Factors Associated With Diabetes Onset During Metformin Versus Placebo Therapy in the Diabetes Prevention Program

Abstract

on behalf of the DPP Research GroupIn the Diabetes Prevention Program, treatment of subjects with impaired glucose tolerance with metformin >3.2 years reduced the risk of developing type 2 diabetes by 30% compared with placebo. This study describes the mechanisms of this effect. In proportional hazards regression models with 2,155 subjects, changes in weight, the insulinogenic index (IGR), fasting insulin, and proinsulin were predictive of diabetes, though to different degrees within each group. The mean change in weight, fasting insulin, and proinsulin, but not IGR, differed between groups during the study. The 1.7-kg weight loss with metformin versus a 0.3-kg gain with placebo alone explained 64% of the beneficial metformin effect on diabetes risk. Adjustment for weight, fasting insulin, proinsulin, and other metabolic factors combined explained 81% of the beneficial metformin effect, but it remained nominally significant (P ‫؍‬ 0.034). After the addition of changes in fasting glucose, 99% of the group effect was explained and is no longer significant. Treatment of high-risk subjects with metformin results in modest weight loss and favorable changes in insulin sensitivity and proinsulin, which contribute to a reduction in the risk of diabetes apart from the associated reductions in fasting glucose. Diabetes 56:1153-1159, 2007 I n the Diabetes Prevention Program (DPP), lifestyle intervention reduced the risk of confirmed type 2 diabetes by 55% relative to placebo (1), most of this effect being explained by the resulting changes in body weight (2). Treatment with metformin led to reductions in body weight and favorable changes in other metabolic factors and reduced the risk of diabetes versus placebo by 30% (1,3).Univariate analyses show that changes in weight and metabolic factors over the 1st year of follow-up are associated with diabetes risk (3). This study evaluates the association between changes in weight, metabolic factors, and other factors, over the complete 3.2 years of followup, with the risk of diabetes among those treated with metformin versus placebo and the extent to which these factors explain the beneficial effects of metformin on the risk of diabetes. RESEARCH DESIGN AND METHODSThe DPP was a randomized clinical trial of 3,819 participants with elevated fasting plasma glucose (FPG) and impaired glucose tolerance (IGT) followed for an average of 3.2 years; 1,079 were assigned to lifestyle intervention, 1,073 to metformin, and 1,082 to placebo. Eligibility criteria and study design were previously described (4). Elevated FPG confers high risk of diabetes among those with IGT (5,6). Measurements. All laboratory measurements were performed centrally: FPG and A1C every 6 months and plasma glucose, total immunoreactive insulin, and proinsulin annually during a 75-g oral glucose tolerance test (OGTT). Diabetes onset was detected by an OGTT at an annual visit, or by a semi-annual fasting glucose level, with confirmation on a second test within 6 weeks (4) using the American Diabetes Association criteri...

Type of preadmission glucose-lowering treatment and prognosis among patients hospitalised with myocardial infarction: a nationwide follow-up study

“…However, it has recently been reported that high proinsulin levels (which are reduced by metformin [24]) are pro-atherosclerotic in women, but not in men [25], and this might provide at least some explanation for our finding.…”

Early Response to Preventive Strategies in the Diabetes Prevention Program

“…3,4 Lachin et al demonstrated that change in fasting glucose over the study duration was the strongest predictor of diabetes risk in the metformin and placebo arms, accounting for 14 % and 25 % of the decrease in risk over the course of the study in these two arms, respectively. 4 Among participants who had both impaired fasting glucose and impaired glucose tolerance at baseline, each standard deviation of mean weight loss was associated with a 34 % increased probability of regression to normal glucose regulation. 13 We now extend our understanding of these benefits by quantifying the predictive value of weight, glucose and HbA1c during the first 12 months of a preventive effort, and thereby inform approaches to intensifying preventive therapies in clinical practice.…”

“…1,2 Prior research in the DPP established that weight loss (more than physical activity) mediates the beneficial effects of lifestyle change, 3 and that both weight loss and reduced glycemia mediate the beneficial effects of metformin. 4 These analyses indicate the contribution of average weight loss over a 3-year period to the success of the trial's interventions. However, clinicians see their patients at high risk of diabetes at least yearly, if not more frequently.…”

Non-pharmacological interventions to reduce the risk of diabetes in people with impaired glucose regulation: a systematic review and economic evaluation.

“…83 Some of the benefits of metformin were the result of weight loss rather than improvements in insulin sensitivity. 203 Lachin et al (2007) 203 estimated that 64% of the metformin benefit was mediated through weight loss. Interestingly, they note that the effect of weight loss achieved with metformin appears to be less than the same weight lost by lifestyle change.…”