<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>