Effects of withdrawal from metformin on the development of diabetes in the Diabetes Prevention Program

OBJECTIVE: In the Diabetes Prevention Program (DPP), metformin significantly reduced the risk of diabetes in individuals with impaired glucose tolerance. Diabetes status was assessed by oral glucose tolerance tests (OGTTs) performed while participants were still taking metformin or placebo. To determine whether the observed benefit was a transient pharmacological effect or more sustained, we performed a repeat OGTT after a short "washout" period during which medications (metformin or placebo) were withheld. RESEARCH DESIGN AND METHODS: All participants assigned to medication who had not developed diabetes at the end of the DPP were asked to have a repeat OGTT after discontinuing the study medication for 1-2 weeks. The predesignated outcome was the odds of diabetes in metformin versus placebo comparisons during the trial and washout combined RESULTS: There were 1,274 participants who participated in the washout study and 529 who did not because they had already developed diabetes. Before the washout, the odds of diabetes in the metformin group was lower than that in the placebo group (odds ratio 0.66, 95% CI 0.54-0.82, P < 0.001). After the washout, diabetes was somewhat more frequently diagnosed in the metformin participants (1.49, 0.93-2.38, P = 0.098). Combining diabetes conversions during the DPP and during the washout, diabetes was diagnosed significantly less frequently in the metformin than the placebo group (0.75, 0.62-0.92, P = 0.005). CONCLUSIONS: The primary analysis of the DPP demonstrated that metformin decreased the risk of diabetes by 31%. The washout study shows that 26% of this effect can be accounted for by a pharmacological effect of metformin that did not persist when the drug was stopped. After the washout the incidence of diabetes was still reduced by 25%.