Metformin, Lifestyle in Prediabetes May Reduce Risk of T2D but Not Major CV Events

Among more than 3000 participants with prediabetes, neither metformin or lifestyle change reduced risk for CV events over 21 years according to Diabetes Prevention Program Outcomes Study investigators.

Use of metformin and lifestyle interventions reduced the risk of progression to type 2 diabetes (T2D) among adults with prediabetes but neither strategy reduced the long-term risk of cardiovascular (CV) disease compared to placebo during a follow-up period of 21 years.

The apparently divergent results from the multicenter US Diabetes Prevention Program Outcomes Study (DPPOS) were published in the journal Circulation, online ahead of print, on May 23, 2022.

“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 from Circulation publisher the American Heart Assocation.

The DPPOS evaluated 21 years of follow-up data for the 3324 adults who took part in the original 3-year landmark Diabetes Prevention Program (DPP) trial, a study launched in 1996 to examine interventions that might prevent or delay development of T2D in adults who entered the study with impaired glucose tolerance.

DPP participants were randomly assigned to metformin 850 mg twice daily (n=1082), intensive lifestyle intervention (enhanced nutrition and physical activity targeting weight loss of 7%), or placebo. Mean baseline age of participants was 51 years, 68% were women, and, the authors note, the cohort was racially diverse with 54.7% being white, 19.9% Black, 15.7% Hispanic, 5.3% Native American, and 4.4% Asian.

Diabetes Prevention Program Outcomes Study

DPPOS was open to all DPP participants and began in 2002, enrolling approximately 90% of the original cohort. During the 18 years of follow-up in DPPOS (through 2019), all participants were offered a less intensive group lifestyle intervention, and, in the metformin group, metformin treatment was continued unmasked. During both studies treatment of CV risk factors was the province of participants’ own health care providers.

The extension study’s primary outcome of interest was the first occurrence of nonfatal myocardial infarction (MI), stroke, or CV death. The study also included an extended CV 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 MI assessed by ECG. Annually during follow-up, the investigators assessed CV risk factors and ECG findings.

Results were reported based on a median 21-year follow up, which included the mean 3-year follow up period of the original DPP.

CV events few, no difference between groups

During that period, 310 participants experienced a first major CV event and, according to the research team, incidence did not differ between treatment groups.

Regarding risk for the primary outcome, researchers found that neither metformin nor lifestyle intervention reduced occurrence. The hazard ratio (HR) for metformin when compared to placebo was 1.03 (95% CI, 0.78-1.37; P = .81) and for the lifestyle intervention vs placebo was 1.14 (95% CI, 0.87-1.5; P = .34). Results persisted after adjustment for risk factors and results were similar when researchers assessed the extended CV outcome.

When they assessed the major CV event components investigators found fewer nonfatal strokes in the metformin vs the placebo group, with no significant difference in rates (HR, 0.57 [95% CI, 0.31-1.06]; P=.07). For the lifestyle intervention group, however, they report the opposite trend, (HR, 1.42 [95% CI, 0.87–2.30]; P=.16).

The risk for CV death in both the metformin and lifestyle groups “trended higher” but did not differ from the placebo group, they report. The research group also found no significant associations between the interventions and incidence of the extended cardiovascular outcome.

When the investigators evaluated data from prespecified subgroups they found no significant heterogeneity for either study intervention by age, sex, race/ethnicity, or development of T2D.

“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,” said writing group chair Goldberg.

“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.”


Reference: Goldberg RB, Orchard TJ, Crandall JP, et al on behalf of the Diabetes Prevention Program Research Group. Effects of long-term metformin and lifestyle interventions on cardiovascular events in Diabetes Prevention Program and its Outcome Study. Circulation. Published online May 23, 2022. https://doi.org/10.1161/CIRCULATIONAHA.121.056756