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Metformin or lifestyle interventions unable to reduce major adverse CV event risk in pre-diabetics

Neither metformin or lifestyle interventions in pre-diabetic patients were able to reduce the risk of major CV outcomes compared to placebo

Using either metformin or lifestyle interventions does not reduce subsequent risk of major cardiovascular (CV) eventsin patients with pre-diabetes, according to the conclusion of a 21-year follow-up study by the Diabetes Prevention Program Research Group.

A 2018 global review of cardiovascular disease (CVD) prevalence in patients with type 2 diabetes found that 32.2% of individuals were affected and that CVD mortality accounted for approximately half of all deaths in these patients. The beneficial effect of anti-diabetic treatments were recognised in 1998, with results from the UK Prospective Diabetes Study showing that metformin reduced all-cause mortality by 36%. In addition, the long-term effects of lifestyle interventions in people with impaired glucose tolerance have 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 set out to establish 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. After only 2.8 years, it was clear that both metformin and lifestyle interventions reduced the incidence of diabetes by 58 and 31%, respectively.

However, while both interventions reduced the development of diabetes, it was uncertain as to whether either intervention might prevent or reduce the incidence of adverse CV outcomes. Consequently, after completion of the DPP study, researchers invited pre-diabetic participants from the original DPP to enrol in a follow-on study. 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 CV event, which was pre-specified as a 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 160pmol/l were followed for a median of 21 years and, of whom, 1073 were assigned to placebo, 1082 to metformin and 1079 to a lifestyle intervention.

During the period of follow-up, a total of 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) or for the lifestyle intervention (HR =1.14, 95% CI 0.87 – 1.40, p = 0.34) compared to placebo. Even when the researchers examined the impact of the two interventions on CV outcomes separately, there were no significant differences 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.

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

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