Metformin, Lifestyle Interventions Can Prevent T2D, But Do Little for CVD Risk in Prediabetes

Ronald Goldberg, MD

Data from the multicenter Diabetes Prevention Program Outcomes Study (DPPOS) underlines the importance of lifestyle changes and optimal medication adherence for prevention of type 2 diabetes, but paints what may be seen as a perplexing picture for clinicians.

Results of the study, which assessed the effects of long-term metformin use and lifestyle interventions on risk of cardiovascular events in the DPPOS, indicate medication adherence and lifestyle intervention were associated with a reduction in risk of type 2 diabetes, but neither reduced risk of major adverse cardiovascular events during the 21-year follow-up period.

“The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of Type 2 diabetes,” said DPPOS writing group chair Ronald Goldberg, MD, a senior faculty member and co-director of the Diabetes Research Institute Clinical Laboratory at the University of Miami’s Miller School of Medicine, in a statement.

Supported by grants from the US Centers for Disease Control and Prevention, the American Heart Association and several divisions of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, DPPOS is a follow-up of the original Diabetes Prevention Program study, which was launched in 1996 with the intent of examining the effect of lifestyle intervention or treatment with metformin to prevent or delay type 2 diabetes in high-risk individuals with prediabetes.

In the original Diabetes Prevention Program, 3234 participants with impaired glucose tolerance were assigned to metformin 850 mg twice-daily, intensive lifestyle intervention, or placebo. As part of DPPOS, follow-up of these patients continued and they were offered a less intensive group lifestyle intervention and unmasked metformin was continued in the metformin group. Overall, DPPOS contained 1073 patients randomized to placebo, 1082 randomized to metformin, and 1079 randomized to intensive lifestyle intervention, with a time-weighted mean follow-up of 21 years.

The primary outcome of interest was first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. The study also included an extended cardiovascular outcome that 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.

Upon analysis, results indicated the reduction in development of type 2 diabetes observed in the original Diabetes Prevention Program study were sustained through the follow-up period. When assessing the risk of the [primary outcome, results suggested neither use of metformin (HR, 1.03 [95% CI, 0.78-1.37]; P=.81) nor lifestyle intervention (HR, 1.14 [95% CI, 0.87-1.50]; P=.34) were associated with a reduction in the primary outcome compared with placebo therapy. Investigators pointed out risk factor adjustment did not change these results.

When assessing major cardiovascular event components, results suggested there were fewer nonfatal strokes in the metformin group than in the placebo group, with no significant difference in rates (HR, 0.57 [95% CI, 0.31-1.06]; P=.07), but the opposite trend was observed for the lifestyle intervention group (HR, 1.42 [95% CI, 0.87–2.30];P=.16). Further analysis demonstrated there was no effect of either intervention on the extended cardiovascular outcome.

“It’s important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce CVD risk. Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it difficult to identify a beneficial effect of lifestyle or metformin intervention,” Goldberg added. “Future research to identify higher risk subgroups is needed to develop a more targeted approach to cardiovascular disease prevention in people with prediabetes and type 2 diabetes.”

This study, “Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study,” was published in Circulation.