Safety and effectiveness of metformin in patients with reduced renal function: A systematic review

To examine clinical and safety outcomes associated with metformin use in patients with impaired renal function.

We searched PubMed and Embase databases from inception to August 2020, supplementing our search with a review of investigator files and reference lists of included studies. Any study reporting original data on metformin and patient-centred outcomes in patients with impaired renal function, defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m² , was included. Post hoc meta-analysis was performed for the outcomes of mortality, cardiovascular events and acidosis.

Nine small prospective studies enrolling patients with significantly impaired renal function identified only one case of clinically apparent lactic acidosis. Among 13 larger retrospective studies, seven examined the risk of mortality across patient subgroups; meta-analysis showed reductions in overall mortality at an eGFR of 45 mL/min/1.73m² or higher but not at an eGFR of less than 45 mL/min/1.73m² . Eight retrospective studies evaluated acidosis as an outcome; meta-analysis showed no increase in risk of acidosis except at an eGFR of less than 30 mL/min/1.73m² , in which group the HR was 1.97 (95% CI 1.03-3.77).

The literature shows metformin to be associated with reduced mortality and no increased risk of acidosis at an eGFR of 45 mL/min/1.73m² or higher. Metformin appears to be associated with fewer benefits and possible increases in the risk of acidosis at an eGFR of less than 30 mL/min/1.73m² . Consistent with US Food and Drug Administration guidelines, metformin should not be used at an eGFR less than 30 mL/min/1.73m² , and further research on its risk-benefit profile at eGFR values approaching 30 mL/min/1.73m² is warranted.