Comparative Safety and Effectiveness of Metformin in Patients with Diabetes and Heart Failure: Systematic Review of Observational Studies Involving 34000 Patients
Background—There is 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 non-trial evidence for metformin in patients with diabetes 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 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 RCTs were identified. Most (5 of 9) studies were published in 2010, and were of good quality. Metformin was associated with reduced mortality compared to controls (mostly sulfonylurea therapy): 23% vs 37%, pooled adjusted risk estimates 0.80, 0.74-0.87; I2=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 to 1.14, I2=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 estimate 0.93, 0.89-0.98, I2=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 and HF, even in those with reduced left ventricular ejection fraction or concomitant chronic kidney disease (CKD). Until trial data becomes available, metformin should be considered the treatment of choice for those with diabetes and HF.
- Received October 18, 2012.
- Accepted February 25, 2013.