Journal
CIRCULATION
Volume 145, Issue 22, Pages 1632-1641Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.121.056756
Keywords
cardiovascular diseases; diabetes mellitus, type 2; metformin
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) [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]
- The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) [U01 DK048387, U01 DK048407, U01 DK048443, U01 DK048400]
- National Institute of Child Health and Human Development
- National Institute on Aging
- National Eye Institute
- National Heart Lung and Blood Institute
- National Cancer Institute
- Office of Research on Women's Health
- National Institute on Minority Health and Health Disparities
- Centers for Disease Control and Prevention
- American Diabetes Association
- NIDDK
- Indian Health Service
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The study found that neither lifestyle intervention nor metformin reduced the incidence of major cardiovascular events over a 21-year period, despite their long-term diabetes prevention effects. It is possible that the provision of group lifestyle intervention to all participants, extensive use of statin and antihypertensive agents outside the study, and a decrease in the use of study metformin over time may have diluted the effects of these interventions.
BACKGROUND: Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in the DPP trial (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study). METHODS: During DPP, 3234 participants with impaired glucose tolerance were randomly assigned to metformin 850 mg twice daily, intensive lifestyle or placebo, and followed for 3 years. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually. RESULTS: Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78-1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87-1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome. CONCLUSIONS: Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all, extensive out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions.
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