Less Cardiovascular Events with Metformin Than Sulfonylureas in Diabetics

A new study from investigators at Vanderbilt University is shining a new light on how cardiovascular outcomes differ for diabetic patients with reduced kidney function when receiving metformin monotherapy compared with sulfonylurea monotherapy.

After reviewing nearly 100,000 patients, investigators determined treatment with metformin was associated with a lower risk of major adverse cardiovascular events (MACE) than sulfonylurea in diabetic patients with reduced kidney function.

In order to assess the associations of MACE with monotherapy treatment with either metformin or sulfonylurea, investigators conducted a retrospective cohort study through examination of patients receiving care within the national Veterans Health Administration. Additional data was pooled from Medicare, Medicaid, and the National Death Index. Data from 2002 through 2015 was included in the current study.

Patients included in the study were 18 years of age and older and considered regular users of VHA care, which investigates defined as an encounter or prescription fill once every 365 days for 2 or more years prior. Only patients with new-onset type 2 diabetes were included and new users of metformin or sulfonylureas glipizide, glyburide, or glimepiride.

Exposures in the current study included persistent use of metformin or sulfonylurea after reaching the threshold for reduced kidney function, which was defined as either an eGFR of less than 60 mL/min/1.73 m2 or serum creatinine level of 1.5 mg/dL for men or 1.4 mg/dL for women.

The primary outcome measure of the study was a composite outcome of MACE including hospitalization for acute myocardial infarction, ischemic of hemorrhagic stroke, transient ischemic attack, or cardiovascular (CV) death. The secondary outcome measure for the study was MACE with transient ischemic attacks not included. Investigators noted that analyses used propensity score weighting to compare cause-specific hazard of MACE between treatment types and estimate cumulative risk accounting for risk of changing therapy or non CV death.

Investigators included a total of 67,749 metformin and 28,976 sulfonylurea monotherapy users in the study. From this, a weighted cohort of 24,679 metformin users and 24,799 sulfonylurea users. Median age of the final cohort was 70 years, 98% (n=48,497) were men, and 82% (n=40,476) were white. Additionally, the group had a median estimated eGFR was 55.8 mL/min/1.73 m2 and hemoglobin A1c level of 6.6% at cohort entry.

During the follow-up period, which had a median duration of 1 year for metformin and 1.2 years for sulfonylurea, investigators identified 1048 MACE outcomes among metformin users (23.0 per 1000 person years) and 1394 events among sulfonylurea users (29.2 per 1000 person years).

The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas. Investigators noted this yielded an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use.

In a related editorial published in JAMA, Deborah Wexler, MD, MSc, of the Diabetes Center at Massachusetts General Hospital, wrote that results of the study align with previous research but added that using this information in practice is a delicate balance.

“The adverse effect profile of sulfonylureas and their very low cost must be balanced against characteristics of other glucose-lowering medications as clinicians consider the best approach for an individual patient,” Wexler wrote.

This study, “Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function,” was published in JAMA.