with impaired glucose tolerance: results from the ACT NOW study. Diabetologia 2013;56 Suppl 1:S106. [DOI: 10.1007/s00125-013-3012-z] [DOI] [Google Scholar]

[CD013516-bib-0028] Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, et al. Reduced beta cell function and inadequate rise in plasma adiponectin characterizes non-responsiveness to pioglitazone in individuals with impaired glucose tolerance in ACT NOW. Diabetes 2013;62:A277. [DOI: 10.2337/db13-859-1394] [DOI] [Google Scholar]

[CD013516-bib-0029] Velez-Garza JA, Giuseppe DA, Alonzo R, Martinez R, Bruder J, Musi N, et al. Pioglitazone does not modulate plasma sclerostin levels in subjects with impaired glucose tolerance (IGT): results from the ACT NOW study. Diabetes. Conference: 76th scientific sessions of the American Diabetes Association, ADA 2016. United states 2016;65 Suppl 1:A291-2. [DOI: 10.2337/db16-861-1374] [DOI] [Google Scholar]

[CD013516-bib-0030] Attallah H, Friedlander AL, Nino-Murcia M, Hoffman AR. Effects of growth hormone and pioglitazone in viscerally obese adults with impaired glucose tolerance: a factorial clinical trial. PLoS Clinical Trials 2007;2(5):e21. [EMBASE: 10.1371/journal.pctr.0020021] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0031] NCT00352287. Study to determine the effects of human growth hormone and pioglitazone in overweight, prediabetic adults [Effects of GH and pioglitazone in viscerally obese adults with IGT]. clinicaltrials.gov/show/NCT00352287 (first received 14 July 2006).

[CD013516-bib-0032] Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Spanheimer RG. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism 2013;98(12):4691-701. [DOI: 10.1210/jc.2012-4096] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0033] NCT00708175. Efficacy of pioglitazone on bone metabolism in postmenopausal women with impaired fasting glucose [A phase 4, randomized, double-blind, placebo-controlled study to evaluate the effect of pioglitazone compared to placebo on bone metabolism in impaired fasting glucose, postmenopausal women for one year of treatment]. clinicaltrials.gov/show/NCT00708175 (first received 2 July 2008).

[CD013516-bib-0034] Che CJ, Zhao QH. Clinical analysis of pioglitazone dispersible tablets in 38 patients with abnormal glucose tolerance in essential hypertension [吡格列酮分散片对原发性高血压糖耐量异常38例临床分析]. Journal of Medical Theory and Practice [医学理论与实践] 2014;(17):2290-1. [Google Scholar]

[CD013516-bib-0035] Chen JH, Wu JN, Su YR, Liu AY, Xu SZ, Huang XY. Intervention study on effects of pioglitazone on patients with impaired glucose tolerance [吡格列酮对糖耐量受损患者的干预治疗研究]. Hainan Medical Journal [海南医学] 2007;18(12):15-7. [DOI: 10.3969/j.issn.1003-6350.2007.12.009] [DOI] [Google Scholar]

[CD013516-bib-0036] Chen RJ. Effect of pioglitazone on hypertension patients with abnormal glucose tolerance [吡格列酮对高血压合并糖耐量异常患者疗效观察]. Shenzhen Journal of Integrated Traditional Chinese and Western Medicine [深圳中西医结合杂志] 2007;17(6):379-80. [10.3969/j.issn.1007-0893.2007.06.017] [Google Scholar]

[CD013516-bib-0037] Gong XY. 吡格列酮在高血压病合并糖耐量异常患者中的应用. Chinese Journal of Clinical Medicine [中国现代临床医学] 2008;7(9):9-11. [Google Scholar]

[CD013516-bib-0038] Deng CR, Fan HW. Pioglitazone prevents conversion to diabetes in patients with impaired glucose tolerance [吡格列酮预防糖耐量受损患者向糖尿病转化]. Guide of China Medicine [中国医药指南] 2013;11(10):205-7. [DOI: 10.3969/j.issn.1671-8194.2013.10.159] [DOI] [Google Scholar]

[CD013516-bib-0039] Fang Q, Fang MX, Yao Y, Feng SY, Yang YP, Xue L, et al. Efficacy and safety of pioglitazone for intervention therapy of impaired glucose regulation [吡格列酮干预糖调节受损的疗效和安全性]. Journal of Clinical Research [医学临床研究] 2013;30(2):239-42. [DOI: 10.3969/j.issn.1671-7171.2013.02.012] [DOI] [Google Scholar]

[CD013516-bib-0040] Gao WX. Curative effect analysis on pioglitazone for treating hypertension with impaired glucose tolerance [吡格列酮对高血压合并糖耐量异常的疗效分析]. Good Health for All [大家健康（中旬版）] 2011;5(5):2-4. [Google Scholar]

[CD013516-bib-0041] Guo Y, Li W, Bao H, Fan CH, Zhang XW. Effect of pioglitazone on endothelial function in elderly patients with impaired glucose tolerance [吡格列酮对老年糖耐量低减患者内皮功能的影响]. Chinese Journal of New Drugs [中国新药杂志] 2009;18(24):2323-6. [Google Scholar]

[CD013516-bib-0042] Guo Y, Bao H, Li W, Su L, Zhang QW, Miao YD. Effect of pioglitazone on carotid atherosclerosis in old-aged impaired glucose tolerance patients [吡格列酮对老年糖耐量低减患者颈动脉硬化的影响]. Chinese Pharmaceutical Journal [中国药学杂志] 2010;45(10):764-7. [Google Scholar]

[CD013516-bib-0043] Han SX. Efficacy of pioglitazone in patients with primary hypertension with impaired glucose tolerance [吡格列酮对原发性高血压伴糖耐量减低患者的疗效观察]. Hebei Medical Journal [河北医药] 2007;29(6):595. [DOI: 10.3969/j.issn.1002-7386.2007.06.040] [DOI] [Google Scholar]

[CD013516-bib-0044] NCT00276497. Role of pioglitazone in preventing diabetes. clinicaltrials.gov/show/NCT00276497 (first received 13 January 2006).

[CD013516-bib-0045] Ramachandran A, Arun N, Shetty AS, Snehalatha C. Efficacy of primary prevention interventions when fasting and postglucose dysglycemia coexist: analysis of the Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2). Diabetes Care 2010;33(10):2164-8. [DOI: 10.2337/dc09-1150] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0046] Ramachandran A, Snehalatha C, Mary S, Selvam S, Kumar CK, Seeli AC, et al. Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian Diabetes Prevention Programme-2 (IDPP-2). Diabetologia 2009;52(6):1019-26. [DOI: 10.1007/s00125-009-1315-x] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0047] Ke XH, Tang LH, Tan ML, Huang YZ. Results of intervention of subsidence of glucose tolerance by using rosiglitazone [糖耐量减退吡格列酮干预治疗的研究]. China Tropical Medicine [中国热带医学] 2006;6(9):1622-31. [DOI: 10.3969/j.issn.1009-9727.2006.09.047] [DOI] [Google Scholar]

[CD013516-bib-0048] Li Y. The value of pioglitazone in the treatment of patients with impaired glucose tolerance [吡格列酮在葡萄糖耐量受损患者治疗中应用的价值]. The Journal of Medical Theory and Practice [医学理论与实践] 2017;30(11):1609-11. [Google Scholar]

[CD013516-bib-0049] Liang ZQ, Tang L. Observation on the interventive effect of pioglitazone hydrochloride on the IGT population of diabetes mellitus [盐酸吡格列酮干预治疗糖耐量减退的疗效观察]. Journal of Guangxi Medical University [广西医科大学学报] 2004;21(2):165-7. [DOI: 10.3969/j.issn.1005-930X.2004.02.004] [DOI] [Google Scholar]

[CD013516-bib-0050] Shi J. Intervention of pioglitazone in the development of pre-diabetes [吡格列酮对糖尿病前期病情演变的干预]. Chinese Journal of Trauma and Disability Medicine [中国伤残医学] 2014;22(23):117. [DOI: 10.13214/j.cnki.cjotadm.2014.23.099] [DOI] [Google Scholar]

[CD013516-bib-0051] Tian F. Effect of pioglitazone on the treatment effect and C-reactive protein of prediabetic patients [探讨吡格列酮对糖尿病前期患者的治疗效果及C反应蛋白的影响]. World Latest Medicine Information [世界最新医学信息文摘] 2015;15(24):131-2. [DOI: 10.3969/j.issn.1671-3141.2015.24.102] [DOI] [Google Scholar]

[CD013516-bib-0052] Wu YX, Wu TY, Li XJ, Wang W, Zhang Q, Xiong HL, et al. Effects of pioglitazone on ambulatory pulse pressure index in patients with elderly essential hypertension and impaired glucose tolerance [吡格列酮对老年原发性高血压伴糖耐量异常患者动态脉压指数的影响]. Journal of Clinical Cardiology [临床心血管病杂志] 2013;29(6):443-5. [Google Scholar]

[CD013516-bib-0053] Xiu SL, Wang L. Effect of pioglitazone on intervention and C-reactive protein in prediabetic patients [吡格列酮对糖尿病前期患者的干预及C反应蛋白的影响]. Chinese Journal of Medicine [中国医刊] 2015;(1):65-7. [DOI: 10.3969/j.issn.1008-1070.2015.01.021] [DOI] [Google Scholar]

[CD013516-bib-0054] Xu HS, Lei MX, Kong DM, Xiang H, Xie XY. Intervention of pioglitazone in patients with glucose tolerance disorder [吡格列酮对糖耐量异常患者的干预作用]. Chinese Journal of Gerontology [中国老年学杂志] 2011;31(14):2640-1. [DOI: 10.3969/j.issn.1005-9202.2011.14.013] [DOI] [Google Scholar]

[CD013516-bib-0055] Yi FS, Li F, Shen LL, Li WJ. Effect of pioglitazone on the treatment effect and C-reactive protein of prediabetic patients [探讨吡格列酮对糖尿病前期患者的治疗效果及C反应蛋白的影响]. Journal of Frontiers of Medicine [医药前沿] 2015;(25):39-40. [DOI: 10.3969/j.issn.2095-1752.2015.25.038] [DOI] [Google Scholar]

[CD013516-bib-0056] Yu XD, Qian ZM, Ge CL. Effects of pioglitazone on endothelin, C-reactive protein and fibrinogen in patients with impaired glucose tolerance [吡格列酮对糖耐量减低患者内皮素、C反应蛋白、纤维蛋白原的影响]. 中国医师进修杂志 [Chinese Journal of Postgraduates of Medicine] 2011;34(18):62-3. [Google Scholar]

[CD013516-bib-0057] Zeng ZH, Cai F, Qiu JF, Liu YQ, Zhou WZ, Weng LH. The effects of different interventions on impaired glucose regulation [糖调节受损人群不同干预方法的临床效果观察]. Health Research [健康研究] 2013;33(5):370-2, 375. [DOI: 10.3969/j.issn.1674-6449.2013.05.016] [DOI] [Google Scholar]

[CD013516-bib-0058] Zhang AH, Li PX, Cao WH, Wei AF, Huang LH. Clinical intervention in patients with IGR [糖调节受损者的临床干预研究]. Acta Academiae Medicinae Weifang [潍坊医学院学报] 2007;29(5):394-7. [Google Scholar]

[CD013516-bib-0059] Zhang FY, Zhao XJ, An YL. Study of pioglitazone intervention effect on impaired glucose regulation [盐酸吡格列酮对葡萄糖调节受损的干预治疗作用]. Journal of Shanxi Medical College for Continuing Education [山西职工医学院学报] 2015;25(1):9-11. [Google Scholar]

[CD013516-bib-0060] Zhao JK. Observation on the effect of pioglitazone intervention in the treatment of glucose tolerance reduction [吡格列酮干预治疗糖耐量减低疗效观察]. 中国实用乡村医生杂志 [Chinese Practical Journal of Rural Doctor] 2009;16(4):32-3. [DOI: 10.3969/j.issn.1672-7185.2009.04.018] [DOI] [Google Scholar]

[CD013516-bib-0061] Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. New England Journal of Medicine 2006;355(22):2297-307. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0062] Serfaty L. Pioglitazone: the beginning of a new era for NASH? Journal of Hepatology 2007;47(1):160-2. [DOI: 10.1016/j.jhep.2007.03.002] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0063] ChiCTR-TRC-08000099. Multicenter research of early intervention for adult metabolic syndrome in Beijing region. www.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-TRC-08000099 (first received 14 august 2008).

[CD013516-bib-0064] ChiCTR-TRC-08000111. A multicenter study of effects of early prevention on adult metabolic syndrome in Beijing region. www.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-TRC-08000111 (first received 14 april 2008).

[CD013516-bib-0065] Anonymous. Pioglitazone for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes. Annals of Internal Medicine 2016;165(5):I15. [DOI: 10.7326/P16-9018] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0066] Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clinical Gastroenterology and Hepatology 2018;16(4):558-66. [DOI: 10.1016/j.cgh.2017.12.001] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0067] Bril F, Lomonaco R, Orsak B, Finch J, Ortiz-Lopez C, Darland C, et al. Safety of statin therapy in patients with prediabetes or T2DM and NASH: a long-term prospective study. Diabetes 2013;62:A164. [DOI: 10.2337/db13-388-679] [DOI] [Google Scholar]

[CD013516-bib-0068] Bril F, Lomonaco R, Orsak B, Hecht J, Ortiz-Lopez C, Hardies J. Predictors of response after extended pioglitazone treatment in patients with prediabetes or T2DM and nonalcoholic steatohepatitis (NASH). Hepatology (Baltimore, Md.) 2013;58(4 Suppl 1):513A-4A. [DOI: ] [Google Scholar]

[CD013516-bib-0069] Bril F, Lomonaco R, Orsak B, Hecht J, Tio F, Cusi K. Is treatment of nonalcoholic steatohepatitis with pioglitazone equally effective in patients with prediabetes compared with type 2 diabetes (T2DM)? American Diabetes Association 2017;66:A64. [Google Scholar]

[CD013516-bib-0070] Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Hecht J, Tio F, et al. Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial. Journal of Clinical Endocrinology and Metabolism 2017;102(8):2950–61. [DOI: 10.1210/jc.2017-00867] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0071] Cases MM. Pioglitazone improves the biological and histological markers of nonalcoholic hepatic steatosis in patients with type 2 diabetes or glucose intolerance [Pioglitazona mejora los marcadores biológicos e histológicos de la esteatosis hepática no alcohólica en pacientes con diabetes tipo 2 o intolerancia a la glucosa]. FMC Formacion Medica continuada en Atencion Primaria 2007;14(5):285. [DOI: 10.1016/S1134-2072(07)71636-5] [DOI] [Google Scholar]

[CD013516-bib-0072] Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long- term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Annals of Internal Medicine 2016;165(5):305-15. [DOI: 10.7326/M15-1774] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0073] Cusi K, Orsak B, Lomonaco R, Bril F, Ortiz-Lopez C, Hecht J, et al. Extended treatment with pioglitazone improves liver histology in patients with prediabetes or type 2 diabetes mellitus and NASH. Hepatology (Baltimore, Md.) 2013;58(4):248A. [DOI: 10.1002/hep.26804] [DOI] [Google Scholar]

[CD013516-bib-0074] Cusi K, Orsak B, Lomonaco R, Finch J, Ortiz-Lopez C, Bril F, et al. Safety and efficacy of long-term pioglitazone treatment for patients with prediabetes or T2DM and NASH. Diabetes 2013;62:A309. [DOI: 10.2337/db13-859-1394] [DOI] [Google Scholar]

[CD013516-bib-0075] Kawaguchi-Suzuki M, Bril F, Cusi K, Langaee T, Gong Y, Frye R. Role of genetic polymorphisms on the improvement of liver histology after pioglitazone treatment in patients with nonalcoholic fatty liver disease (NAFLD). Hepatology (Baltimore, Md.) 2014;60:591A. [DOI: ] [Google Scholar]

[CD013516-bib-0076] Portillo-Sanchez P, Bril F, Lomonaco R, Barb D, Orsak B, Bruder JM, et al. Effect of pioglitazone on bone mineral density in patients with nonalcoholic steatohepatitis: a 36-month clinical trial. Journal of Diabetes 2019;11(3):223-31. [DOI: 10.1111/1753-0407.12833] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0077] Portillo Sanchez P, Bril F, Lomonaco R, Maximos M, Bruder J, Orsak B, et al. Effects of extended pioglitazone treatment (PIO) on bone metabolism in patients with prediabetes and type 2 diabetes mellitus (T2DM). Diabetes 2014;63:A293-4. [DOI: ] [Google Scholar]

[CD013516-bib-0078] Sunny N, Bril F, Kalavalapalli S, Sanchez PP, Maximos M, Biernacki D, et al. Pioglitazone therapy improves insulin suppression of branched chain amino acids in patients with prediabetes or T2DM and NAFLD. Diabetes 2015;64:A341. [DOI: ] [Google Scholar]

[CD013516-bib-0079] Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes, Obesity & Metabolism 2004;6(4):280-5. [DOI: 10.1111/j.1462-8902.2004.0348.x] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0080] EudraCT2005-004421-26. Effect of pioglitazone on intima media thickness, endothelial function and heart rate variability in patients with impaired glucose tolerance. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-004421-26 (first received 18 July 2006).

[CD013516-bib-0081] EudraCT2006-002084-49. Vascular function in impaired glucose tolerance - effect of pioglitazone. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-002084-49 (first received 13 September 2006).

[CD013516-bib-0082] Inzucchi SE, Viscoli CM, Young LH, Furie KL, Gorman M, Lovejoy A, et al. Diabetes prevention with pioglitazone in insulin resistant patients with cerebrovascular disease. American Diabetes Association 2016;Conference: 76th Scientific Sessions of the American Diabetes Association, ADA 2016. United States. 65(Suppl 1):A99. [Google Scholar]

[CD013516-bib-0083] Inzucchi SE, Viscoli CM, Young LH, Furie KL, Gorman M, Lovejoy AM, et al. Pioglitazone prevents diabetes in patients with insulin resistance and cerebrovascular disease. Diabetes Care 2016;39(10):1684-92. [DOI: 10.2337/dc16-0798] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0084] Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. New England Journal of Medicine 2016;374(14):1321-31. [DOI: 10.1056/NEJMoa1506930] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0085] Mayor S. Pioglitazone may reduce cardiovascular events in high risk patients with prediabetes. BMJ (Clinical Research Ed.) 2016;352:i1029. [DOI] [PubMed]

[CD013516-bib-0086] Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, et al. Correction: pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial (Journal of Physical Chemistry (2019). JAMA Neurology. [DOI: 10.1001/jamaneurol.2019.0475] [DOI] [PMC free article] [PubMed]

[CD013516-bib-0087] Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, et al. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurology 2019;76(5):526-35. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0088] Treating insulin resistance in patient after stroke for prevention of stroke and myocardial infarction after ischemic stroke and transient ischemic attack. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2008-005546-23-DE.

[CD013516-bib-0089] Young LH, Viscoli CM, Schwartz GG, Inzucchi SE, Curtis JP, Gorman MJ, et al. Heart failure after ischemic stroke or transient ischemic attack in insulin-resistant patients without diabetes mellitus treated with pioglitazone. Circulation 2018;138(12):1210-20. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0090] Tanaka R, Okuma Y, Miyamoto N, Tanaka Y, Yamashiro K, Watada H, et al. Effects of pioglitazone in patients with impaired glucose tolerance after stroke; progress report from J-SPIRIT study. International Journal of Stroke 2010;5 Suppl 2:195.

[CD013516-bib-0091] Tanaka R, Yamashiro K, Okuma Y, Shimura H, Nakamura S, Ueno Y, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT study. Journal of Atherosclerosis and Thrombosis 2015;22(12):1305-16. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0092] Tanaka R, Yamashiro K, Tanaka Y, Miyamoto N, Ueno Y, Watanabe M, et al. Effects of pioglitazone in patients with abnormal glucose metabolism after stroke: the J-SPIRIT study. Cerebrovascular Diseases 2013;36 Suppl 2:32 (P59). [DOI: 10.1159/000356197] [DOI]

[CD013516-bib-0093] Tanaka R, Yamashiro K, Tanaka Y, Miyamoto N, Ueno Y, Watanabe M, et al. Effects of pioglitazone in patients with abnormal glucose metabolism after stroke. The J-SPIRIT study. Stroke; a Journal of Cerebral Circulation 2013;44(2):Abst.ATP416.

[CD013516-bib-0094] UMINR000015768. Juntendo the stroke prevention study in insulin resistance and impaired glucose tolerance (J-SPIRIT study). upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015768 (first received 1 December 2005).

[CD013516-bib-0095] Karim MR, Ahmed H, Paul RK, Chowdhury M, Alam MS, Saha A. Comparative study between pentoxifylline and pioglitazone in the treatment of non-alcoholic fatty liver disease among newly detected glucose intolerant patients. Mymensingh Medical Journal : MMJ 2016;25(2):198-204. [PubMed] [Google Scholar]

[CD013516-bib-0096] Kawamori R, Yoshii H. Drug therapy in subjects with impaired glucose tolerance. Nippon Rinsho - Japanese Journal of Clinical Medicine 1996;54(10):2750-3. [PubMed] [Google Scholar]

[CD013516-bib-0097] Kobayashi M. Effect of pioglitazone, one of TZDs, on IGT-patients. Nippon Rinsho - Japanese Journal of Clinical Medicine 2005;63 Suppl 2:462-70. [PubMed] [Google Scholar]

[CD013516-bib-0098] Lan C, Ruan DF. Pioglitazone in the treatment of 60 patients with glucose tolerance reduction [吡格列酮治疗糖耐量减退60例]. China Pharmaceuticals [中国药业] 2012;21(13):80-1. [DOI: 10.3969/j.issn.1006-4931.2012.13.052] [DOI] [Google Scholar]

[CD013516-bib-0099] Li RJ, Li SH, Wu K. Effects of pioglitazone on stent restenosis in coronary heart disease patients with impaired glucose tolerance [吡格列酮对冠心病合并糖耐量异常患者冠脉支架内再狭窄的影响]. Journal of Guangdong Medical College [广东医学院学报] 2009;27(6):620-3. [DOI: 10.3969/j.issn.1005-4057.2009.06.006] [DOI] [Google Scholar]

[CD013516-bib-0100] Liu MH. The early intervention effect of pioglitazone in IGT patients [吡格列酮对IGT患者早期干预效果的探究]. Guide of China Medicine [中国医药指南] 2015;13(17):158-9. [Google Scholar]

[CD013516-bib-0101] Cheon J, Sun Nam J, Kim J, Kim S, Kyung C, Baek H, et al. Additional benefits of pioglitazone to lifestyle modification in patients at increased risk for diabetes and newly developed diabetes. American Diabetes Association 2014;63:A289. [Google Scholar]

[CD013516-bib-0102] Nam JS, Kim JW, Kang SA, Park JS, Ahn CW, Cha BS, et al. Additional benefits of pioglitazone to lifestyle modification in patients at increased risk for diabetes and newly developed diabetes. American Diabetes Association 2013;62:A596. [Google Scholar]

[CD013516-bib-0103] NCT00015626. A clinical trial to prevent the complications of insulin resistance (including type-2 diabetes). ClinicalTrials.gov/show/NCT00015626 (first received 26 april 2001).

[CD013516-bib-0104] NCT00306826. Pioglitazone in impaired glucose tolerance. clinicaltrials.gov/show/NCT00306826 (first received 24 May 2006).

[CD013516-bib-0105] NCT00470262. Effects of PPAR ligands on ectopic fat accumulation and inflammation. clinicaltrials.gov/show/NCT00470262 (first received 7 May 2007).

[CD013516-bib-0106] NCT00633282. Role of pioglitazone and berberine in treatment of non-alcoholic fatty liver disease [Role of pioglitazone and berberine in treatment of non-alcoholic fatty liver disease (NAFLD) patients with impaired glucose regulation or type 2 diabetes mellitus]. clinicaltrials.gov/show/NCT00633282 2008.

[CD013516-bib-0107] NCT00722631. Anti-inflammatory effects of pioglitazone [Detection of plaque inflammation and visualization of anti-inflammatory effects of pioglitazone on plaque inflammation in subjects with impaired glucose tolerance and type 2 diabetes mellitus by FDG-PET/CT]. clinicaltrials.gov/ct2/show/NCT00722631 2007.

[CD013516-bib-0108] NCT01006018. DPP-4 inhibition and TZD for DM prevention (DInT DM). clinicaltrials.gov/show/NCT01006018 (first received 7 june 2013).

[CD013516-bib-0109] Norris SL, Carson S, Roberts C. Comparative effectiveness of pioglitazone and rosiglitazone in type 2 diabetes, prediabetes, and the metabolic syndrome: a meta-analysis. Current Diabetes Reviews 2007;3(2):127-40. [DOI: 10.2174/157339907780598216] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0110] UMIN000001035. Therapeutic efficacy of pioglitazone for non-alcoholic fatty liver desease(NAFLD) patients with impaired glucose tolerance or type 2 diabetes. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000001215 2008.

[CD013516-bib-0111] Wu FM. Clinical study of pioglitazone on chronic heart failure and urinary albumin in prediabetic patients [瑞彤对糖尿病前期慢性心衰及尿白蛋白的临床研究]. 实用糖尿病杂志 [Journal of Practical Diabetology] 2008;4(3):46-8. [DOI: 10.3969/j.issn.1673-9191.2008.03.038] [DOI] [Google Scholar]

[CD013516-bib-0112] Yang HB, Zhao XY, Zhang JY, Du YY, Wang XF. Pioglitazone induces regression and stabilization of coronary atherosclerotic plaques in patients with impaired glucose tolerance. Diabetic Medicine 2012;29(3):359-65. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0113] UMINC000000230. Effects of pioglitazone on coronary atherosclerotic plaques of patients with impaired glucose tolerance or type 2 diabetes mellitus:a randomized,open rabelled,prospective study [Effects of pioglitazone on coronary atherosclerotic plaques:a randomized,open rabelled,prospective study of pioglitazone intervention on coronary atherosclerosis (PIGEON) using intravascular ultrasound]. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000000230 2010.

[CD013516-bib-0114] Yokoyama J, Sutoh N, Higuma T, Horiuchi D, Katoh C, Yokota T, et al. Efficacy and safety of low-dose pioglitazone after primary coronary angioplasty with the use of bare metal stent in patients with acute myocardial infarction and with type 2 diabetes mellitus or impaired glucose tolerance. Heart and Vessels 2007;22(3):146-51. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0115] Zhang QX. Clinical effect of pioglitazone on hypertension with diabetes mellitus with abnormal glucose tolerance [吡格列酮对高血压合并糖尿病糖耐量异常的临床疗效分析]. Diabetes New World [糖尿病新世界] 2014;34(10):9. [Google Scholar]

[CD013516-bib-0116] Zhao XY, Zhang JY, Yang HB, Li L, Du YY, Wang XF. Pioglitazone regresses coronary plaques in patients of impaired glucose tolerance combined with coronary borderline lesions [吡格列酮缩小糖耐量异常患者冠状动脉斑块面积的临床研究]. Chinese Circulation Journal [中国循环杂志] 2011;26(6):418-21. [DOI: 10.3969/j.issn.1000-3614.2011.06.006] [DOI] [Google Scholar]

[CD013516-bib-0117] Zhou WD. The intervention study on impaired glucose tolerance [糖耐量减低的干预研究]. Journal of Clinical Research [医学临床研究] 2006;23(5):714-6. [Google Scholar]

[CD013516-bib-0118] ChiCTR-PRC-06000005. Beijing prediabetes reversion program [Pre-diabetes reversion program in Beijing]. www.chictr.org.cn/showproj.aspx?proj=9520 (first received March 2007).

[CD013516-bib-0119] Duan W, Luo Y, Wang H, Ji L. A compliance evaluation model of lifestyle intervention in prediabetes. American Diabetes Association 2014;63:A208. [DOI: 10.2337/db14-665-832] [DOI] [Google Scholar]

[CD013516-bib-0120] Luo Y, Paul SK, Zhou X, Chang C, Chen W, Guo X, et al. Rationale, design, and baseline characteristics of Beijing Prediabetes Reversion Program: a randomized controlled clinical trial to evaluate the efficacy of lifestyle intervention and/or pioglitazone in reversion to normal glucose tolerance in prediabetes. Journal of Diabetes Research 2017;2017:7602408. [DOI: 10.1155/2017/7602408] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0121] Luo Y, Zhou X, Wang H, Ji L. Study design and baseline characteristics of Beijing Pre-diabetes Reversion Program (BPRP). American Diabetes Association 2012;61:A626. [DOI: 10.2337/db12-2323-2568] [DOI] [Google Scholar]

[CD013516-bib-0122] NCT02969798. Pre-diabetes in subject with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) [Preservation of beta cell function in pre-diabetes in subject with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)]. clinicaltrials.gov/ct2/show/nct02969798 (first received 21 November 2016).

[CD013516-bib-0123] Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 2006;55(5):1430-5. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0124] American Diabetes Association. Report on the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183-97. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0125] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S5-20. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0126] American Diabetes Association. Standards of medical care in diabetes - 2008. Diabetes Care 2008;31 Suppl 1:S12-54. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0127] American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 Suppl 1:S62-9. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0128] American Diabetes Association. Standards of medical care in diabetes - 2015. Diabetes Care 2015;38 Suppl 1:S1-93. [PMID: ] [PubMed] [Google Scholar]

[CD013516-bib-0129] American Diabetes Association (ADA). Standards of medical care in diabetes - 2017. Diabetes Care 2017;40 Suppl 1:S 11-33. [Google Scholar]

[CD013516-bib-0130] Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ 2003;326(7382):219. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0131] Babai S, Auclert L, Le-Louet H. Safety data and withdrawal of hepatotoxic drugs. Therapie 2018;S0040-5957(18):30036-2. [DOI: 10.1016/j.therap.2018.02.004] [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0132] Bell ML, McKenzie JE. Designing psycho-oncology randomised trials and cluster randomised trials: variance components and intra-cluster correlation of commonly used psychosocial measures. Psycho-oncology 2013;22:1738-47. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0133] Borenstein M, Higgins JP, Hedges LV, Rothstein HR. Basics of meta-analysis: I² is not an absolute measure of heterogeneity. Research Synthesis Methods 2017;8(1):5-18. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0134] Borenstein M. Prediction intervals. www.meta-analysis.com/prediction (accessed 1 September 2019).

[CD013516-bib-0135] Boutron I, Altman DG, Hopewell S, Vera-Badillo F, Tannock I, Ravaud P. Impact of spin in the abstracts of articles reporting results of randomized controlled trials in the field of cancer: the SPIIN randomized controlled trial. Journal of Clinical Oncology 2014;32(36):4120-6. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0136] Buch MH, Aletaha D, Emery P, Smolen JS. Reporting of long-term extension studies: lack of consistency calls for consensus. Annals of the Rheumatic Diseases 2011;70(6):886-90. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0137] Centers for Disease Control and Prevention. 2014 National Diabetes Statistics Report. www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html (accessed 15 October 2015).

[CD013516-bib-0138] Cheng C, Kushner H, Falkner BE. The utility of fasting glucose for detection of prediabetes. Metabolism: Clinical and Experimental 2006;55(4):434-8. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0139] Search terms: prediabetes drugs. clinicaltrials.gov/ct2/results?term=prediabetes+drugs&Search=Search (accessed 7 June 2019).

[CD013516-bib-0140] Cochrane. CENTRAL creation details. www.cochranelibrary.com/central/central-creation (accessed 21 August 2018).

[CD013516-bib-0141] Cohen D. Rosiglitazone: what went wrong? BMJ (Clinical Research Ed.) 2010;341:c4848. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0142] Consolidated Standards of Reporting Trials (CONSORT). The CONSORT statement. www.consort-statement.org (accessed 7 June 2019).

[CD013516-bib-0143] Cooper C, Varley-Campbell J, Carter P. Established search filters may miss studies when identifying randomized controlled trials. Journal of Clinical Epidemiology 2019;112(Aug):12-9. [DOI: 10.1016/j.jclinepi.2019.04.002] [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0144] Corbett MS, Higgins JP, Woolacott NF. Assessing baseline imbalance in randomised trials: implications for the Cochrane risk of bias tool. Research Synthesis Methods 2014;5(1):79-85. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0145] Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Correction to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2019;62(5):873. [PMID: ] [DOI] [PubMed]

[CD013516-bib-0146] Deeks JJ, Higgins JP, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

[CD013516-bib-0147] DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism: Clinical and Experimental 1989;38(4):387-95. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0148] Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 2002;346(6):393-403. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0149] Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374(9702):1677-86. [DOI] [PMC free article] [PubMed]

[CD013516-bib-0150] Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374(9702):1677-86. [DOI: 10.1016/S0140-6736(09)61457-4] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0151] Dunkley AJ, Bodicoat DH, Greaves CJ, Russell C, Yates T, Davies MJ, et al. Diabetes prevention in the real world: effectiveness of pragmatic lifestyle interventions for the prevention of type 2 diabetes and of the impact of adherence to guideline recommendations: a systematic review and meta-analysis. Diabetes Care 2014;37(4):922-33. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0152] Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 2001;344(18):1343-50. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0153] Gosmanov AR, Wan J. Low positive predictive value of hemoglobin A1c for diagnosis of prediabetes in clinical practice. American Journal of the Medical Sciences 2014;348(3):191-4. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0154] McMaster University (developed by Evidence Prime) GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), accessed 7 June 2019. Available at gradepro.org.

[CD013516-bib-0155] Hart B, Lundh A, Bero L. Effect of reporting bias on meta-analyses of drug trials: reanalysis of meta-analyses. BMJ 2012;344:d7202. [DOI: 10.1136/bmj.d7202] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0156] Haw JS, Galaviz KI, Straus AN, Kowalski AJ, Magee MJ, Weber MB, et al. Long-term sustainability of diabetes prevention approaches: a systematic review and meta-analysis of randomized clinical trials. JAMA Internal Medicine 2017;177(12):1808-17. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0157] Hemmingsen B, Sonne DP, Metzendorf MI, Richter B. Insulin secretagogues for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No: CD012151. [DOI: 10.1002/14651858.CD012151.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0158] Hemmingsen B, Krogh J, Metzendorf MI, Richter B. Sodium-glucose cotransporter (SGLT) 2 inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No: CD012106. [DOI: 10.1002/14651858.CD012106.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0159] Hemmingsen B, Sonne DP, Metzendorf MI, Richter B. Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No: CD012204. [DOI: 10.1002/14651858.CD012204.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0160] Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539-58. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0161] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327(7414):557-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0162] Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. Journal of the Royal Statistical Society: Series A (Statistics in Society) 2009;172(1):137-59. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0163] Higgins JP, Li T, Deeks JJ (editors). Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

[CD013516-bib-0164] Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

[CD013516-bib-0165] Hoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ 2014;348:g1687. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0166] Hoffmann TC, Oxman AD, Ioannidis JP, Moher D, Lasserson TJ, Tovey DI, et al. Enhancing the usability of systematic reviews by improving the consideration and description of interventions. BMJ 2017;358:j2998. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0167] Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Medical Research Methodology 2005;5:13. [DOI: 10.1186/1471-2288-5-13] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0168] Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, et al. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. Canadian Medical Association Journal 2013;185(4):E201-11. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0169] International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice //1997 CFR & ICH Guidelines. In: PA 19063-2043. USA: Barnett International/PAREXEL, 1997.

[CD013516-bib-0170] International Diabetes Federation (IDF). IDF Diabetes Atlas. 6th edition. Brussels: International Diabetes Federation, 2013. [Google Scholar]

[CD013516-bib-0171] International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32(7):1327-34. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0172] Inzucchi SE. Clinical practice. Diagnosis of diabetes. New England Journal of Medicine 2012;367(6):542-50. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0173] Jones CW, Keil LG, Holland WC, Caughey MC, Platts-Mills TF. Comparison of registered and published outcomes in randomized controlled trials: a systematic review. BMC Medicine 2015;13:282. [DOI: 10.1186/s12916-015-0520-3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0174] Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ 2010;340:c365. [DOI: 10.1136/bmj.c365] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0175] Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open 2017;7(1):e013927. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0176] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic and meta-analyses of studies that evaluate interventions: explanation and elaboration. PLoS Medicine 2009;6(7):e1000100. [DOI: 10.1371/journal.pmed.1000100] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0177] Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No: MR000033. [DOI: 10.1002/14651858.MR000033.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0178] Marshall IJ, Noel-Storr AH, Kuiper J, Thomas J, Wallace BC. Machine learning for identifying randomized controlled trials: an evaluation and practitioner’s guide. Research Synthesis Methods 2018;9(4):602-14. [DOI: 10.1002/jrsm.1287 ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0179] Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 2009;302:977-84. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0180] McDonald S, Noel-Storr AH, Thomas J. Harnessing the efficiencies of machine learning and Cochrane Crowd to identify randomised trials for individual Cochrane reviews. Global Evidence Summit, Cape Town, South Africa 13-16 Semptember 2017.

[CD013516-bib-0181] Meader N, King K, Llewellyn A, Norman G, Brown J, Rodgers M, et al. A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation. Systematic Reviews 2014;3:82. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0182] Megan B, Pickering RM, Weatherall M. Design, objectives, execution and reporting of published open-label extension studies. Journal of Evaluation in Clinical Practice 2012;18(2):209-15. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0183] Merlotti C, Morabito A, Pontiroli AE. Prevention of type 2 diabetes; a systematic review and meta-analysis of different intervention strategies. Diabetes, Obesity & Metabolism 2014;16(8):719-27. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0184] Morris DH, Khunti K, Achana F, Srinivasan B, Gray LJ, Davies MJ, et al. Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis. Diabetologia 2013;56(7):1489-93. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0185] National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039-57. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0186] Ninomiya H, Hirata A, Kozawa J, Nakata S, Kimura T, Kitamura T, et al. Treatment of mitochondrial diabetes with a peroxisome proliferator-activated receptor (PPAR)-gamma agonist. Internal Medicine (Tokyo, Japan) 2016;55(9):1143-7. [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0187] Noel-Storr AH, the Project Transform team. Cochrane Crowd: new ways of working together to produce health evidence. Evidence Live 2018, Oxford, UK 18–20 June 2018.

[CD013516-bib-0188] Pang B, Zhao L-H, Li X-L, Song J, Li Q-W, Liao X, et al. Different intervention strategies for preventing type 2 diabetes mellitus in China: a systematic review and network meta-analysis of randomized controlled trials. Diabetes, Obesity & Metabolism 2018;20(3):718-22. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0189] Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine 2015;373(1):11-22. [DOI] [PubMed]

[CD013516-bib-0190] The Cochrane Collaboration Review Manager 5 (RevMan 5). Version 5.4. Copenhagen: The Cochrane Collaboration, 2020.

[CD013516-bib-0191] Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No: CD006060. [DOI: 10.1002/14651858.CD006060.pub2] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0192] Richter B, Hemmingsen B, Metzendorf MI, Takwoingi Y. Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia. Cochrane Database of Systematic Reviews 2018, Issue 10. Art. No: CD012661. [DOI: 10.1002/14651858.CD012661.pub2] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0193] Riley RD, Kauser I, Bland M, Thijs L, Staessen JA, Wang J, et al. Meta-analysis of randomised trials with a continuous outcome according to baseline imbalance and availability of individual participant data. Statistics in Medicine 2013;32(16):2747-66. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0194] Schernthaner G, Currie CJ, Schernthaner GH. Do we still need pioglitazone for the treatment of type 2 diabetes? A risk-benefit critique in 2013. Diabetes Care 2013;36 Suppl 2:S155-61. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0195] Schroll JB, Bero L. Regulatory agencies hold the key to improving Cochrane Reviews of drugs [editorial]. Cochrane Database of Systematic Reviews 2015;4:10.1002/14651858.ED000098. [DOI] [PMC free article] [PubMed]

[CD013516-bib-0196] Schünemann HJ, Higgins JP, Vist GE, Glasziou P, Akl EA, Skoetz N, et al. Chapter 14: Completing ‘Summary of findings’ tables and grading the confidence in or quality of the evidence. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors), Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from www.training.cochrane.org/handbook.

[CD013516-bib-0197] Selvin E, Steffes MW, Ballantyne CM, Hoogeveen RC, Coresh J, Brancati FL. Racial differences in glycemic markers: a cross-sectional analysis of community-based data. Annals of Internal Medicine 2011;154(5):303-9. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0198] Thomas J, Noel-Storr AH, Marshall I, Wallace B, McDonald S, Mavergames C, et al. Living systematic review network. Living systematic reviews: 2. combining human and machine effort. Journal of Clinical Epidemiology 2017;S0895-4356(17):30604-2. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0199] Viera AJ. Predisease: when does it make sense? Epidemiologic Reviews 2011;33:122-34. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0200] World Health Organization/International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: report of a WHO/IDF consultation. www.who.int/diabetes/publications/Definition%20and%20diagnosis%20of%20diabetes_new.pdf 2006;(accessed 17 March 2017).

[CD013516-bib-0201] Alberti KM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Medicine 1998;15(7):539-53. [DOI] [PubMed] [Google Scholar]

[CD013516-bib-0202] World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. In: Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, Switzerland: World Health Organization, 1999:1-59. [Google Scholar]

[CD013516-bib-0203] Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008;336(7644):601-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD013516-bib-0204] Yudkin JS, Montori VM. The epidemic of pre-diabetes: the medicine and the politics. BMJ 2014;349:g4485. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus

Emil Ørskov Ipsen

Kasper S Madsen

Yuan Chi

Ulrik Pedersen-Bjergaard

Bernd Richter

Maria-Inti Metzendorf

Bianca Hemmingsen

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

Adverse effects of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Diagnostic criteria for 'prediabetes'

Types of interventions

Intervention

Comparisons

Minimum duration of intervention

Minimum duration of follow‐up

Summary of specific exclusion criteria

Types of outcome measures

Primary outcomes

Secondary outcomes

Method of outcome measurement

Timing of outcome measurement

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

1. Overview of study populations.

Dealing with duplicate and companion publications

Data from clinical trials registers

Assessment of risk of bias in included studies

Summary assessment of risk of bias

Risk of bias for a study across outcomes

Risk of bias for an outcome within a study and across domains

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

'Summary of findings' table

Summary of findings 1. Summary of findings: pioglitazone monotherapy versus another pharmacological glucose‐lowering monotherapy.

Summary of findings 2. Summary of findings: pioglitazone monotherapy versus intensive behaviour‐changing intervention.

Summary of findings 3. Summary of findings: pioglitazone monotherapy versus placebo.

Summary of findings 4. Summary of findings: pioglitazone monotherapy versus no intervention.

Results

Description of studies

Results of the search

1.

Included studies

Source of data

Comparisons

Overview of study populations

Study design

Settings

Participants