Neither metformin nor lifestyle interventions reduce risk of major adverse CV outcomes in pre-diabetics

Use of either metformin or lifestyle interventions was unable to reduce the risk of a major adverse cardiovascular (CV) event in patients with pre-diabetes.

This was the key finding from a 21-year follow-up study by the Diabetes Prevention Program Research Group.

A 2018 global review of cardiovascular disease (CVD) in patients with type 2 diabetes found a prevalence of 32.2% and noted that CVD mortality accounts for approximately half of all deaths in these patients. In 1998, results from the UK Prospective Diabetes Study showed that metformin use reduced all-cause mortality by 36%.

Moreover, a study of the long-term effects of lifestyle interventions in people with impaired glucose tolerance found that such interventions delayed the onset of type 2 diabetes, as well as reducing the incidence of cardiovascular and all-cause mortality.

With a potential cardiovascular and mortality benefit from both metformin or lifestyle interventions aimed at weight reduction and increased physical activity, the Diabetes Prevention Program Research Group examined the value of each intervention in a randomised trial (the Diabetes Prevention Program (DPP) study) which was published in 2002.

The study assigned 3234 non-diabetic participants with elevated fasting and post-load plasma glucose concentrations, to either placebo, metformin (850mg twice daily), or a lifestyle-modification programme. The results showed that both metformin and lifestyle interventions, reduced the incidence of diabetes in persons at high risk by 58% and 31% respectively over an average of 2.8 years.

Based on these findings, the researchers invited pre-diabetic participants from the original DPP to enrol in a follow-on study to determine whether metformin and lifestyle interventions could reduce the incidence of adverse cardiovascular outcomes.

Participants continued with the same dose of metformin (850mg twice daily) and the lifestyle intervention. The primary outcome was the first occurrence of a major cardiovascular event which was pre-specified as non-fatal myocardial infarction, non-fatal stroke or fatal CVD.

Metformin or lifestyle interventions and CVD outcomes

A total of 3234 individuals with a baseline mean age of 51 years (68% women) and with a mean fasting blood insulin level of 160 pmol/L, were followed for a median of 21 years and of whom, 1073 were assigned to placebo, 1082 metformin and 1079 a lifestyle intervention.

During the period of follow-up, 310 individuals experienced an adverse cardiovascular event; 101 for patients assigned to metformin and 111 to the lifestyle intervention. These events did not differ significantly compared with placebo (hazard ratio, HR = 1.03, 95% CI 0.78 – 1.37, p = 0.81, metformin vs placebo) and a hazard ratio of 1.14 (95% CI 0.87 – 1.40, p = 0.34) for lifestyle vs placebo.

When considering non-fatal myocardial infarctions and strokes separately, there no significant differences for either intervention compared to placebo.

The authors concluded that despite the value of each intervention to reduce the risk of developing overt type 2 diabetes, neither was associated with a reduced risk of cardiovascular events in pre-diabetic patients.

Citation
Goldberg RB et al. Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study Circulation 2022