Glucagon-Like Peptide-1 Receptor Agonists in Patients with Heart Failure with Reduced Ejection Fraction

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiovascular outcomes in obesity and HFpEF; however, their safety and efficacy in heart failure with reduced ejection fraction (HFrEF) remain uncertain. AIMS: We sought to evaluate the efficacy and safety of GLP-1 RAs in patients with HFrEF. METHODS: We conducted a multicenter 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, BMI, HbA1c, and guideline-directed medical therapy. Primary outcomes were 1-year all-cause mortality and acute decompensated HF (ADHF) hospitalizations. Secondary outcomes included new ACS, stroke/TIA, AF/flutter, and VT/VF events. RESULTS: A total of 127,021 patients met inclusion criteria. After PSM, 2,550 patients (n=1,275 per group) were analyzed (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-1 RAs had a lower risk of all-cause mortality (7.1% vs 10.2% OR: 0.68, 95% CI: 0.51-0.90; p=0.006). Time-to-event analysis was also consistent (matched HR: 0.54 [95% CI: 0.41-0.7]; p<0.0001). Patients in the GLP-1 RA group also had a lower risk of ADHF (27.7% vs 32.8% OR: 0.79 [95% CI: 0.66-0.93]; p=0.005). 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.