The researchers randomly assigned 3,234 participants with impaired glucose tolerance to 850 mg metformin twice daily, intensive lifestyle, or placebo, and followed them for 3 years during the DPP trial.
During the next 18 years of follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention; unmasked metformin was continued in the metformin group.
The primary outcome was the first occurrence of nonfatal myocardial infarction (MI), stroke, or cardiovascular (CV) death. An extended CV 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 MI by ECG. ECGs and CV risk factors were evaluated annually.
During the 21-year median follow-up, 310 participants experienced a first major CV event; incidence did not differ by treatment group. Researchers discovered that neither metformin nor lifestyle intervention diminished the primary outcome. They also noted that when compared with placebo, the hazard ratio (HR) for metformin versus placebo was 1.03 (95% CI, 0.78-1.37; P = .81) and the HR for lifestyle versus placebo was 1.14 (95% CI, 0.87-1.5; P = .34). When researchers evaluated the extended CV outcome, results persisted after adjustment for risk factors and results were comparable.
The authors concluded that neither metformin nor lifestyle reduced MACE in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all patients, extensive out-of-study use of statin and antihypertensive agents, and a decrease in the use of study metformin together with out-of-study metformin use over time may have mitigated the effects of the interventions.
The researchers wrote, "These findings ultimately need to be evaluated in the context of the role of metformin and lifestyle intervention in diabetes prevention. Both interventions have demonstrated long-term reduction in diabetes development in DPP/DPPOS. Although it is reassuring that metformin was not associated with any overall unfavorable effects on CVD [cardiovascular disease], it is surprising that neither intervention yielded benefit for CVD through their effect on diabetes prevention. It may be that a beneficial effect related to diabetes prevention was not apparent in our study because the development of diabetes in its very early stages may not, per se, have increased cardiovascular risk above the effect of known risk factors."
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