The pleiotropic effects of metformin: time for prospective studies

Abstract

The global prevalence of diabetes has risen to epidemic proportions and the trend is predicted to continue. The consequent burden of cardiovascular morbidity and mortality is a major public health concern and new treatments are required to mitigate the deleterious effects of cardiovascular disease in diabetic patients. Ischaemia-reperfusion injury is well known to exacerbate the harmful effects of acute myocardial infarction and subsequent therapeutic reperfusion, and several mechanical and pharmacological approaches to mitigating this injury have been investigated. Metformin, which is cheap, relatively safe and widely used in type 2 diabetes, is one such pharmacotherapy with considerable pre-clinical evidence for cardioprotective utility beyond its glucose-lowering effect. However, despite convincing basic evidence its translation to clinical application has largely been limited to studies of cardiovascular risk. There are several barriers to prospective randomized assessment in the context of acute myocardial infarction, not least the accessibility and already widespread use of metformin among patients with type 2 diabetes at high risk of cardiovascular events. In the place of class 1 evidence, well-designed prospective cohort studies of the potential pleiotropic utility of metformin in cardiovascular disease, and particularly its benefit in ischaemia-reperfusion injury, are needed. Given the availability of metformin worldwide, this is particularly true in low- and middle-income countries where the optimal therapy for acute myocardial infarction, primary percutaneous coronary intervention, may not be available, and instead patients are managed with thrombolysis. As this is less effective, metformin as an adjunct to thrombolysis (or PPCI) could represent an effective, cheap means of cardioprotection with global relevance.

Fig. 1

Proposed cardioprotective mechanisms of metformin. It is suggested that metformin confers cardioprotection by inhibiting mitochondrial complex I and inhibiting AMP deaminase, which both increase cytosolic AMP:ATP ratio. This activates AMPK causing the phosphorylation of eNOS, an integral part of the RISK pathway. Furthermore, increased AMP:ATP facilitates the extracellular diffusion of adenosine and its subsequent activation of the RISK pathway via a G protein-coupled receptor. Metformin may also activate PI3K directly. The RISK pathway inhibits MPTP opening which mitigates the detrimental effects of calcium influx and ROS generation at reperfusion. Ado adenosine, AMP adenosine monophosphate, AMPK adenosine monophosphate-activated protein kinase, ATP adenosine triphosphate, eNOS endothelial nitric oxide synthase, ENT equilibrative nucleoside transporter; Erk, extracellular signal-regulated kinases, GPCR G protein-coupled receptor, IMP inosine monophosphate, MEK1/2 mitogen-activated protein kinase, mK _ATP mitochondrial ATP-sensitive potassium channel, mPKC mitochondrial protein kinase C, MPTP mitochondrial permeability transition pore, NADH nicotinamide adenine dinucleotide, NO nitric oxide, OCT1 organic cation transporter 1, PI3K phosphoinositide 3 kinase, RISK reperfusion injury salvage kinase, ROS reactive oxygen species.