Baltimore, MD—Considering the risk of lactic acidosis, is metformin safe to use in patients with chronic kidney disease?

That was the question addressed in two large retrospective cohorts of patients with diabetes mellitus. Results published in JAMA Internal Medicine suggest that metformin use was not significantly associated with incident acidosis at an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2.

The study from Johns Hopkins University points out that, in the United States, about one million patients with type 2 diabetes mellitus and mild-to-moderate kidney disease do not receive guideline-directed therapy with metformin. The reason, they suggest, might be uncertainty about the risk of acidosis in patients with chronic kidney disease.

Researchers sought to quantify the association between metformin use and hospitalization with acidosis across the range of estimated glomerular filtration rate, accounting for change in eGFR stage over time. 

To do that, they focused on a community-based cohort of 75,413 patients with diabetes in the Geisinger Health System, with time-dependent assessment of eGFR stage from January 2004 until January 2017. Those participants averaged 60.4 years old and slightly more than half, 51%, were female.

Results then were replicated in 67,578 new metformin users and 14,439 new sulfonylurea users from 2010 to 2015, with data coming from 350 private U.S. health systems. 

The study team identified 2,335 hospitalizations with acidosis over a median follow-up of 5.7 years (interquartile range, 2.5-9.9 years). Yet, they report, compared with alternative diabetes management, time-dependent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98; 95% CI, 0.89-1.08) or in patients with eGFR 45 to 59 mL/min/1.73 m2 (adjusted HR, 1.16; 95% CI, 0.95-1.41) and eGFR 30 to 44 mL/min/1.73 m(adjusted HR, 1.09; 95% CI, 0.83-1.44). 

Researchers caution, however, that metformin use was associated with an increased risk of acidosis at eGFR less than 30 mL/min/1.73 m2 (adjusted HR, 2.07; 95% CI, 1.33-3.22). 

The report notes that results remained consistent when new metformin users were compared with new sulfonylurea users (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.77; 95% CI, 0.29-2.05), in a propensity-matched cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.71; 95% CI, 0.45-1.12), when baseline insulin users were excluded (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 1.16; 95% CI, 0.87-1.57), and in the replication cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.86; 95% CI, 0.37-2.01).

“In two real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73 m2,” study authors conclude. “Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30 mL/min/1.73 m2.”

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