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Metformin improves survival in intensive careunit patients, but why? Niels P Riksen1,2*, Gerard A Rongen1,2 and Peter Pickkers3 See related research by Christiansen et al., http://ccforum.com/content/17/5/R192 We read with interest the study by Christiansen and col- tolerance of various organs against IRI and potently leagues in the previous issue of Critical Care. In a large modulates inflammation Indeed, pharmacological cohort study, the authors report that among diabetic pa- elevation of endogenous adenosine modulates the in- tients who are admitted to the ICU, the preadmission use flammatory response during experimental human endo- of metformin is associated with a lower mortality rate.
Here, we highlight that metformin limits ischemia- In the study by Christiansen and colleagues, many pa- reperfusion injury (IRI) and modulates inflammation by tients were admitted to the ICU because of cardiovascu- increased adenosine receptor stimulation and propose lar diseases or (non-)cardiac surgery. It is likely that in that these mechanisms contribute to the reported sur- these patients IRI contributes to organ dysfunction.
Therefore, we propose that the survival benefit of met- In prospective studies in patients with diabetes, met- formin is caused by limitation of IRI and inflammation formin use is associated with lower cardiovascular mor- due to increased adenosine receptor signaling. Based on tality compared with alternative glucose-lowering agents, this hypothesis, several randomized controlled trials are suggesting a direct cardioprotective effect of metformin currently being performed to investigate whether met- In animal studies, metformin potently limits myocar- formin reduces myocardial injury in patients with a dial infarct size This is caused, at least in part, by in- myocardial infarction and patients undergoing cardiac adenosine Adenosine receptor stimulation increases with interest the results of these trials.
Author’s responseChristian F Christiansen Metformin and prognosis of critical illness: a whereas there were no decreased mortality in patients admitted after acute cardiothoracic surgery. Despite sta- I would like to thank Riksen and colleagues for their re- tistically imprecise estimates in the subgroups, it raises a sponse to our article and for emphasizing that preven- question about timing of metformin along the clinical tion of IRI could contribute to our finding of a decreased mortality among diabetic ICU patients with In sepsis, there is a proposed bi-phasic inflammatory preadmission metformin use The association we response, and any effect of potential anti-inflammatory found was present in, but not restricted to, the subgroup drugs, such as metformin, may be present only if admin- of patients admitted after elective cardiothoracic surgery, istered before or during the early hyper-inflammatoryphase of infection whereas administration during thelater hypo-inflammatory phase may be detrimental Department of Pharmacology-Toxicology, Radboud University Medical Centre, PO Box 9101, Geert Grooteplein 10, 6525 EZ, Nijmegen, reperfusion may be crucial [Studies of drug use in pa- tients at high risk of critical illness (for example, patients 2Department of Internal Medicine, Radboud University Medical Centre, undergoing elective major surgery) are therefore import- PO Box 9101, Geert Grooteplein 10, 6525 EZ, Nijmegen, The NetherlandsFull list of author information is available at the end of the article ant for our understanding of potential beneficial effects, as this exposure occurs before the inflammatory responseand the ischemia-reperfusion.
Therefore, I find it highly interesting that Riksen and col- leagues are conducting trials with metformin administeredbefore coronary artery bypass grafting and after myocardialinfarction (and Althoughthe magnitude of the inflammatory response is different,the studies will probably provide knowledge about the in-fluence of timing of metformin administration in relationto myocardial injury.
AbbreviationsIRI: Ischemia-reperfusion injury.
Competing interestsThe authors declare that they have no competing interests.
Author details1Department of Pharmacology-Toxicology, Radboud University MedicalCentre, PO Box 9101, Geert Grooteplein 10, 6525 EZ, Nijmegen, TheNetherlands. 2Department of Internal Medicine, Radboud University MedicalCentre, PO Box 9101, Geert Grooteplein 10, 6525 EZ, Nijmegen, TheNetherlands. 3Department of Intensive Care Medicine, Radboud UniversityMedical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
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10.1186/cc13156Cite this article as: Riksen et al.: Metformin improves survival inintensive care unit patients, but why? Critical Care 2013, 17:471

Metformin and prognosis of critical illness: a question of timing?

Source: http://ccforum.com/content/pdf/cc13156.pdf