BackgroundMedications that impact insulin sensitivity or cause weight gain may increase heart failure risk. Our aim was to compare heart failure and cardiovascular death outcomes among patients initiating sulfonylureas for diabetes mellitus treatment versus metformin.Methods and ResultsNational Veterans Health Administration databases were linked to Medicare, Medicaid, and National Death Index data. Veterans aged ≥18 years who initiated metformin or sulfonylureas between 2001 and 2011 and whose creatinine was <1.4 (females) or 1.5 mg/dL (males) were included. Each metformin patient was propensity score‐matched to a sulfonylurea initiator. The outcome was hospitalization for acute decompensated heart failure as the primary reason for admission or a cardiovascular death. There were 126 867 and 79 192 new users of metformin and sulfonylurea, respectively. Propensity score matching yielded 65 986 per group. Median age was 66 years, and 97% of patients were male; hemoglobin A1c 6.9% (6.3, 7.7); body mass index 30.7 kg/m2 (27.4, 34.6); and 6% had heart failure history. There were 1236 events (1184 heart failure hospitalizations and 52 cardiovascular deaths) among sulfonylurea initiators and 1078 events (1043 heart failure hospitalizations and 35 cardiovascular deaths) among metformin initiators. There were 12.4 versus 8.9 events per 1000 person‐years of use (adjusted hazard ratio 1.32, 95%CI 1.21, 1.43). The rate difference was 4 heart failure hospitalizations or cardiovascular deaths per 1000 users of sulfonylureas versus metformin annually.ConclusionsPredominantly male patients initiating treatment for diabetes mellitus with sulfonylurea had a higher risk of heart failure and cardiovascular death compared to similar patients initiating metformin.

IMPORTANCE Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown. OBJECTIVE To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m 2 or creatinine Ն1.4 mg/dL for women or Ն1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016). EXPOSURES New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function. MAIN OUTCOMES AND MEASURES MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death. RESULTS There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m 2 [IQR, 51.6-58.2] and hemoglobin A 1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding 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. CONCLUSIONS AND RELEVANCE Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.