Glucagon-like peptide-1 receptor agonists in patients with heart failure with reduced ejection fraction.

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiovascular outcomes in obesity and heart failure and preserved ejection fraction; however, their safety and efficacy in heart failure with reduced ejection fraction (HFrEF) remain uncertain. We sought to evaluate the efficacy and safety of GLP-1RAs in patients with HFrEF. METHODS: We conducted a multicentre retrospective cohort study of adult patients with HFrEF (LVEF ≤40%) between 2021 and 2024. Patients receiving semaglutide, tirzepatide, or liraglutide were compared with GLP-1RA-naïve patients. Propensity score matching (PSM) (1:1; caliper 0.1) was conducted to balance demographics, comorbidities, LVEF, body mass index (BMI), haemoglobin A1c (HbA1c), and guideline-directed medical therapy. Primary outcomes were 1-year all-cause mortality and acute decompensated HF (ADHF) hospitalizations. Secondary outcomes included new acute coronary syndrome (ACS), stroke/transient ischaemic attack (TIA), atrial fibrillation (AF)/flutter, and ventricular tachycardia (VT)/ventricular fibrillation (VF) events. RESULTS: A total of 127 021 patients met inclusion criteria. After PSM, 2550 patients (n = 1275 per group) were analysed (mean age 61.5 ± 13 years, 33.5% female, 66% White, mean HbA1c 8.1 ± 2.1%, mean LVEF 30 ± 8.7%, mean BMI 34.5 ± 8.4 kg/m2). Patients prescribed GLP-1RAs had a lower risk of all-cause mortality [7.1% vs 10.2%, odds ratio (OR): 0.68, 95% confidence interval (CI): 0.51-0.90; P = .006]. Time-to-event analysis was also consistent [matched hazard ratio: 0.54 (95% CI: 0.41-0.7); P < .0001]. Patients in the GLP-1RA group also had a lower risk of ADHF [27.7% vs 32.8% OR: 0.79 (95% CI: 0.66-0.93); P = .005]. New onset ACS, stroke/TIA, AF/flutter, and VT/VF events were similar in both groups. CONCLUSIONS: In this real-world cohort, GLP-1RA therapy in HFrEF was associated with reduced mortality and ADHF without an increase in arrhythmic events. Prospective randomized trials are needed to validate these findings.