Importance: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to have benefits when used in patients with heart failure. The comparative outcomes of SGLT2 inhibitors relative to each other has not been well defined and may impact medication selection.

Objective: To determine the comparative outcomes of empagliflozin and dapagliflozin on reducing the composite of all-cause mortality and hospitalizations in patients with heart failure.

Design, setting, and participants: This multicenter retrospective cohort study included patients with heart failure from August 18, 2021, and December 6, 2022, in the TriNetX Research Collaborative, a centralized database of deidentified electronic medical record data from a network of 81 health care organizations. Eligible patients had a diagnosis of heart failure, had never received an SGLT2 inhibitor previously, and were newly started on empagliflozin or dapagliflozin. Patients were followed up for 1 year.

Exposure: Initiation of dapagliflozin or empagliflozin.

Main outcomes and measures: The primary outcome was the time to the composite of all-cause mortality or hospitalization between study days 1 to 365. Kaplan-Meier analyses, hazard ratios (HRs), and 95% CIs were used to assess the primary outcome.

Results: Among 744 914 eligible patients, 28 075 began empagliflozin (15 976 [56.9%]) or dapagliflozin (12 099 [43.1%]). After nearest-neighbor matching for demographics, diagnoses, and medication use, there were 11 077 patients in each group. Of patients who received empagliflozin, 9247 (57.9%) were male, 3130 (19.6%) were Black individuals, and 9576 (59.9%) were White individuals. Similarly, of those who received dapagliflozin, 7439 (61.5%) were male, 2445 (20.2%) were Black individuals, and 7131 (58.9%) were White individuals. Patients receiving empagliflozin were less likely to experience the composite of all-cause mortality or hospitalization compared with those initiated on dapagliflozin (3545 [32.2%] vs 3828 [34.8%] events; HR, 0.90 [95% CI, 0.86-0.94]) in the year following SGLT2 inhibitor initiation and less likely to be hospitalized (HR, 0.90 [95% CI, 0.86-0.94]). All-cause mortality did not differ between exposure groups (HR, 0.91 [95% CI, 0.82-1.00]). There was no difference in mean hemoglobin A1c or adverse events between groups.

Conclusions and relevance: In this cohort study, patients who initiated empagliflozin were less likely to experience the composite of all-cause mortality or hospitalization compared with patients who started dapagliflozin. Additional studies are needed to confirm these finding.