DPP 2002.

Methods	Parallel randomised controlled clinical trial, randomisation ratio 1:1
Participants	Inclusion criteria: ≥ 25 years, BMI ≥ 24 kg/m2 in Asians BMI ≥ 22 kg/m2, FPG 95‐125 mg/dl (5.3‐6.9 mmol/L) and 2 hour plasma glucose after an OGTT 140‐199 mg/dL (7.8‐11.0 mmol/L). Because of the relative higher rate of progression from impaired glucose tolerance to diabetes in Native Americans and the small size of the population, the glucose requirement for eligibility in the Southwest American Indian Center will be fasting glucose < 126 mg/dL (7.0 mmol/L) and 2 hour plasma glucose after an OGTT 140‐199 mg/dL (7.8‐11.0 mmol/L). Exclusion criteria: T2DM, participants taking medicines known to alter glucose tolerance, ever used glucose‐lowering drugs during pregnancy, illnesses that could seriously reduce their life expectancy or their ability to participate in the trial, cardiovascular disease (hospitalisation for treatment of heart disease in past 6 months; NYHA class > 2; left bundle branch block or third degree atrioventricular block; aortic stenosis; SBP > 180 mmHg or DBP > 105 mmHg); cancer requiring treatment in the past five years (unless prognosis is considered good); renal disease; gastrointestinal disease; anaemia (hematocrit < 36.0% in men or < 33.0% in women); electrolyte abnormality (serum potassium < 3.2 or > 5.5 mmol/L). Diagnostic criteria: impaired glucose tolerance (2 hour plasma glucose after an OGTT 140‐199 mg/dl (7.8‐11.0 mmol/L)) and elevated fasting glucose (FPG 95‐125 mg/dl (5.3‐6.9 mmol/L)) (ADA 1997).
Interventions	Number of study centres: 27 Treatment before study: none Run‐in period: 3 weeks; during the run‐in period the participants had to fill out a daily dairy and placebo pills according to a schedule Extension period: yes, an additional follow‐up with a median of 5.7 years (IQR 5.5–5.8) after end of the intervention period
Outcomes	Composite outcome measures reported: yes (Quote from publication: ".....a composite microvascular‐neuropathic outcome for diabetic retinopathy, nephropathy, or reduced light touch sensation in the feet. Secondary outcomes include the individual components of the composite primary outcome, cardiovascular disease, further development of diabetes, measures of glycaemia, insulin secretion, insulin sensitivity, cardiovascular disease risk factors, physical activity, nutrition, bodyweight, health‐related quality of life, and economic assessments.")
Study details	Trial terminated early: yes, the trial was stopped one year earlier than originally planned due to larger intervention effect of diet and physical activity than anticipated.
Publication details	Language of publication: English Funding: commercial funding (Lipha (Merck‐Sante) provided medicines, and LifeScan donated materials)/non‐commercial funding (the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the Office of Women’s Health, the National Center for Minority Health and Human Disease, the Centers for Disease Control and Prevention, and the American Diabetes Association) Publication status: peer‐reviewed journal
Stated aim of study	Quote from publication: "The principal objective of the DPP is to prevent or delay the development of NIDDM in those persons who are at high risk for its development by virtue of having impaired glucose tolerance"
Notes	Individuals who meet only one of the glucose inclusion criteria was re‐screened after 6 months. Because of the relative higher rate of progression from impaired glucose tolerance to T2DM in Native Americans and the small size of the population, the glucose requirement for eligibility in the Southwest American Indian Center differed (see above) The trial included initially four intervention groups. The metformin group is not included in this review. The troglitazone group was discontinued in 1998 because of potential liver toxicity.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "A sequence of randomization numbers within a clinical center will be constructed of the form XXYZZZ, where XX is the clinical center number, Y is a number that indicates assignment to either the intensive lifestyle intervention or pharmacological treatment, and ZZZ is a three digit sequence number within each XXY combination. The DPP Coordinating Center will prepare the master randomization list with assignments to the three treatment groups within a clinical center using the standard urn design. The sequence of pharmacological randomization numbers within a clinical center with the specific pharmacological treatment assignment (i.e., metformin or placebo) will be forwarded, in confidence, to the drug distribution center for drug labelling and distribution. Pharmacological treatment assignment to the sequence of pharmacological randomization numbers will be known only by the staff of the DPP Coordinating Center and the drug distribution center." Comment: adequate generation of random sequence ensured
Allocation concealment (selection bias)	Low risk	Quote from publication: "A sequence of randomization numbers within a clinical center will be constructed of the form XXYZZZ, where XX is the clinical center number, Y is a number that indicates assignment to either the intensive lifestyle intervention or pharmacological treatment, and ZZZ is a three digit sequence number within each XXY combination. The DPP Coordinating Center will prepare the master randomization list with assignments to the three treatment groups within a clinical center using the standard urn design. The sequence of pharmacological randomization numbers within a clinical center with the specific pharmacological treatment assignment (i.e., metformin or placebo) will be forwarded, in confidence, to the drug distribution center for drug labelling and distribution. Pharmacological treatment assignment to the sequence of pharmacological randomization numbers will be known only by the staff of the DPP Coordinating Center and the drug distribution center." Comment: adequate allocation concealment ensured
Blinding of participants and personnel (performance bias) all‐cause mortality/cardiovascular mortality	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." Comment: no blinding but judged that the outcome is not likely to be influenced by lack of blinding, investigator‐assessed outcome measurement
Blinding of participants and personnel (performance bias) incidence of T2DM	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." and "Primary outcome data (OGTT and FPG results) measured centrally will remain masked to the investigators and to the participants until confirmed progression from IGT to diabetes" Comment: assessed centrally unblinded, the outcome is not likely to be influenced by lack of blinding. Participants and investigators blinded to until progression to T2DM
Blinding of participants and personnel (performance bias) measures of blood glucose control	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." and "Primary outcome data (OGTT and FPG results) measured centrally will remain masked to the investigators and to the participants until confirmed progression from IGT to diabetes" and Plasma lipid levels and HbA1c measured centrally will remain masked to the investigators and to the participants during the study." Comment: assessed centrally unblinded, the outcome is not likely to be influenced by lack of blinding. Participants and investigators blinded to until progression to T2DM
Blinding of participants and personnel (performance bias) socioeconomic effects	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." Comment: no blinding but judged that the outcome is not likely to be influenced by lack of blinding, investigator‐assessed outcome measurement
Blinding of participants and personnel (performance bias) Health related quality of life	High risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." Comment: no blinding and the outcome is likely to be influenced by lack of blinding, self‐reported outcome measurement
Blinding of outcome assessment (detection bias) all‐cause/cardiovascular mortality	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." Comment: no blinding but judged that the outcome is not likely to be influenced by lack of blinding, investigator‐assessed outcome measurement
Blinding of outcome assessment (detection bias) incidence of T2DM	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." and "Primary outcome data (OGTT and FPG results) measured centrally will remain masked to the investigators and to the participants until confirmed progression from IGT to diabetes" Comment: assessed centrally unblinded, the outcome is not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) measures of blood glucose control	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." and "Primary outcome data (OGTT and FPG results) measured centrally will remain masked to the investigators and to the participants until confirmed progression from IGT to diabetes" and "Plasma lipid levels and HbA1c measured centrally will remain masked to the investigators and to the participants during the study." Comment: assessed centrally unblinded, the outcome is not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) socioeconomic effects	Low risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." Comment: no blinding but judged that the outcome is not likely to be influenced by lack of blinding, investigator‐assessed outcome measurement
Blinding of outcome assessment (detection bias) Health related quality of life	High risk	Quote from publication: "Masking intensive lifestyle intervention assignment to the participants is not possible and masking the investigators is not practical." Comment: no blinding and the outcome is likely to be influenced by lack of blinding, self‐reported outcome measurement
Incomplete outcome data (attrition bias) all‐cause/cardiovascular mortality	Low risk	Quote from publication: "At the close of the study, 99.6 percent of the participants were alive, of whom 92.5 percent had attended a scheduled visit within the previous five months" Comment: not stated how many participants who had known vital status in each intervention group at the end of follow‐up for the DPP trial. However, at inception of the number with unknown mortality status are relatively low. At inception of the DPPOS the number between the intervention groups we balanced.
Incomplete outcome data (attrition bias) incidence of T2DM	Low risk	Quote from publication: "At the close of the study, 99.6 percent of the participants were alive, of whom 92.5 percent had attended a scheduled visit within the previous five months" Comment: not stated how many participants who had known vital status at the end of follow‐up for the DPP trial. However, at inception of the DPPOS a relatively low and balanced number of participants in the intervention groups could not be included.
Incomplete outcome data (attrition bias) measures of blood glucose control	Low risk	Comment: not stated how many participants who had known vital status at the end of follow‐up for the DPP trial. However, at inception of the DPPOS a relatively low and balanced number between the intervention groups could not be included.
Incomplete outcome data (attrition bias) time to progression to T2DM	Low risk	Comment: "At the close of the study, 99.6 percent of the participants were alive, of whom 92.5 percent had attended a scheduled visit within the previous five months"
Incomplete outcome data (attrition bias) socioeconomic effects	Low risk	Comment: not clearly described how many participants included in the costs analyses, but as the study have a high follow‐up rate, we assume that nearly all participants are included.
Incomplete outcome data (attrition bias) Health related quality of life	Low risk	Quote from publication: The current report and analyses includes 3,234 participants seen at baseline, who were randomly assigned to one of the three treatment arms investigated. Comment: article reporting health related quality of life do not report the number of participants with available data at follow‐up
Selective reporting (reporting bias)	High risk	Comment: several outcome are likely to be measured and analysed, but not reported, e.g. hypoglycaemia, non‐serious adverse events. outcomes published in many different publications. Many outcomes are reported incompletely so that they cannot be entered in a meta‐analysis
Other bias	High risk	Comment: trial terminated early for benefit Comment: received funding from a pharmaceutical company