Abstract Body (Do not enter title and authors here): Background:
HFpEF frequently coexists with obesity and type 2 diabetes, both of which are associated with adverse cardiometabolic outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like semaglutide have shown promise in weight and glycemic control, while tirzepatide, a dual GIP/GLP-1 receptor agonist, may offer superior metabolic effects. However, comparative real-world cardiovascular outcomes in HFpEF patients remain understudied.

Methods:
We conducted a retrospective cohort study using the TriNetX Research Network. Adults with a diagnosis of HFpEF and obesity who were treated with either semaglutide or tirzepatide were identified.The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, cholelithiasis, and pancreatitis. Propensity score matching (1:1) was performed for age, sex, race, comorbidities, and baseline medications
Results:
After matching, 40,047 patients were included (Semaglutide: 20,028; Tirzepatide: 20,019). All-cause mortality was higher with Semaglutide (2.9% vs 2.0%; OR 1.47, 95% CI 1.29–1.67, p<0.001). Myocardial infarction occurred in 2.8% of Semaglutide users vs 2.2% with Tirzepatide (OR 1.28, p=0.001), while heart failure exacerbations were more frequent with Semaglutide (10.1% vs 8.3%; OR 1.24, p=0.012). Acute kidney injury was also slightly higher in the Semaglutide group (7.0% vs 6.2%; OR 1.14, p=0.016), as were readmissions (13.1% vs 10.2%; OR 1.33, p<0.001). Rates of cholelithiasis (1.7% vs 1.5%) and pancreatitis (0.4% vs 0.4%) were comparable. Kaplan-Meier survival analysis demonstrated significantly better survival with Tirzepatide (85.8% vs 74.7%, p<0.001), with a corresponding hazard ratio of 1.28 (95% CI 1.12–1.45), favoring Tirzepatide.

Conclusions:
In this large real-world cohort of obese patients with HFpEF, Tirzepatide was associated with lower risks of all-cause mortality, cardiovascular events, HF exacerbation, and readmissions compared to Semaglutide, without a significant increase in adverse events. These findings support the potential cardioprotective role of Tirzepatide and warrant prospective validation in HFpEF populations.