More evidence supporting the "cautious use" of metformin in selected patients with type 2 diabetes and mild to moderate chronic kidney disease (CKD) is emerging

A new analysis of two large retrospective patient cohorts in the United States shows there was no significant association between metformin therapy and incident lactic acidosis in those with an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m2.

Rates of acidosis in metformin users with an eGFR range of 30 to 44 or 45 to 59 mL/min/1.73 m2 were comparable with those in patients who had never been treated with metformin, according to Benjamin Lazarus, MBBS, MPH, from Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues.

This was the case even after controlling for confounding variables, such as age, comorbid conditions, cardiovascular risk factors, serum bicarbonate levels, and concomitant medications, including insulin, the study authors say in their report, published June 4 in JAMA Internal Medicine.

"These findings support the recent expansion of the eGFR thresholds for metformin use by the [US Food and Drug Administration (FDA)], and recommendations from other regulatory bodies, which suggest that metformin can be used when eGFR is 45 to 59 mL/min/1.73 m2 and cautiously when eGFR is 30 to 44 mL/min/1.73 m2," they write.

In an invited commentary, Chester B. Good, MD, MPH, from the Veteran Affairs Center for Medication Safety in Hines, Illinois, and Leonard M. Pogach, MD, from the Department of Veterans Affairs New Jersey Healthcare System in East Orange, say this study "increases our confidence that metformin is safe to use in patients with mild to moderate CKD."

Caveats Critical With Metformin and Moderate CKD

Metformin has been the first-line treatment of choice for type 2 diabetes in the United States and Europe for decades, the researchers note.

However, its use in patients with CKD has been contraindicated until quite recently, when the FDA decided in 2016 to permit the use of metformin in patients with mild CKD (eGFR, 45 mL/min/1.73 m2 or greater).

When the eGFR falls to between 30 and 45, which is moderate CKD, the FDA recommends further caution with a careful risk/benefit calculation before deciding to stop or continue the medication. Metformin use is still contraindicated in those with advanced CKD (eGFR <30 mL/min/1.73 m2).

Despite this change in recommendations, about 1 million eligible patients in the United States do not receive guideline-directed metformin therapy, possibly because of "uncertainty regarding the risk of acidosis in patients with [CKD]," Lazarus and colleagues say.

And despite the reassurance from this new study, Good and Pogach say many questions still remain, including how the benefits and risks of metformin in patients with CKD stack up against those observed with newer medications for type 2 diabetes that also offer cardiovascular protection, such as liraglutide (Victoza; Novo Nordisk) and empagliflozin (Jardiance; Boehringer Ingelheim Pharmaceuticals, Inc).