Repurposing Metformin for Cardiovascular Disease

Although introduced for use as a diabetic medication in 1957, metformin remains the cornerstone of diabetic drug management in patients with type 2 diabetes mellitus (T2D). Its widespread use has largely been underpinned by the United Kingdom Prospective Diabetes Study that reported lower cardiovascular mortality and morbidity in patients treated with metformin in comparison with alternative glucose-lowering drugs, despite similar glycemic control. A recent meta-analysis suggests that the cardiovascular effects of metformin could be smaller than that reported by United Kingdom Prospective Diabetes Study; however, this should be interpreted with caution because there has only been a small number of randomized controlled trials.1 Although patients who have cardiovascular disease (CVD) with T2D comorbidity are likely to benefit most from metformin, indications of cardiovascular benefit over other diabetes treatments has driven interest in repurposing metformin to treat CVD, irrespective of diabetes status.Identified before the era of target-driven drug discovery programs, metformin’s cellular mechanism is poorly established. The most likely cellular effect underlying antihyperglycemic responses is the inhibition of mitochondrial enzymes, including complex I. Mitochondrial suppression by metformin activates AMP-activated protein kinase; however, AMP-activated protein kinase–independent targets also contribute to effects on glycemia, and, in addition, benefits of the drug in CVD may also be exerted by mechanisms distinct from its metabolic actions. In our recent work, for example, we have been …