In a new study conducted by Ronald B. Goldberg and colleagues, it was shown that despite long-term diabetes prevention, neither metformin nor lifestyle modifications prevented major cardiovascular events in the Diabetes Prevention Program Outcomes Study (DPPOS) after 21 years.

PAUSE
The findings of this study were published in Circulation.
Although lifestyle interventions and metformin have been found to prevent diabetes, their efficiency in avoiding cardiovascular disease linked with diabetes development remains unknown. As a result, the purpose of this investigation was to see if these therapies lowered the incidence of major cardiovascular events among participants in the Diabetes Prevention Program trial and Diabetes Prevention Program Outcomes Study over a 21-year median follow-up period.

During the DPP, 3234 patients with weakened glucose tolerance were randomly allocated to metformin 850 mg twice daily, an intensive lifestyle intervention, or a placebo and were monitored for three years. During the subsequent 18-year average follow-up in DPPOS, all patients were provided a less rigorous group lifestyle intervention, and the metformin group continued to receive unmasked metformin. The primary outcome was the first stroke, nonfatal myocardial infarction, or cardiovascular mortality determined by conventional criteria. The primary result or hospitalization for heart failure or unstable angina, coronary heart disease, coronary or peripheral revascularization, identified by angiography, or silent myocardial infarction by ECG were all considered prolonged cardiovascular outcomes. ECGs and cardiovascular risk variables were assessed on a yearly basis.

The key findings of this study were as follow:
1. Metformin and lifestyle interventions had no effect on the primary outcome: metformin versus placebo hazard ratio was 1.03 and lifestyle versus placebo hazard ratio was 1.14, respectively.
2. These results were unaffected by risk factor adjustment.
3. There was no effect of either strategy on the long-term cardiovascular prognosis.
In conclusion, neither metformin nor lifestyle prevented major cardiovascular events in DPPOS after 21 years even after long-term diabetes prevention. The provision of a group lifestyle intervention to all participants, widespread out-of-study use of statins and antihypertensive medications, and a decline in study metformin use combined with out-of-study metformin use across time may have diluted the treatments' benefits.
Reference:
Goldberg, R. B., Orchard, T. J., Crandall, J. P., Boyko, E. J., Budoff, M., Dabelea, D., Gadde, K. M., Knowler, W. C., Lee, C. G., Nathan, D. M., Watson, K., & Temprosa, M. (2022). Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study. In Circulation. Ovid Technologies (Wolters Kluwer Health). https://doi.org/10.1161/circulationaha.121.056756