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Effects of Long-Term Metformin and Lifestyle on MACE in Diabetes Prevention Program
Quick Takes
- Neither metformin nor the lifestyle interventions reduced MACE compared with placebo, despite decreasing diabetes development among those with impaired glucose tolerance or early type 2 diabetes.
- It is possible that extensive out-of-study use of lipid-lowering and antihypertensive medications, a less intensive lifestyle intervention for DPPOS participants, and increased out-of-study metformin use over time may have limited the apparent effects of the interventions and have been valuable preventive strategies.
- The study highlights beneficial effects of optimal glucose-lowering, lipid-lowering, and antihypertensive treatment strategies in the setting of impaired glucose tolerance or early type 2 diabetes.
Study Questions:
What is the effect of the original DPP (Diabetes Prevention Program) trial randomization to metformin or lifestyle interventions on major adverse cardiovascular events (MACE) compared with placebo?
Methods:
The investigators assessed the effect of the original DPP randomization to metformin or lifestyle interventions on MACE compared with placebo. During DPP, 3,234 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 the DPPOS (Diabetes Prevention Program Outcomes Study), 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 electrocardiography (ECG). ECGs and cardiovascular risk factors were measured annually. Treatment effects were tested and expressed as hazard ratios and 95% confidence limits.
Results:
Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% confidence interval [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:
The authors reported that neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes.
Perspective:
This 21-year follow-up of the DPP participants who began with impaired glucose tolerance and were followed in DPPOS found that neither metformin nor the lifestyle interventions reduced MACE compared with placebo, despite decreasing diabetes development. It is possible that extensive out-of-study use of lipid-lowering and antihypertensive medications, a less intensive lifestyle intervention for DPPOS participants, and increased out-of-study metformin use over time may have limited the apparent effects of the interventions and have been valuable preventive strategies. The study also highlights potential beneficial effects of optimal glucose- lowering, lipid-lowering, and antihypertensive treatment strategies in the setting of impaired glucose tolerance or early type 2 diabetes.
Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Acute Heart Failure, Interventions and Imaging, Angiography, Nuclear Imaging
Keywords: Angina, Unstable, Angiography, Antihypertensive Agents, Cardiometabolic Risk Factors, Coronary Disease, Diabetes Mellitus, Type 2, Electrocardiography, Glucose, Glucose Intolerance, Heart Failure, Life Style, Lipids, Metabolic Syndrome, Metformin, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Outcome Assessment, Health Care, Primary Prevention, Risk Factors, Stroke, Vascular Diseases
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