Metformin Appears Safe for Most Diabetics with CKD

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The oral antidiabetic drug metformin does not increase the risk of hospitalization for acidosis in patients with mild to moderate CKD, according to a “real world” study in JAMA Internal Medicine.

The community-based cohort study included 75,413 patients with type 2 diabetes in a large regional healthcare system who had serum creatinine measurements between 2004 and 2017. Metformin use and dose were analyzed for association with hospital admission for acidosis, accounting for time-related changes in eGFR. The study included replication in a sample of 67,578 new metformin users and 14,439 new sulfonylurea users, drawn from an individual-level inpatient and outpatient claims database.

The healthcare system cohort was 51% female, with a mean age of 60.4 years. At a median 5.7 years’ follow-up, there were 2335 hospitalizations with acidosis. Of these, only 29 had acidosis as the primary diagnostic code.

Overall, there was no significant association between time-dependent metformin use and incident acidosis, compared to alternative diabetes treatment. The risk of acidosis increased along with eGFR. However, the association became significant only at an eGFR of less than 30 mL/min/1.73 m2: adjusted hazard ratio 2.07. The association remained significant after adjustment for time-dependent use of a wide range of other medications. Lower eGFR was associated with a higher incidence of acidosis, whether or not the patients were using metformin.

The results were similar on analysis of new metformin versus sulfonylurea users, in a propensity-matched cohort, and on analysis excluding patients using insulin at baseline. In the replication analysis, there was no significant difference in acidosis risk for metformin versus sulfonylurea users, even at eGFR values less than 30 mL/min/1.73 m2.

About 20% of patients with type 2 diabetes have an eGFR of less than 60 mL/min/1.73 m2. Metformin is the first-line treatment for type 2 diabetes. However, it may be avoided in diabetic patients with CKD due to concerns about drug accumulation and lactic acidosis.

The new study, based on extensive data from two real-world settings, finds no association between metformin and incident acidosis in patients with type 2 diabetes and eGFR of 30 to 60 mL/min/1.73 m2. Metformin appears to increase acidosis risk only for diabetic patients with eGFR of less than 30 mL/min/1.73 m2. The researchers write, “From a public health perspective, the potential benefits of using metformin for patients with [diabetes] and CKD are vast, given the increasing number of people affected with both diseases worldwide” [Lazarus BN, et al. Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study. JAMA Intern Med 2018; DOI:10.1001/jamainternmed.2018.0292].