Does Metformin Increase the Risk for Lactic Acidosis in CKD?

Nisha Bansal, MD, MAS


October 31, 2019

Is Metformin Safe in Patients With CKD?

Metformin is currently recommended as a first-line therapy for treatment of type 2 diabetes mellitus because of its low cost, side-effect profile, and possible systemic benefits. Despite these advantages, cautious use of metformin has been recommended by the US Food and Drug Administration (FDA) in patients with chronic kidney disease (CKD) due to safety concerns, including risk for lactic acidosis. Specifically, the label states that metformin is contraindicated at an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, and it is not recommended to initiate metformin at an eGFR < 45 mL/min/1.73 m2.

Despite these recommendations, the data on the risk for lactic acidosis in patients with CKD on metformin have been conflicting; some studies have shown increased risk while others have not.[1,2,3] A recent large study that was published in JAMA Internal Medicine was conducted to better understand the risk for lactic acidosis in patients with CKD using large clinical datasets and sophisticated statistical methodology.[4]

Metformin Use and Risk for Lactic Acidosis

In this paper,[4] the authors studied a community-based cohort of patients with a diagnosis of diabetes mellitus and a postdiagnosis serum creatinine measurement who were receiving care in the Geisinger Health System. Metformin use and dose were determined from electronic prescription records.

The eGFR was calculated from clinically measured serum creatinines and the CKD-Epidemiology equation. Of note, eGFR was time-updated throughout the follow-up period, allowing patients to change eGFR categories in the analysis. The primary outcome of a hospitalization for acidosis was determined by ICD-9 codes.

In the cohort of 75,413 patients with diabetes, the mean age was 60 years and 51% of patients were women. At the time of cohort enrollment, 14,662 patients had an eGFR < 60 mL/min/1.73 m2 and 1765 had an eGFR < 30 mL/min/1.73 m2. Median follow-up was approximately 6 years. A total of 45% of patients were taking metformin at enrollment and the remainder were subsequently prescribed metformin during follow-up. The median duration of metformin use was 2.8 years.

Compared with patients not taking metformin, metformin use was not associated with increased risk for lactic acidosis overall (including patients with any level of kidney function). However, when examining the association of metformin use and risk for lactic acidosis across eGFR categories, there was a statistically significant association between metformin use and risk for acidosis among patients with an eGFR < 30 mL/min/1.73 m2. Patients with an eGFR < 30 mL/min/1.73 m2 had a twofold increased risk for acidosis (HR, 2.07; 95% confidence interval, 1.33-3.22).

These results were consistent when adjusted for other time-dependent medication use, such as cardiovascular medications, insulin, and other diabetic medications. The authors also performed additional analyses:

  • comparing metformin new users to sulfonylurea new users;

  • a propensity score—matched analysis within strata of eGFR; and

  • a replication analysis of patients from a nationwide database of healthcare claims.

Even in these three additional analyses, findings were all similar, supporting greater risk for acidosis among patients with an eGFR < 30 mL/min/1.73 m2.

Where Does This Study Leave Us?

The results from this study support the recent guidelines by the FDA and other regulatory bodies that recommend against using metformin at an eGFR < 30 mL/min/1.73 m2 and cautious use when the eGFR is 30-44 mL/min/1.73 m2. A few caveats about the study should be noted, however. While the findings are compelling, this is an observational study, not a clinical trial, so causality cannot be determined. Residual confounding remains a possibility despite the sophisticated analytic approach.

The findings from this study are compelling and should prompt further investigation of safety of commonly used medications in CKD in general. Furthermore, a more personalized and renewed approach to the treatment of diabetes in patients with concomitant advanced CKD is necessary, given the risks likely associated with metformin as well as introduction of newer diabetic agents into clinical practice.

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