Type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD) can cautiously take metformin without increased risk of lactic acidosis as long as their estimated glomerular filtration rate (eGFR) is 30 mL/min/1.73 m2 or higher, according to a new study published in JAMA Internal Medicine.
“Our study demonstrates that the first-line and common diabetes medication is safer in patients with CKD than once thought,” said senior study author Morgan Grams, MD, PhD, MHS, associate professor of medicine and epidemiology, Johns Hopkins University School of Medicine, Baltimore, MD. “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.”
Metformin is frequently avoided in patients with CKD because of the risk of drug accumulation and lactic acidosis. This concern arose following the withdrawal of phenformin from the US market in 1978 along with case reports of metformin-associated lactic acidosis in patients with CKD.
More recently, regulatory guidelines have opened the door to metformin use in patients with mild to moderate CKD. For instance, the US Food and Drug Administration now states that metformin use is contraindicated only in patients with an eGFR of less than 30 mL/min/1.73 m2 and is “not recommended” to start at an eGFR of less than 45 mL/min/1.73 m2.
Although changes have been made to guidelines, researchers have yet to elucidate the safety of metformin in T2DM patients with an eGFR of less than 60 mL/min/1.73 m2, with data from research inconclusive.
In the current study, Dr. Grams and colleagues intended to shed light on the dynamic between metformin use and lactic acidosis in T2DM patients with a gamut of eGFR values, with a primary endpoint of hospitalized acidosis events.
The investigators conducted two large retrospective studies in T2DM patients who were taking metformin and had postdiagnosis serum creatinine measurements. The first cohort consisted of 75,413 diabetes patients (mean age 60.4 years, 51% women, mean BMI 34.1). The team replicated these results in 67,578 new metformin users and 14,439 new sulfonylurea users.
The investigators found that in both cohorts of T2DM patients, metformin use was not significantly linked to acidosis hospitalization in subjects with an eGFR of at least 30 mL/min/1.73 m2. Notably, metformin use was significantly correlated with a heightened acidosis risk only in patients with eGFR less than 30 mL/min/1.73 m2 (adjusted HR 2.07, 95% CI 1.33-3.22). These results persisted when accounting for eGFR stage over time and covariates. The results also held in adjusted, active comparator, and propensity score-matched analysis, and in the replication cohort of 82,017 patients.
The authors wrote that these results bolster “the recent expansion of the eGFR thresholds for metformin use by the 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.”
Dr. Grams and colleagues cited several limitations to their study. For instance, if the effect of metformin use on lactic acidosis was mediated by a decline in eGFR, then the researchers’ utilization of time-dependent eGFR could have biased results toward the null hypothesis, or no difference. Additionally, most of the study participants were white, which could limit generalizability.
“Our results support cautious use of metformin in patients with type 2 DM and eGFR of at least 30 mL/min/1.73 m2,” concluded the researchers.
In an accompanying commentary, first author Chester B. Good, MD, MPH, Center for Value-Based Pharmacy Initiatives, UPMC Health Plan, Pittsburgh, PA, recommended that T2DM patients participate in deciding which antiglycemic treatment option is best.
“[G]iven the lack of direct evidence comparing newer agents with metformin for new T2DM patients with CKD, a shared-decision model is ideal for considering with which drug to initiate pharmacotherapy,” wrote Dr. Good and Leonard M. Pogach, MD, MBA, Research Service, Department of Veterans Affairs New Jersey Healthcare System, East Orange, NJ. “Because metformin, liraglutide, and empagliflozin have been shown to improve clinically relevant outcomes in patients with T2DM (and the latter two have indications to lower the risk of adverse cardiovascular events in adults with T2DM), we recommend that these medications should be considered when starting antiglycemic therapy in the CKD population.”
The commenters suggested that when presented with a choice of antiglycemic drugs, many CKD patients will elect to take metformin, which is inexpensive, safe, and effective.
This study was funded by grants from the National Institutes of Health.