Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown promise in improving metabolic and cardiovascular profiles in patients with obesity. However, its potential benefits in patients with heart failure with preserved ejection fraction (HFpEF) remain unclear. We conducted a real-world, retrospective cohort study using the TriNetX global database. A total of 14,154 patients with HFpEF were included after 1:1 propensity score matching. Tirzepatide use was associated with significantly lower risks of the primary composite outcome of heart failure exacerbation and all-cause mortality (HR 0.52), as well as reductions in major adverse cardiovascular events (HR 0.64) and major adverse kidney events (HR 0.44). Subgroup analyses demonstrated consistent benefits across different strata. Sensitivity analyses using alternative exposure definitions confirmed the robustness of the findings. These results support the potential clinical utility of tirzepatide in HFpEF management and warrant further investigation in randomized controlled trials.

Aims: Managing patients with atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) is challenging. While sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) show cardiovascular benefits, the impact of combining these agents is unclear. This study evaluated whether adding GLP-1 RA to SGLT2i provides additional benefits in patients with both ASCVD and HF. Methods and results: This retrospective observational study utilized the TriNetX database to analyse patients with ASCVD and HF who initiated GLP-1 RA with SGLT2i or SGLT2i alone from 1 August 2016 to 30 September 2024. A total of 2 797 317 patients were identified, with 96 051 patients meeting inclusion criteria. After propensity score matching, 5272 patients in each group were analysed. Primary outcomes included mortality or hospitalization within 1 year; secondary outcomes examined mortality, hospitalization, and heart failure exacerbation (HFE). Patients receiving GLP-1RA and SGLT2i therapies had significantly lower risk of mortality or hospitalization [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.74–0.83], mortality (HR 0.72; 95% CI 0.62–0.84), hospitalization (HR 0.78; 95% CI 0.73–0.83), and HFE (HR 0.77; 95% CI 0.72–0.83) vs. SGLT2i alone. Subgroup analyses showed consistent benefits in patients with HFpEF, HFrEF, patients with diabetes, obesity, chronic kidney disease, or those using semaglutide or dulaglutide, while liraglutide use showed a neutral effect. Drug-related side effects were monitored as safety outcomes, which showed no significant differences between groups. Conclusions: In ASCVD and HF patients, adding GLP-1 RA to SGLT2i reduces 1-year mortality and hospitalization, warranting further investigation in diverse settings.

Background: Mineralocorticoid receptor antagonists (MRAs) reduce mortality and hospitalization in patients with heart failure (HF). Finerenone, a selective nonsteroidal MRA, has recently demonstrated clinical benefits in patients with HF. However, real‐world evidence comparing nonsteroidal and steroidal MRAs in HF is lacking. Methods: We conducted a retrospective, propensity score–matched cohort study using the TriNetX database. Adult patients diagnosed with HF from January 2021 to February 2025 who initiated nonsteroidal or a steroidal MRA were included. The primary outcome was a composite of all‐cause mortality, all‐cause hospitalization, and worsening HF at 1 year. Secondary outcomes included each component individually and safety events. Subgroup and sensitivity analyses were performed, including Kaplan–Meier survival, E‐value estimation, and landmark analysis. Results: After matching, 1619 patients were included in each group. The incidence of the primary composite outcome was significantly lower in the nonsteroidal MRAs group (hazard ratio [HR], 0.79 [95% CI, 0.70–0.90]; P <0.001). Nonsteroidal MRAs were also associated with lower risks of all‐cause mortality (HR, 0.49), hospitalization (HR, 0.80), and worsening HF (HR, 0.76). Subgroup analyses showed consistent benefit. No significant differences in safety outcomes were observed. Conclusions: In this large real‐world cohort, nonsteroidal MRAs use was associated with improved 1‐year clinical outcomes compared with steroidal MRAs in patients with HF. These findings support the potential clinical utility of nonsteroidal MRAs across HF phenotypes and highlight the need for further randomized studies to validate these results.