OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve outcomes in heart failure with preserved ejection fraction (HFpEF), but no head-to-head study has compared liraglutide and dulaglutide, two widely used GLP-1 RAs; we aimed to address this gap.
METHODS: Using the TriNetX US Collaborative Network (November 2025), we identified 99,683 adults with HFpEF who newly initiated liraglutide (n=37,386) or dulaglutide (n=62,297). One-to-one propensity-score matching on >50 baseline covariates yielded 36,851 matched pairs for 1-year analysis and 33,686 pairs with 5-years follow-up. Primary outcome was all-cause mortality; secondary outcomes included acute heart failure events, all-cause hospitalization, myocardial infarction, stroke, and hypoglycemia at 1 and 5-years assessed by Kaplan-Meier survival analysis and Cox-proportional hazards models.
RESULTS: After matching, baseline characteristics were virtually identical. At 1 year, liraglutide was associated with lower all-cause mortality (HR 0.738, 95% CI 0.675-0.806, p<0.0001), acute heart failure events (HR 0.862, 0.830-0.894, p<0.0001), hospitalization (HR 0.927, 0.901-0.954, p<0.0001), stroke (HR 0.900, 0.863-0.939, p<0.0001), and hypoglycemia (HR 0.891, 0.808-0.983, p=0.021) versus dulaglutide. Benefits persisted and amplified at 5 years: all-cause mortality HR 0.775, acute heart failure HR 0.820, and stroke HR 0.848. Myocardial infarction reduction emerged only at 5 years (HR 0.907, 0.880-0.935, p<0.0001).
CONCLUSION: In this large propensity score-matched real-world cohort of patients with HFpEF, liraglutide was associated with significantly lower risks of mortality, heart failure events, hospitalization, stroke, and hypoglycemia than dulaglutide at 1 and 5 years. These observational findings suggest potential within-class heterogeneity and warrant further investigation in head-to-head trials.
