Abstract Body (Do not enter title and authors here): Background
Patients with type 2 diabetes mellitus (T2DM) and heart failure with preserved ejection fraction (HFpEF) are at increased risk for adverse cardiovascular outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as Semaglutide, and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RAs such as Tirzepatide, have both demonstrated cardiovascular benefits in patients with T2DM and HFpEF. However, direct comparative data between Tirzepatide and Semaglutide in this high-risk population remain limited.

Hypothesis
We hypothesized that among patients with T2DM and HFpEF, treatment with Tirzepatide would be associated with improved 1-year outcomes compared to semaglutide.

Methods
Using the TriNetX network, we identified adults (≥18 years) with T2DM and HFpEF who were initiated on Tirzepatide or Semaglutide. The index date was defined by therapy initiation, and outcomes were assessed over 1 year of follow-up. Outcomes included all-cause mortality, all-cause hospitalization, heart failure exacerbation, cerebrovascular accident (CVA), and atrial fibrillation/flutter. One-to-one propensity score matching was performed on demographics, body mass index, comorbidities, baseline HbA1c, and concurrent medications to balance the cohorts. The final matched sample consisted of 3,757 patients in each group. Odds ratios (OR) with 95% confidence intervals (CI) and p-values were reported for each outcome.
Results
After matching, baseline characteristics were well balanced between the Tirzepatide and Semaglutide groups. At 1-year follow-up, Tirzepatide was associated with significantly lower odds of all-cause mortality (OR 0.66, 95% CI 0.48–0.91; p<0.01), all-cause hospitalization (OR 0.75, 95% CI 0.69–0.83; p<0.01), heart failure exacerbation (OR 0.71, 95% CI 0.61–0.84; p<0.01) and CVA (OR 0.82, 95% CI 0.66–0.99; p=0.04) compared with semaglutide. There was no significant difference in atrial fibrillation/flutter between the groups (OR 0.90, 95% CI 0.81–1.01; p=0.07) (Figure 1).

Conclusion
In adults with T2DM and HFpEF, treatment with Tirzepatide was associated with better 1-year mortality and cardiovascular outcomes than semaglutide. These findings suggest that Tirzepatide may confer additional cardiovascular benefits over semaglutide in this high-risk population, warranting further investigation in prospective trials.