Analysis of long-term follow-up of a randomized clinical trial with departures from assigned treatments: Estimation of metformin effects on diabetes and its complications in the Diabetes Prevention Program Outcomes Study

The Diabetes Prevention Program (DPP) was a 3-year randomized clinical trial evaluating lifestyle and metformin interventions compared with placebo for diabetes prevention in high-risk adults. Both interventions significantly reduced diabetes incidence, prompting the long-term DPP Outcomes Study (DPPOS) to assess the progression of diabetes and its complications over 22 years. During follow-up, departures from the original metformin or placebo assignment occurred primarily because of development of diabetes that, by protocol, was managed by clinicians outside the study after participants developed diabetes with HbA1c ≥7.0%. This led to changes in metformin treatment and addition of other glucose-lowering therapies. Using statistical methods designed to estimate intervention effects despite these deviations, we consistently found that metformin reduced diabetes incidence. However, using these methods to evaluate whether use of metformin for pre-diabetes confers continued benefits after diabetes diagnosis did not substantially change the conclusions from the simpler intention-to-treat analysis that did not account for treatment changes. All the analytic methods used resulted in similar metformin effect estimates with 95% confidence intervals for hazard ratios including 1.0 (no effect) for all outcomes except for diabetes incidence. Elucidating metformin’s long-term role in mitigating diabetes-related complications beyond its effects on diabetes prevention is challenging.