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29th November 2021
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.