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

1st June 2022

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.

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

Metformin use in pre-diabetics with a BMI > 35 reduced incident cardiovascular disease

29th November 2021

Metformin use in pre-diabetics with a BMI greater than 35 lowered the incidence of cardiovascular disease during a three year follow-up period

Metformin use in patients with pre-diabetes and a body mass index (BMI) greater than 35 led to a lower incidence of cardiovascular disease. This was the finding of a study presented at the American Heart Association Scientific Sessions 2021.

Metformin is approved both in the US and Europe for use along with diet and exercise to lower blood sugar levels in patients with type 2 diabetes. However, the drug has been shown to reduce the rate of conversion from prediabetes to diabetes. This effect of metformin was identified in a 2002 trial with over 3000 non-diabetic patients who had elevated fasting and post loading glucose concentrations. The results showed that in combination with diet and exercise, metformin reduced the incidence of diabetes in high risk patients.

This has led to an increased ‘off-label’ use of the drug in patients with pre-diabetes, although a recent article in 2020, has suggested that metformin should not be used to treat pre-diabetic patients for three main reasons. Firstly, around two-thirds of pre-diabetics do not go on to develop diabetes. Secondly, a third of patients can return to normal glucose levels and finally, patients with pre-diabetes are not at risk for the microvascular complications of diabetes, thus metformin has no impact on this important outcome. In contrast however, other work has found that the presence of pre-diabetes is associated with an increased risk of cardiovascular disease. Furthermore, the American Diabetes Association (ADA) does suggest that metformin can be considered in pre-diabetic patients with additional risk factors such as a BMI ≥35, if they are age less than 60 years, or have history of gestational diabetes. The ADA also advocates use of the drug in those with a rising haemoglobin A1c  despite the use of lifestyle interventions.

For the present study, the researchers turned to a health insurance claims database to examine the extent to which pre-diabetic patients, with or without metformin, developed cardiovascular disease (CVD). For the purposes of their analysis, pre-diabetes was defined by a HbA1c of 5.7-6.4, a fasting glucose 100-125 mg/dL or an oral glucose tolerance test result of 140-199 mg/dL, which is the usual definition of pre-diabetes. Excluded patients were those under 25 years of age and with FDA-approved metformin indications including type 1 diabetes, cardiovascular disease, chronic kidney disease or gestational diabetes.


Analysis of the database identified 149,654 patients with prediabetes, of whom 8,624 (5.8%) were prescribed metformin with an average age of 65.9 years (57.3% female). The average BMI among those prescribed metformin was 33.1 which was significantly different to the non-metformin pre-diabetic group (p < 0.001). In addition, the metformin group had a statistically higher incidence of hypertension (78% vs 61%, p < 0.001) and dyslipidaemia (60% vs 48%, p < 0.001).

After a follow-up period of 2.8 years, 24% of the pre-diabetic cohort developed CVD. When dichotomising results by BMI, among the metformin cohort with a BMI > 35, a lower proportion developed CVD compared to those with a BMI < 35 (21.2% vs 28%, p < 0.001). A similar significant result was observed for gender and BMI, with a lower incidence of CVD among those with a BMI > 35. However, while the proportion of metformin patients under 65 years of age who developed CVD was numerically lower for those with a BMI > 35 (11.3% vs 12.6%), the difference was not statistically significant (p = 0.428).

The authors concluded that among in patients with a BMI > 35, using metformin resulted in a lower proportion of developing CVD over the following three years and that these data supported the recommendations outlined by the ADA.


Murrillo JE et al. Abstract 9819: Real World Data: Off-Label Metformin in Patients with Prediabetes is Associated with Improved Cardiovascular Outcomes. AHA 2021