An early step in the occurrence of atherosclerosis is the binding of monocytes with the activated endothelium. Subsequently, monocytes infiltrate into the vascular wall, and differentiate into macrophages, thereby laying the platform for the development of mature atherosclerotic plaque. Recent data obtained from experimental models showed that metformin blocked the conversion of monocytes to macrophages and inhibited angiotensin II‐induced atherosclerotic plaque formation. It has also been reported that metformin reduced infiltration of macrophages into the vascular wall, simultaneously decreasing secretion of inflammatory cytokines in an experimental model of atherogenesis. This action on angiogenesis was related to stimulation of the 5-adenosine monophosphate-activated protein kinase (AMPK)/inhibition of mammalian target of rapamycin (mTOR) by metformin. Furthermore, experimental studies have also reported other potentially vascular protective mechanisms of this drug. These include inhibition of fission of mitochondria in endothelial cells, protection of mitochondrial function during and after myocardial ischemia, reduced cholesterol uptake or enhanced cholesterol efflux from macrophages, and reduced formation of foam cells or neointima in the developing plaque.¹

Few trials completed in the recent past have demonstrated the effects of metformin on surrogate measures of atherosclerotic vascular disease, including carotid-intima media thickness, calcification, and vascular reactivity in individuals with nondiabetic dysglycemia and those with type 1 and type 2 diabetes. Besides, many observational studies have shown metformins effects on monocytes/macrophages, carotid plaque, vascular smooth muscle and endothelial cells, including via AMPK activation.² One of the studies, the REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) study provides evidence of metformin’s efficacy in reducing atherosclerotic burden in patients with type 2 diabetes. The findings of this study showed a minor and transient reduction with metformin in comparison to placebo of one measure of carotid atherosclerosis in people with type 1 diabetes with cardiovascular risk factors overa treatment period of 3 years.¹ Given the above-mentioned beneficial actions of metformin, it appears to be a valuable agent for preventing atherosclerosis.

References

1. Zilov AV, Abdelaziz SI, AlShammary A, et al. Mechanisms of action of metformin with special reference to cardiovascular protection. Diabetes Metab Res Rev. 2019;35(7):e3173.
2. Jenkins AJ, Welsh P, Petrie JR, et al. Metformin, lipids and atherosclerosis prevention. CurrOpinLipidol. 2018 Aug;29(4):346-353.