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We read with interest the study by Christiansen and colleagues [1] in the previous issue of Critical Care. In a large cohort study, the authors report that among diabetic patients who are admitted to the ICU, the preadmission use of metformin is associated with a lower mortality rate. Here, we highlight that metformin limits ischemiareperfusion injury (IRI) and modulates inflammation by increased adenosine receptor stimulation and propose that these mechanisms contribute to the reported survival benefit. In prospective studies in patients with diabetes, metformin use is associated with lower cardiovascular mortality compared with alternative glucose-lowering agents, suggesting a direct cardioprotective effect of metformin [2]. In animal studies, metformin potently limits myocardial infarct size [2]. This is caused, at least in part, by increased formation of the endogenous nucleoside adenosine [3]. Adenosine receptor stimulation increases tolerance of various organs against IRI and potently modulates inflammation [4]. Indeed, pharmacological elevation of endogenous adenosine modulates the inflammatory response during experimental human endotoxemia [5]. In the study by Christiansen and colleagues, many patients were admitted to the ICU because of cardiovascular diseases or (non-)cardiac surgery. It is likely that in these patients IRI contributes to organ dysfunction. Therefore, we propose that the survival benefit of metformin is caused by limitation of IRI and inflammation due to increased adenosine receptor signaling. Based on this hypothesis, several randomized controlled trials are currently being performed to investigate whether metformin reduces myocardial injury in patients with a myocardial infarction and patients undergoing cardiac surgery (NCT01438723 and NCT01217307). We await with interest the results of these trials.

Metformin improves survival in intensive care unit patients, but why?