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.
Christiansen CF, Johansen MB, Christensen S, O’Brien JM, Tønnesen E,Sørensen HT: Preadmission metformin use and mortality amongintensive care patients with diabetes: a cohort study. Crit Care 2013,17:R192.
Messaoudi SE, Rongen GA, de Boer RA, Riksen NP: The cardioprotectiveeffects of metformin. Curr Opin Lipidol 2011, 22:445–453.
Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Gonçalves L,Providência L, Rongen GA, Smits P, Mocanu MM, Yellon DM: Metforminprevents myocardial reperfusion injury by activating the adenosinereceptor. J Cardiovasc Pharmacol 2009, 53:373–378.
Ramakers BP, Riksen NP, van der Hoeven JG, Smits P, Pickkers P: Modulationof innate immunity by adenosine receptor stimulation. Shock 2011,36:208–215.
Ramakers BP, Riksen NP, Stal TH, Heemskerk S, van den Broek P, Peters WH,van der Hoeven JG, Smits P, Pickkers P: Dipyridamole augments theantiinflammatory response during human endotoxemia. Crit Care 2011,15:R289.
Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N EnglJ Med 2003, 348:138–150.
Toft P, Tønnesen E: Immune-modulating interventions in critically illseptic patients: pharmacological options. Expert Rev Clin Pharmacol 2011,4:491–501.
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?
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