The LIRA-HF trial: liraglutide in heart failure with reduced ejection fraction and obesity – a 30-month randomized trial

Background GLP-1 receptor agonists reduce cardiovascular events in type 2 diabetes, but their role in heart failure with reduced ejection fraction (HFrEF) remains controversial due to concerns over heart rate elevation and potential arrhythmogenicity observed in prior trials. Purpose To evaluate whether liraglutide added to comprehensive guideline-directed medical therapy (GDMT) improves the hierarchical composite of death, heart failure (HF) hospitalizations, and quality of life in patients with HFrEF and obesity. Methods This single-centre, randomized, single-blind trial enrolled 590 patients with chronic HFrEF (LVEF ≤40%), NYHA II-III, BMI ≥32 kg/m², and stable optimized GDMT (beta-blockers 98.5%, SGLT2i 99%). Patients were randomized 1:1 to liraglutide (target 1.8 mg daily) or GDMT alone. Primary outcome was the win ratio composite of all-cause death, HF hospitalizations, and change in KCCQ-CSS at 30 months. Heart rate was closely monitored. Per protocol, ivabradine was initiated in sinus rhythm with HR >75 bpm; in atrial fibrillation (AF), rate control was optimized with beta-blockers. Results Baseline characteristics were balanced (mean age 64 years, 68% male, mean LVEF 29%, mean BMI 34.2, AF 39%). Liraglutide improved the primary outcome (Win Ratio 1.36; 95% CI 1.14–1.62; p<0.001). HF hospitalizations were reduced (19.7% vs. 27.5%; HR 0.74; 95% CI 0.58–0.94; p=0.01; NNT=13). All-cause mortality was similar (12.5% vs. 13.6%; HR 0.93; 95% CI 0.73–1.18; p=0.54). KCCQ-CSS improved (+5.8 points; p<0.001). Weight loss was substantial (-8.5% vs. -0.7%; p<0.001). Liraglutide increased heart rate by +5.2 bpm (p<0.001). Among 48 patients (16.3%) with sinus tachycardia on liraglutide, ivabradine controlled HR in 92.7%. In AF, beta-blocker optimization achieved rate control in 89.6%. No ventricular arrhythmias occurred. Safety profiles were comparable. Conclusion In patients with HFrEF and obesity on optimal GDMT, liraglutide significantly reduced HF hospitalizations and improved quality of life, with neutral mortality and manageable heart rate effects. Although additional pharmacotherapy for rate control was required—ivabradine in sinus tachycardia and intensified beta-blockade in AF—the net clinical benefit supports liraglutide as a safe adjunctive therapy in this population.