Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients

Abstract

Background: There is an ongoing controversy regarding the safety and effectiveness of metformin in the setting of heart failure (HF). Therefore, we undertook a systematic review of the trial and nontrial evidence for metformin in patients with diabetes mellitus and HF.

Methods and results: We conducted a comprehensive search for controlled studies, evaluating the association between metformin and morbidity and mortality in people with diabetes mellitus and HF. Two reviewers independently identified citations, extracted data, and evaluated quality. Risk estimates were abstracted and pooled where appropriate. As measures of overall safety, we examined all-cause mortality and all-cause hospitalizations. Nine cohort studies were included; no randomized controlled trials were identified. Most (5 of 9) studies were published in 2010 and were of good quality. Metformin was associated with reduced mortality compared with controls (mostly sulfonylurea therapy): 23% versus 37% (pooled adjusted risk estimates: 0.80; 0.74-0.87; I(2)=15%; P<0.001). No increased risk was observed for metformin in those with reduced left ventricular ejection fraction (mortality pooled adjusted risk estimate: 0.91; 0.72-1.14; I(2)=0%; P=0.34), nor in those with HF and chronic kidney disease (pooled adjusted risk estimate: 0.81; 0.64-1.02; P=0.08). Metformin was associated with a small reduction in all-cause hospitalizations (pooled adjusted risk estimate: 0.93; 0.89-0.98; I(2)=0%; P=0.01). Metformin was not associated with increased risk of lactic acidosis.

Conclusions: The totality of evidence indicates that metformin is at least as safe as other glucose-lowering treatments in patients with diabetes mellitus and HF and even in those with reduced left ventricular ejection fraction or concomitant chronic kidney disease. Until trial data become available, metformin should be considered the treatment of choice for patients with diabetes mellitus and HF.

Keywords: diabetes mellitus; heart failure; metformin; mortality.