UNLABELLED: To examine the association between premorbid metformin exposure and mortality, hyperlactatemia, and organ dysfunction in sepsis. DATA SOURCES: PubMed and EMBASE (with Medline via Ovid) databases were searched for all studies of premorbid metformin exposure and sepsis published between January 1974 and August 2018. STUDY SELECTION: Studies of at least 20 patients with sepsis that reported data on metformin use, mortality, and/or organ dysfunction were independently selected. DATA EXTRACTION: Two reviewers abstracted data on study design, settings, study quality, participants, metformin exposure, mortality, initial lactate levels, and organ dysfunction. Risk of bias was independently assessed. DATA SYNTHESIS: Eight observational studies fulfilled our criteria, comprising 4,144 patients with sepsis including 562 diabetics on metformin. Premorbid metformin exposure was associated with reduced mortality in sepsis (odds ratio, 0.57; 95% CI, 0.40-0.80). Between studies heterogeneity was low (i 2 = 43%; τ2 = 0.1; p = 0.09). Premorbid metformin exposure was not significantly associated with initial lactate levels (mean difference, 0.39 [-0.50 to 1.28]; i 2 = 72%; p = 0.39). CONCLUSIONS: The meta-analysis suggests that premorbid metformin exposure is associated with decreased mortality in sepsis but not with hyperlactatemia. What are the potential mechanisms and whether there is any effect on organ dysfunction remain unclear.

Centre for Immunology and Allergy Research Westmead Millenium Institute Westmead NSW Australia

Department of Intensive Care Medicine Nepean Hospital Penrith NSW Australia

Medical Intensive Care Unit 1st Department of Medicine University Hospital and Biomedicine Centre Pilsen Charles University Prague Czech Republic

Nepean Clinical School Sydney Medical School University of Sydney Penrith NSW Australia

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