Effect of metformin on acidosis limited to very low eGFR
Patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) who used metformin did not appear to have a higher incidence of acidosis-related hospitalizations, except those with an eGFR* lower than 30 mL/min/1.73m2, according to a community-based study.
“[Metformin] is frequently avoided in patients with CKD because of the concern of drug accumulation and lactic acidosis. Regulatory and professional society guidelines suggest that metformin may be an option in patients with mild to moderate CKD,” said the researchers. [JAMA 2014;312:2668-2675]
“Our results support cautious use of metformin in patients with T2D and eGFR of at least 30 mL/min/1.73 m2,” said study senior author Associate Professor Morgan Grams from the Johns Hopkins University School of Medicine, Baltimore, Maryland, US.
“On the other hand, our observation of increased risk among patients with eGFR <30 mL/min/1.73m2 strengthens the evidence against metformin use in this group,” added Grams and co-authors.
Researchers analysed data of 75,413 patients with T2D (mean age 60.4 years, 51 percent female) who were enrolled in the Geisinger Health System in Pennsylvania, US, between 2004 and 2017. Of these, 34,095 were receiving metformin at study onset, while 13,781 were prescribed metformin over the follow-up period. Patients were followed up for a median 5.7 years during which time there were 2,335 hospitalizations due to acidosis.
The number of acidosis incidents increased with decreasing eGFR levels, regardless of use or non-use of metformin (eg, four, 10, and 24 events per 1000 person-years with eGFR 60–89, 30–44, and <30 mL/min/1.73m2).
The time-dependent use of metformin was not associated with overall incidence of acidosis-related hospitalization compared with non-use (use of other diabetes therapies), regardless of eGFR level (adjusted hazard ratio [adjHR], 0.98, 95 percent confidence interval [CI], 0.89–1.08). [JAMA Intern Med 2018;178:903-910]
The findings were similar among patients with eGFR 45–59 mL/min/1.73m2 (adjHR, 1.16, 95 percent CI, 0.95–1.41) and those with eGFR 30–44 mL/min/1.73m2 (adjHR, 1.09, 95 percent CI, 0.83–1.44).
However, an association was observed between metformin use and acidosis-related hospitalization in patients with eGFR <30 mL/min/1.73m2 (adjHR, 2.07, 95 percent CI, 1.33–3.22).
Subgroup analyses comparing acidosis incidence in new sulfonylurea and metformin users revealed a similar association between metformin use and acidosis incidence overall and at eGFR 45–59 and 30–44 mL/min/1.73m2 (adjHR, 0.91, 1.03, and 0.77, respectively), as was the case in a propensity score-matched cohort comparing metformin and other diabetes medications (adjHR, 0.82 and 0.71 at eGFR 45–59 and 30–44 mL/min/1.73m2, respectively), and in a replicate cohort comprising 82,017 patients from a nationwide claims database (adjHR, 0.83 and 0.86 at GFR 45–59 and 30–44 mL/min/1.73m2, respectively).
Similarly, increased risk of acidosis with metformin was demonstrated among patients with eGFR <30 mL/min/1.73m2 after excluding baseline insulin use (adjHR, 2.22) and adjusting for baseline HbA1c (adjHR, 2.22) or incident diabetes (adjHR, 2.37).
“Our study demonstrates that the first-line and common diabetes medication is safer in patients with CKD than once thought,” said Grams.
“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,” she added.
As a majority of the study population was Caucasian, the authors cautioned against generalizing these results to other ethnicities. Residual confounding also could not be ruled out given the observational design of the study.