Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

<b>Objective: </b>To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. <p><b>Research Design and Methods: </b>From 1996-1999,<b> </b>3234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized.<b> </b>Causes of deaths through December 31, 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios were estimated from Cox-proportional hazard regression models and Fine-Gray models, respectively.</p> <p><b>Results:</b> Over a median of 21 (IQR 20-21) years, 453 participants died. Cancer was the leading cause of death (n=170), followed by cardiovascular disease (n=131). Compared to placebo, metformin did not influence mortality from all causes (HR 0.99, 95% CI 0.79, 1.25), cancer (HR 1.04, 95% CI 0.72, 1.52) or cardiovascular disease (HR 1.08, 95% CI 0.70, 1.66). Similarly, lifestyle modification did not impact all-cause (HR 1.02, 95% CI 0.81, 1.28), cancer (HR 1.07, 95% CI 0.74, 1.55) or cardiovascular disease (HR 1.18, 95% CI 0.77, 1.81) mortality. Analyses adjusted for diabetes status and duration, body mass index, cumulative glycemic exposure, and cardiovascular risks yielded similar results for all-cause mortality.</p> <p><b>Conclusions: </b>Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.</p>