Abstract
Introduction
Diabetes mellitus is now seen as a progressive disorder of glucose metabolism, affecting about 5% of the population worldwide, over 85% of whom have type 2 diabetes. Type 2 diabetes may occur with obesity, hypertension and dyslipidaemia (the metabolic syndrome), which are powerful predictors of CVD. Blood glucose levels rise progressively over time in people with type 2 diabetes regardless of treatment, causing microvascular and macrovascular complications.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions in adults with type 2 diabetes? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: combined oral drug treatment, diet, education, insulin (continuous subcutaneous infusion), insulin, intensive treatment programmes, meglitinides (nateglinide, repaglinide), metformin, monotherapy, blood glucose self-monitoring (different frequencies), and sulphonylureas (newer or older).
Key Points
Diabetes mellitus is now seen as a progressive disorder of glucose metabolism; it affects about 5% of the population worldwide, over 85% of whom have type 2 diabetes.
Type 2 diabetes is often associated with obesity, hypertension, and dyslipidaemia (the metabolic syndrome), which are powerful predictors of CVD.
Type 2 diabetes is a disease in which glucose levels rise over time, with or without treatment and irrespective of the type of treatment given. This rise may lead to microvascular and macrovascular complications.
Most people with type 2 diabetes will eventually need treatment with oral hypoglycaemic agents.
Metformin reduces glycated haemoglobin by 1−2% and reduces mortality compared with diet alone, without increasing weight, but it can cause hypoglycaemia compared with placebo.
Sulphonylureas reduce HbA1c by 1−2% compared with diet alone. Older sulphonylureas can cause weight gain and hypoglycaemia, but the risk of these adverse effects may be lower with newer-generation sulphonylureas.
Meglitinides (nateglinide, repaglinide) may reduce HbA1c by 0.4-0.9% compared with placebo, but may cause hypoglycaemia.
Combined oral drug treatment may reduce HbA1c levels more than monotherapy, but increases the risk of hypoglycaemia.
Insulin is no more effective than sulphonylureas in improving glucose control in people with newly diagnosed type 2 diabetes, and is associated with a higher rate of major hypoglycaemic episodes, and with weight gain.
Individual or group intensive educational programmes may reduce HbA1c compared with usual care, although studies have been of poor quality.
Insulin improves glycaemic control in people with inadequate control of HbA1c from oral drug treatment, but is associated with weight gain, and an increased risk of hypoglycaemia.
Adding metformin to insulin improves glucose control compared with insulin alone, but increases gastrointestinal adverse effects. However, the combination may cause less weight gain than insulin alone.
Monitoring of blood glucose levels has not been shown to improve glycaemic control in people not being treated with insulin.
Diet may be less effective than metformin or sulphonylureas in improving glucose control, although sulphonylureas were associated with higher rates of hypoglycaemia. However, there is consensus that weight reduction in people with type 2 diabetes can improve glycaemic control, as well as conferring other health benefits.
About this condition
Definition
The term diabetes mellitus encompasses a group of disorders characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects of insulin secretion, insulin action, or both. Type 2 diabetes is the most common form of diabetes, and defects of both insulin action and insulin secretion are usually present by the time of diagnosis. The WHO now recognises diabetes as a progressive disorder of glucose metabolism in which individuals may move between normoglycaemia (fasting plasma venous glucose less than 6.1 mmol/L), impaired glucose tolerance (fasting plasma venous glucose less than 7.0 mmol/L and plasma glucose between 7.8 mmol/L and 11.1 mmol/L after 2 hours of 75 g oral glucose load), or impaired fasting glycaemia (fasting venous plasma glucose between 6.1 mmol/L and 7.0 mmol/L), and frank hyperglycaemia (fasting plasma venous glucose 7.0 mmol/L or more or 11.1 mmol/L or more 2 hours after 75 g oral glucose load). As a consequence of the inability of the body to use glucose as an energy source, blood glucose levels rise and symptoms such as thirst, polyuria, blurring of vision, or weight loss may develop. Diagnosis: In the presence of symptoms, diabetes may be diagnosed on the basis of a single random elevated plasma glucose (11.1 mmol/L or more). In the absence of symptoms, the diagnosis should be based on blood glucose results in the diabetes range taken at different time points, either from a random sample, or fasting (plasma blood glucose 7.0 mmol/L or more), or from the oral glucose tolerance test (plasma blood glucose 11.1 mmol/L or more 2 hours after 75 g glucose load). Population: For the purpose of this review, we have excluded pregnant women and acutely unwell adults (e.g. after surgery or MI).
Incidence/ Prevalence
Type 2 diabetes constitutes about 85-95% of all diabetes in resource-rich countries and accounts for an even higher percentage in resource-poor countries. It is estimated that, in 2006, some 194 million people worldwide, or 5% of the adult population, have diabetes.This is an increase in prevalence from 177 million in 2000. It is predicted that the prevalence of diabetes will continue to increase and reach 333 million, or 6%, by 2025. By 2025, the region with the greatest number of people with diabetes is expected to be South-East Asia, with about 82 million people with type 2 diabetes. Incidence and prevalence figures for children and adolescents are unreliable, but there is some evidence that type 2 diabetes is becoming more common in adolescents and young adults, especially in resource-poor countries.The overall estimated prevalence of 5% for type 2 diabetes conceals considerable variation in prevalence, which ranges from less than 2% in some African countries to over 14% in some populations.
Aetiology/ Risk factors
By definition, the specific reasons for the development of the defects of insulin secretion and insulin action that characterise type 2 diabetes are unknown. The risk of type 2 diabetes increases with age and lack of physical activity, and occurs more frequently in people with obesity, hypertension, and dyslipidaemia (the metabolic syndrome). Features of the metabolic syndrome can be present for up to 10 years before disorders of glycaemic control become apparent, and are powerful predictors of CVD and abnormal glucose tolerance (impaired glucose tolerance or diabetes). Type 2 diabetes also occurs more frequently in women with previous gestational diabetes, and certain ethnic groups. There is also evidence of a familial, probably genetic, predisposition.
Prognosis
People with type 2 diabetes have blood glucose levels which have been shown to rise progressively from the time of diagnosis, with or without treatment, and irrespective of the type of treatment given. Blood glucose levels above the normal range have been shown to be associated not only with the presence of symptoms, but with an increased risk of long-term microvascular and macrovascular complications.
Aims of intervention
To control blood glucose levels in order to maximise quality of life and prevent diabetic emergencies, such as ketoacidosis and non-ketotic hyperosmolar coma; to maintain HbA1c levels and manage cardiovascular risk factors within the target range required to reduce the risk of microvascular and macrovascular complications; to improve quality of life, while minimising adverse effects of treatment.
Outcomes
Primary outcomes: Rate of rise of HbA1c; quality of life; adverse events (incidence of and mortality from hypoglycaemia, incidence of and mortality from lactic acidosis, non-ketotic hyperosmolar coma); weight gain; fluid retention; neuropsychological impairment. Secondary outcomes: All-cause mortality Excluded outcomes: Long-term outcomes such as development of retinopathy, nephropathy, neuropathy, and CVD.
Methods
BMJ Clinical Evidence search and appraisal October 2006. The following databases were used to identify studies for this review: Medline 1966 to October 2006, Embase 1980 to October 2006, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to evaluate relevant studies. Study-design criteria for inclusion in this review were: published systematic reviews and RCTs in any language. RCTs included 20 or more people, of whom 80% or more were followed up. There was no minimum length of follow-up required to include studies, with the exception of HbA1c levels, for which length of follow-up was 3 months. Studies were at least assessor-blinded: we excluded all studies described as "open", "open label", or not blinded. Crossover trials were included only if results were reported at the end of the initial treatment period before crossover. Educational interventions are defined as interventions, single, or multiple, that provide information, self-management programmes, or both. Interventions primarily focused on the organisational aspects of delivery of care have been excluded. Studies testing the effects of multiple intervention programmes without an education component have been excluded. For the comparison of human insulin versus insulin analogues, we included reviews or RCTs that compared agents with similar profiles. Human insulin and insulin analogues were searched for as basal and premixed insulins. It is not possible to blind RCTs of insulin analogues as they differ in appearance to conventional soluble insulin. Since our search did not aim to include open-label RCTs, we may have inadvertently excluded relevant RCTs of insulin analogues. We have included one open-label RCT, but it is to be noted that this may not reflect all the available evidence. Subsequent updates of the review will include these data. We use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for diabetes: glycaemic control in type 2
| Important outcomes | Reduction in HbA1c levels, quality of life, mortality, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of interventions for glycaemic control in adults with type 2 diabetes? | |||||||||
| 11 (at least 514 people) | Glycated haemoglobin levels | Metformin v placebo | 4 | –3 | +1 | 0 | 0 | Low | Quality points deducted for uncertainty about quality of RCTs, inclusion of cross-over study, and uncertainty about methods of measurement. Consistency point added for dose response |
| 1 (753) | Glycated haemoglobin levels | Adding metformin to a diet v diet alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and uncertainty about quality of RCTs |
| 1 (753) | Mortality | Adding metformin to a diet v diet alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results, and uncertainty about quality of studies |
| 11 (at least 514 people) | Adverse effects | Metformin v placebo | 4 | –3 | +1 | 0 | 0 | Low | Quality points deducted for uncertainty about quality of RCTs, inclusion of cross-over study, and uncertainty about methods of measurement. Consistency point added for dose response |
| 1 (753) | Adverse effects | Adding metformin to a diet v diet alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and uncertainty about quality of RCTs |
| 1 (8732) | Adverse effects | Metformin v usual care | 4 | –1 | 0 | 0 | 0 | Moderate | Quality points deducted for incomplete reporting of results |
| 1 (2711) | Glycated haemoglobin levels | Older sulphonylureas v diet | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for narrow inclusion criteria |
| 1 (46) | Glycated haemoglobin levels | Older sulphonylureas v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for narrow inclusion criteria |
| 4 (1102) | Glycated haemoglobin levels | Newer sulphonylureas v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 1 (569) | Quality of life | Newer sulphonylureas v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 3 (1667) | Glycated haemoglobin levels | Newer v older sulphonylureas | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 1 (845) | Glycated haemoglobin levels | Newer sulphonylureas v each other | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for narrow inclusion criteria |
| 1 (2711) | Adverse effects | Older sulphonylureas v diet alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 2 (1621) | Adverse effects | Newer v older sulphonylureas | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 1 (845) | Adverse effects | Newer sulphonylureas v each other | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 3 (1315) | Glycated haemoglobin levels | Meglitinides v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (370) | Glycated haemoglobin levels | Meglitinides v older sulphonylureas | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (132) | Glycated haemoglobin levels | Meglitinides v newer sulphonylureas | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (964)] | Adverse effects | Meglitinides v placebo | 4 | –1 | +1 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results. Consistency point added for dose effect |
| 3 (370) | Adverse effects | Meglitinides v older sulphonylureas | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (132) | Adverse effects | Meglitinides v newer sulphonylureas | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (3876) | Glycated haemoglobin levels | Insulin v sulphonylureas as initial treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (3876) | Glycated haemoglobin levels | Insulin v sulphonylureas as initial treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 1 RCT and 2 studies (5909) | Quality of life | Insulin v sulphonylureas as initial treatment | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and for inclusion of cross-sectional studies and longitudinal studies |
| 1 (3876) | Adverse effects | Insulin v sulphonylureas as initial treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (239)] | Glycated haemoglobin levels | Continous subcutaneous insulin infusion v optimised subcutaneous insulin injections | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for population differences |
| 2 (239) | Adverse effects | Continous subcutaneous insulin infusion v optimised subcutaneous insulin injections | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for population differences |
| 4 (343)] | Glycated haemoglobin levels | Insulin v continuation of oral hypoglycaemic agents | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and for not assessing differences between treatments |
| 2 (131)] | Quality of life | Insulin v continuation of oral hypoglycaemic agents | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data, and incomplete reporting of results |
| 4 (343) | Adverse effects | Insulin v continuation of oral hypoglycaemic agents | 4 | –1 | 0 | 0 | 0 | Moderate | Quality points deducted for incomplete reporting of results |
| 2 (396) | Glycated haemoglobin levels | Insulin v insulin plus metformin | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (396) | Adverse effects | Insulin v insulin plus metformin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality points deducted for incomplete reporting of results |
| 1 (62) | Glycated haemoglobin levels | Insulin analogues v conventional insulin | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and open-label RCT |
| 1 (62) | Adverse effects | Insulin analogues v conventional insulin | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, open-label RCT and for no direct comparison between groups |
| 5 (2113) | Glycated haemoglobin levels | Combined oral hypoglycaemics v monotherapy (older sulphonyl ureas plus metformin) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (494) | Glycated haemoglobin levels | Combined oral hypoglycaemics (newer sulphonyl ureas plus metformin) v monotherapy | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (1138) | Glycated haemoglobin levels | Combined oral hypoglycaemics (meglitinide plus metformin) v monotherapy | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (452) | Glycated haemoglobin levels | Combined oral hypoglycaemics (metformin plus acarbose) v monotherapy | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for incomplete reporting of results |
| 3 (358) | Glycated haemoglobin levels | Combined oral hypoglycaemics (sulphonylureas plus acarbose) v monotherapy | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (1434) | Adverse effects | Combined oral hypoglycaemics (older sulphonyl ureas plus metformin ) v monotherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for comparing different adverse effects |
| 2 (494) | Adverse effects | Combined oral hypoglycaemics (newer sulphonyl ureas plus metformin) v monotherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (609) | Adverse effects | Combined oral hypoglycaemics (meglitinide plus metformin) v monotherapy | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 3 (304) | Adverse effects | Combined oral hypoglycaemics v monotherapy (metformin plus acarbose ) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (358) | Adverse effects | Combined oral hypoglycaemics (sulphonylureas plus acarbose) v monotherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 19 (2774) | Glycated haemoglobin levels | Intensive education v usual care | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for methodological weaknesses |
| 5 (1006) | Glycated haemoglobin levels | Group education v usual care | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for methodological weaknesses |
| 2 (403) | Quality of life | Group education v usual care | 4 | –3 | –1 | 0 | 0 | Very low | Quality points deducted for inadequate blinding, uncertainty about randomisation in one RCT, intention-to-treat analysis flaws, and short follow-up. Consistency point deducted for conflicting results |
| 2 (158) | Glycated haemoglobin levels | Group education v individual education | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results |
| 3 (2449) | Glycated haemoglobin levels | Intensive-treatment programmes v usual care | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for conflicting results. Directness points deducted for population recruited affecting generalisability of results (differences in education, and glycaemic control) |
| 3 (344) | Glycated haemoglobin levels | Blood glucose self-monitoring v urine glucose self-monitoring | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- EQ5D
is a self-administered quality-of-life questionnaire used to characterise current health states. It consists of 5 domains relating to mobility, self-care, usual activity, pain, and anxiety/depression, and a visual analogue scale. Participants indicate their level of health by checking one of three boxes for each domain. Weights are used to score the responses to the 5 domains, with scores ranging from 0 to 1 (where a score of 1 represents a perfect health state). The visual analogue scale ranges from 0 to 100, where 100 represents the best possible health state.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Bala Srinivasan, Department of Diabetes and Endocrinology, University Hospitals of Leicester NHS Trust, Leicester, UK.
Nick Taub, Department of health sciences, University of Leicester, Leicester, UK.
Kamlesh Khunti, Department of health sciences, University of Leicester, Leicester, UK.
Melanie Davies, Leicester Royal Infirmary, Leicester, UK.
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