Review looks at metformin safety, effectiveness in patients with reduced renal function

Metformin appears to be associated with reduced mortality at estimated glomerular filtration rates as low as 45 mL/min/1.73 m2, but safety concerns arise with rates at or below 30 mL/min/1.73 m2.


Metformin may be safe and beneficial in patients with some degree of reduced renal function, but risk increases as estimated glomerular filtration rates (eGFRs) decrease, according to a recent review.

Researchers used studies published through August 2020 to perform a systematic review of clinical and safety outcomes associated with metformin use in patients with impaired renal function. Studies were included if they reported original data on metformin use and patient-centered outcomes in patients with impaired renal function, defined as an eGFR below 60 mL/min/1.73 m2. Post hoc meta-analyses were done to examine the outcomes of mortality, cardiovascular events, and acidosis. The results were published May 19 by Diabetes Obesity and Metabolism.

Nine prospective studies and 13 retrospective studies were included. In the prospective studies, only one case of clinically apparent lactic acidosis was identified. Meta-analysis of the seven retrospective studies that looked at risk for death across patient subgroups found a reduction in overall mortality associated with metformin in patients with an eGFR of 45 mL/min/1.73 m2 or greater but not those with an eGFR below 45 mL/min/1.73 m2. Four of the retrospective studies looked at cardiovascular outcomes, and meta-analysis found no significant associations between metformin and reduced cardiovascular disease risk in any eGFR group or overall. In eight retrospective studies that evaluated acidosis as an outcome, meta-analysis showed no increase in acidosis risk with metformin, except among patients with an eGFR of 30 mL/min/1.73 m2 or less, with a pooled hazard ratio of 1.97 (95% CI, 1.03 to 3.77).

The authors noted that only one of the studies included in their analysis was a randomized controlled trial and that publication bias was possible, among other limitations. They concluded that metformin is associated with reduced mortality and no increased risk for acidosis at an eGFR of 45 mL/min/1.73 m2 or greater but that safety concerns arise at an eGFR at or below 30 mL/min/1.73 m2, with no evidence suggesting benefit from metformin among these patients.

“Overall, these findings are highly consistent with current FDA and clinical guidelines, which endorse liberal use of metformin above eGFR 45, cautious use including avoiding new initiation in patients with eGFR between 30 and 45, and a continued contraindication below eGFR 30 ml/min/1.73m2,” the authors wrote. “There is a clear need to refine the evidence base on metformin's safety in stage 3b CKD [chronic kidney disease], possibly eventually allowing further liberalization of metformin use in that eGFR range. Such studies may be particularly important given increasing interest in newer drugs as alternatives to metformin in patients with established [cardiovascular disease], heart failure, and CKD.”