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

Abstract

The Diabetes Prevention Program (DPP) was a 3-year randomized clinical trial (RCT) with evaluation of lifestyle and metformin interventions compared with placebo for diabetes prevention in high-risk adults. Both interventions significantly reduced diabetes incidence, prompting the long-term Diabetes Prevention Program 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%. Diabetes development 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 prediabetes confers continued benefits after diabetes diagnosis did not substantially change the conclusions from those of the simpler intention-to-treat analysis that did not account for treatment changes. All of the analytic methods used resulted in similar metformin effect estimates with 95% CIs 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.

Graphical abstract

Figure 1

Percentage of participants taking metformin (in study or out of study) by year and treatment group. The upper panel includes only exams in participants without diabetes or with diabetes from the time period before the diabetes management change (i.e., before the first examination with diabetes and HbA_1c ≥7.0%). The lower panel includes all examinations in all participants, with or without diabetes. The x-axis labels denote the DPP follow-up years (DPP Y01, etc.) and DPPOS follow-up years (OS Y1, etc.). MET, metformin; PLAC, placebo.

Figure 2

Fractions of annual examinations at which participants reported taking placebo (or no drug), metformin, other glucose-lowering drug, or combinations, according to time before or after the diabetes management change, i.e., the first examination with diabetes and HbA_1c ≥7.0%. MET, metformin; PLAC, placebo.

Figure 3

Incidence rates (events/1,000 person-years at risk) for five outcomes by treatment group. Narrow bars show rates stratified by time before (B) and after (A) the diabetes management change, i.e., the first occurrence in each participant of diabetes with HbA_1c ≥7.0% (after which diabetes was managed outside of the study). Wide bars show incidence rates during the total (T) follow-up period. The diabetes outcome is not shown because, by definition, all time at risk occurred before the diagnosis of diabetes. Further, the diabetes incidence rates were much higher (66.7 events/1,000 person-years for the placebo group and 55.1 for the metformin group) and would be outside the scale of this figure. MACE, major adverse cardiovascular events; Obesity-Ca, obesity-related cancer.

Figure 4

HRs with 95% CIs for estimated metformin effects for six outcomes by four methods. ITT: intention to treat; AT: each examination scored as any metformin taken or not (dichotomous); IV: instrumental variable; IPCW: inverse-probability-of-censoring weighting. Outcome definitions and numbers of events are shown in Table 3 and Supplementary Table 1. Details can be found in Supplementary Table 3.