Glucagon-Like Peptide-1 Receptor Agonists and Heart Failure Hospitalization in a Real-World Cardiometabolic...

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a cardiometabolic syndrome driven by obesity and related metabolic risk factors, yet strategies to prevent progression to clinically overt heart failure in at-risk populations remain limited. We evaluated the association between initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy and subsequent heart failure hospitalization among adults with cardiometabolic risk and no prior heart failure using the TriNetX US Collaborative Network (2010 to 2024). In a new-user, active-comparator design, adults initiating a GLP-1RA were compared with those initiating sitagliptin, with 1:1 propensity score matching to balance demographics, cardiometabolic comorbidities, medications, and laboratory measures. The primary outcome was heart failure hospitalization, assessed from 1 day through 5 years after treatment initiation. Secondary outcomes included clinically diagnosed HFpEF, defined by International Classification of Diseases, Tenth Revision codes, and all-cause mortality. After matching, 219,189 patients were included in each group with well-balanced baseline characteristics. During follow-up, GLP-1RA initiation was associated with a lower cumulative incidence of heart failure hospitalization compared with sitagliptin (5.4% vs 8.1%; risk ratio 0.66; 95% confidence interval 0.65 to 0.68), with consistent findings across landmark, era-restricted, and agent-specific sensitivity analyses. Associations were also observed for lower rates of clinically diagnosed HFpEF (risk ratio 0.72; 95% confidence interval 0.70 to 0.74) and all-cause mortality. In conclusion, among adults with cardiometabolic risk and no prior heart failure, initiation of GLP-1RA therapy was associated with lower rates of heart failure hospitalization compared with sitagliptin, suggesting potential modification of clinical trajectories leading to overt heart failure that warrants confirmation in prospective studies.