Hospitalization for Heart Failure Among Patients With Diabetes Mellitus and Reduced Kidney Function Treated With Metformin Versus Sulfonylureas: A Retrospective Cohort Study

Abstract

Background Metformin and sulfonylurea are commonly prescribed oral medications for type 2 diabetes mellitus. The association of metformin and sulfonylureas on heart failure outcomes in patients with reduced estimated glomerular filtration rate remains poorly understood. Methods and Results This retrospective cohort combined data from National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylurea who reached an estimated glomerular filtration rate of 60 mL/min per 1.73 m 2 or serum creatinine of 1.5 mg/dL and continued metformin or sulfonylurea were included. The primary outcome was hospitalization for heart failure. Echocardiogram reports were obtained to determine each patient's ejection fraction (EF) (reduced EF <40%; midrange EF 40%–49%; ≥50%). The primary analysis estimated the cause‐specific hazard ratios for metformin versus sulfonylurea and estimated the cumulative incidence functions for heart failure hospitalization and competing events. The weighted cohort included 24 685 metformin users and 24 805 sulfonylurea users with reduced kidney function (median age 70 years, estimated glomerular filtration rate 55.8 mL/min per 1.73 m 2 ). The prevalence of underlying heart failure (12.1%) and cardiovascular disease (31.7%) was similar between groups. There were 16.9 (95% CI, 15.8–18.1) versus 20.7 (95% CI, 19.5–22.0) heart failure hospitalizations per 1000 person‐years for metformin and sulfonylurea users, respectively, yielding a cause‐specific hazard of 0.85 (95% CI, 0.78–0.93). Among heart failure hospitalizations, 44.5% did not have echocardiogram information available; 29.3% were categorized as reduced EF, 8.9% as midrange EF, and 17.2% as preserved EF. Heart failure hospitalization with reduced EF (hazard ratio, 0.79; 95% CI, 0.67–0.93) and unknown EF (hazard ratio, 0.84; 95% CI 0.74–96) were significantly lower in metformin versus sulfonylurea users. Conclusions Among patients with type 2 diabetes mellitus who developed worsening kidney function, persistent metformin compared with sulfonylurea use was associated with reduced heart failure hospitalization.

Heart Failure: An Underappreciated Complication of Diabetes. A Consensus Report of the American Diabetes Association

“…Metformin. Metformin remains the most widely used of oral medications for T2D (1,155). Metformin improves insulin sensitivity, is typically weight neutral or may induce weight loss, effectively prevents diabetes development, and is affordable given its low costs (156).…”

“…However, in contrast to the safety and possible benefits of metformin, several observational studies have suggested that sulfonylurea therapy may be associated with increased risk of HF events compared with metformin or with other agents (2). Evidence from a large retrospective cohort, with data combined from the National Veterans Health Administration, Medicare, Medicaid, and the National Death Index, that included 24,685 metformin users and 24,805 sulfonylurea users with reduced kidney function (median age 70 years, estimated glomerular filtration rate 55.8 mL/min/1.73 m 2 ) showed significantly fewer HF hospitalizations per 1,000 person-years for metformin compared with sulfonylurea users (155). In addition, in a most recent comparative effectiveness study with analysis of data from 128,293 participants with T2D in the U.S. Department of Veterans Affairs, of whom 23,870 received an SGLT2i and 104,423 received a sulfonylurea, it was reported that SGLT2i treatment was associated with a reduced risk of all-cause mortality compared with sulfonylureas (162).…”

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

“…Metformin reduced the risk of admission for HF compared to thiazolidinediones, sulfonylureas, or other non-metformin contemporary regimens, and once again versus sulfonylureas in T2DM patients who persisted in the use of biguanide despite reduced kidney function [ 13 , 14 , 181 , 198 , 205 ]. This benefit was confirmed by systematic reviews and meta-analyses [ 189 , 190 , 191 , 196 ].…”

Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure

“…diabetes published since the appearance of this meta-analysis (2017) support its findings, with reduced mortality versus non-metformin treatment [36,37], reduced hospitalisation versus non-metformin treatment [38], or reduced hospitalisation versus sulfonylurea treatment in patients with comorbid CKD [39]. Another cohort study suggested that metformin versus sulfonylurea as initial pharmacologic antihyperglycaemic treatment was associated with a lower risk of hospitalisation for HF in a population with a low prevalence of HF at baseline [40].…”