Could metformin be a game changer for heart health in non-diabetics?

By Dr. Sushama R. Chaphalkar, PhD.Sep 24 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in eBioMedicine, researchers use Mendelian randomization (MR) to investigate the effects of perturbing seven metformin targets on the cardiometabolic health of the general and non-diabetic populations. The perturbation of these known metformin targets was associated with beneficial effects on blood pressure and body mass index (BMI) in non-diabetic individuals.

Study: Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals: a Mendelian randomization study. Image Credit: Anastasiya Artcomma / Shutterstock.com

Background

Type 2 diabetes is associated with cardiovascular disease, with several antidiabetic drugs reported to have beneficial effects on cardiometabolic health. Metformin is one of the most commonly used drugs globally for first-line antidiabetic therapy.

Evidence obtained from clinical trials suggests that metformin has a good safety profile and may have benefits in cardiometabolic diseases such as coronary death, cardiovascular disease, and body weight in diabetic individuals. However, the effects of metformin on blood pressure in diabetic individuals are unclear. Likewise, the impact of metformin on cardiometabolic diseases in those with normal glycated hemoglobin (HbA1c) levels has not been studied thoroughly.

The current study aimed to determine the average and target-specific effects of seven known metformin targets on eight cardiometabolic phenotypes using two-sample MR in the general population. One-sample MR was also used to study the effect of metformin targets on the cardiometabolic health of non-diabetic persons. MR, an epidemiologic approach, utilizes germline genetic variants to explore the causal relationship between a modifiable exposure and outcome.

About the study

The seven known pharmacological targets of metformin investigated in this study included AMP-activated protein kinase (AMPK), mitochondrial complex I (MC1), mitochondrial glycerol 3 (MG3), growth differentiation factor 15 (GDF15), glucagon-like peptide-1 (GLP1), fructose bisphosphatase-1 (FBP1), and adenylyl cyclase (ADCY1).

Thirty-four genetic variants were selected to proxy the long-term effects of these metformin targets. Four different MR methods were applied to examine the genetic associations of HbA1c, BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP) with the metformin targets. Furthermore, 23 independent variants were used to instrument the circulating HbA1c levels.

Additionally, eight cardiometabolic phenotypes were identified with metformin used as treatment, including coronary artery disease (CAD), SBP, DBP, low-density-lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, BMI, and atrial fibrillation.

The average HbA1c-lowering effect of five metformin targets on all cardiometabolic outcomes was determined. The target-specific analysis established the impact of each metformin target on individual cardiometabolic outcomes.

One-sample MR was used to determine the average and target-specific effects of perturbation of metformin targets on BMI, SBP, and DBP in 338,425 non-diabetic individuals in the United Kingdom Biobank.

Study findings

The genetically proxied perturbation of five metformin targets, which was equal to a 0.62% decrease in HbA1c, was associated with a reduced risk of CAD, as well as reduced BMI, SBP, and DBP levels. Furthermore, the perturbation of metformin targets reduced the risk of type 2 diabetes in the general population.

The causal effects of metformin targets on cardiometabolic disease phenotypes remained consistent, even when multivariable MR outcomes were adjusted for red blood cell counts. No association of metformin targets was observed with atrial fibrillation and lipid phenotypes. Furthermore, one-sample MR results suggested that the seven metformin targets showed averaged and target-specific beneficial effects on BMI, SBP, and DBP in non-diabetic individuals.

The study findings suggest that metformin targets may play a role in potentially reducing the cardiovascular disease burden in the general and non-diabetic population. However, the study has certain limitations, as it does not estimate the direct effects of metformin use and assumes no strong interaction between the targets. Further research is needed to confirm these findings in generalized populations in different subgroups and across geographies.

Conclusions

The perturbation of seven metformin targets positively impacts the BMI and blood pressure of non-diabetic individuals. However, more clinical trials need to be conducted to understand whether these beneficial effects can be achieved with the use of metformin. Additionally, there is a need to determine the optimal dosages and duration of potential metformin use in non-diabetic individuals, as well as evaluate the potential risks and benefits of long-term use.