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A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction

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  • Nienke A Hesen
  • Niels P Riksen
  • Bart Aalders
  • Merel Ritskes-Hoitinga
  • Saloua El Messaoudi
  • Kimberley E Wever

Abstract

Metformin improves cardiovascular prognosis in patients with diabetes mellitus, compared to alternative glucose-lowering drugs, despite similar glycemic control. Direct cardiovascular protective properties have therefore been proposed, and studied in preclinical models of myocardial infarction. We now aim to critically assess the quality and outcome of these studies. We present a systematic review, quality assessment and meta-analysis of the effect of metformin in animal studies of experimental myocardial infarction. Through a comprehensive search in Pubmed and EMBASE, we identified 27 studies, 11 reporting on ex vivo experiments and 18 reporting on in vivo experiments. The primary endpoint infarct size as percentage of area at risk was significantly reduced by metformin in vivo (MD -18.11[-24.09,-12.14]) and ex vivo (MD -18.70[-25.39, -12.02]). Metformin improved the secondary endpoints left ventricular ejection fraction (LVEF) and left ventricular end systolic diameter. A borderline significant effect on mortality was observed, and there was no overall effect on cardiac hypertrophy. Subgroup analyses could be performed for comorbidity and timing of treatment (infarct size and mortality) and species and duration of ischemia (LVEF), but none of these variables accounted for significant amounts of heterogeneity. Reporting of possible sources of bias was extremely poor, including randomization (reported in 63%), blinding (33%), and sample size calculation (0%). As a result, risk of bias (assessed using SYRCLE’s risk of bias tool) was unclear in the vast majority of studies. We conclude that metformin limits infarct-size and improves cardiac function in animal models of myocardial infarction, but our confidence in the evidence is lowered by the unclear risk of bias and residual unexplained heterogeneity. We recommend an adequately powered, high quality confirmatory animal study to precede a randomized controlled trial of acute administration of metformin in patients undergoing reperfusion for acute myocardial infarction.

Suggested Citation

  • Nienke A Hesen & Niels P Riksen & Bart Aalders & Merel Ritskes-Hoitinga & Saloua El Messaoudi & Kimberley E Wever, 2017. "A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction," PLOS ONE, Public Library of Science, vol. 12(8), pages 1-18, August.
    • Handle: RePEc:plo:pone00:0183664
    DOI: 10.1371/journal.pone.0183664
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    References listed on IDEAS

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    1. Simone J Jonker & Theo P Menting & Michiel C Warlé & Merel Ritskes-Hoitinga & Kimberley E Wever, 2016. "Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 11(3), pages 1-19, March.
    2. Kimberley E Wever & Theo P Menting & Maroeska Rovers & J Adam van der Vliet & Gerard A Rongen & Rosalinde Masereeuw & Merel Ritskes-Hoitinga & Carlijn R Hooijmans & Michiel Warlé, 2012. "Ischemic Preconditioning in the Animal Kidney, a Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 7(2), pages 1-10, February.
    3. Kimberley E Wever & Carlijn R Hooijmans & Niels P Riksen & Thomas B Sterenborg & Emily S Sena & Merel Ritskes-Hoitinga & Michiel C Warlé, 2015. "Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies," PLOS ONE, Public Library of Science, vol. 10(11), pages 1-17, November.
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