The finding that metformin limits myocardial infarct size and remodeling in animal models of myocardial infarction suggests that patients suffering from myocardial ischaemia could benefit from treatment with metformin, even when these patients do not have diabetes. Currently, several clinical trials are being performed to test this hypothesis.

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The use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFα by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y inhibition impaired platelet reactivity, there was no correlation with cytokine responses.

In patients with diabetes mellitus, the incidence of cardiovascular disease is increased, and the outcome following cardiovascular events is worse. The antihyperglycemic drug metformin appears to limit cardiovascular death in patients with type 2 diabetes. Indeed, preclinical studies have demonstrated that metformin limits (myocardial) ischemia and reperfusion injury, independent from its glucose-lowering effect. This cardioprotection is mediated by activation of the Reperfusion Injury Salvage Kinase (RISK) pathway, activation of AMPK and by an increased formation of adenosine. In addition, metformin can modulate several cardiovascular risk factors and reduces the development of heart failure in murine models. Consequently, treatment with metformin might potentially improve cardiovascular outcome in patients at risk for myocardial ischemia, even if these patients do not have diabetes. In the current paper, we focus on the direct cardioprotective actions of metformin and the mechanisms that underlie these effects.

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