GLP-1 receptor agonists associated with lower mortality in HFrEF on GDMT

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medRxiv Published April 19, 2026 Medically reviewed April 25, 2026 Study authors: Yousafzai, O.; Kanwal, K.; Annie, F. H.; Rinehart, S. DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider these observational associations as hypothesis-generating; confirm with prospective randomized trials before routine use in HFrEF.

This retrospective, multicenter cohort study used the TriNetX Research Network to compare adults with HFrEF (LVEF ≤40%) receiving guideline-directed medical therapy (GDMT) who initiated GLP-1 receptor agonists (GLP-1RAs) versus GDMT alone. After 1:1 propensity score matching, each cohort included 1,518 patients and were followed for 2 years. The primary outcome was all-cause mortality.

Over 2 years, all-cause mortality was lower in the GLP-1RA group (12.8% vs 23.8%; HR 0.48; 95% CI 0.40–0.57; p<0.001). Major adverse cardiovascular events were also reduced (35.8% vs 47.4%; HR 0.64; 95% CI 0.58–0.72; p<0.001). Critical care utilization was lower (18.4% vs 28.9%; HR 0.55; 95% CI 0.47–0.64; p<0.001), as was acute kidney failure (29.2% vs 37.3%; HR 0.67; 95% CI 0.59–0.76; p<0.001).

Safety signals for pancreatitis and substance-related disorders were low and not significantly different between groups. Serious adverse events, discontinuations, and overall tolerability were not reported.

Key limitations include the retrospective design and use of propensity-score matched cohorts rather than randomization. Residual confounding and unmeasured variables could influence results. The authors note that findings support a potential role for GLP-1RAs as a complementary therapy in HFrEF, but prospective randomized trials are needed to confirm these observations and determine whether GLP-1RAs should be incorporated as a fifth pillar of GDMT.

Study Details

Study typeRct

EvidenceLevel 2

PublishedApr 2026

View Original Abstract ↓

Abstract Background: Despite widespread adoption of contemporary guideline-directed medical therapy (GDMT), patients with heart failure with reduced ejection fraction (HFrEF) continue to experience substantial residual morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiometabolic benefits in diabetes and obesity, but their role in HFrEF remains uncertain. Objectives: To evaluate whether the addition of GLP-1RAs to optimized GDMT is associated with improved clinical outcomes in patients with HFrEF (NYHA class II-IV). Methods: We conducted a retrospective, multicenter cohort study using the TriNetX Research Network. Adults ([≥]18 years) with HFrEF (LVEF [≤]40%) receiving GDMT between January 2020 and October 2024 were included. Patients treated with GLP-1RAs were compared with those on GDMT alone. After 1:1 propensity score matching, 1,518 patients were included in each cohort. Outcomes over 2 years included all-cause mortality, major adverse cardiovascular events (MACE), critical care utilization, and acute kidney failure. Time-to-event analyses were performed using Kaplan-Meier methods and Cox proportional hazards models. Results: In the matched cohort (mean age [~]63 years, [~]33% female), GLP-1RA use was associated with significantly lower all-cause mortality compared with GDMT alone (12.8% vs 23.8%; hazard ratio [HR] 0.48; 95% CI 0.40-0.57; p<0.001), corresponding to an absolute risk reduction of 11.0%. MACE was also reduced (35.8% vs 47.4%; HR 0.64; 95% CI 0.58-0.72; p<0.001). Additionally, GLP-1RA therapy was associated with lower critical care utilization (18.4% vs 28.9%; HR 0.55; 95% CI 0.47-0.64; p<0.001) and reduced acute kidney failure (29.2% vs 37.3%; HR 0.67; 95% CI 0.59-0.76; p<0.001). Rates of pancreatitis and substance-related disorders were low and not significantly different between groups. Conclusions: Among patients with HFrEF receiving contemporary GDMT, adjunctive GLP-1RA therapy was associated with significant reductions in mortality, cardiovascular events, and healthcare utilization. These findings support the potential role of GLP-1RAs as a novel, mechanism-complementary therapy in HFrEF. Prospective randomized trials are needed to confirm these observations and determine whether GLP-1RAs should be incorporated as a fifth pillar of GDMT.