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

posted on 25.10.2021, 19:58 by Christine G. Lee, Brandy Heckman-Stoddard, Dana Dabelea, Kishore M. Gadde, David Ehrmann, Leslie Ford, Philip Prorok, Edward J. Boyko, Xavier Pi-Sunyer, Amisha Wallia, William C. Knowler, Jill P. Crandall, Marinella Temprosa, the Diabetes Prevention Program Research Group
Objective: 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.

Research Design and Methods: From 1996-1999, 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. 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.

Results: 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.

Conclusions: 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.


Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, U01 DK048400, by providing funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP/DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. . McKesson BioServices