While patients with type 2 diabetes mellitus (T2DM) and heart failure (HF) are frequently prescribed dipeptidyl peptidase-4 inhibitors (DPP-4is), emerging evidence suggests glucagon-like peptide-1 receptor agonists may offer improved outcomes. This study compared the effectiveness of tirzepatide versus DPP-4i in patients with T2DM and HF. Adults with T2DM and HF treated between 2022 and 2025 were included. Cohort A comprised patients receiving tirzepatide, and Cohort B comprised patients receiving DPP-4is. Prespecified subgroup analyses were conducted for HF with reduced ejection fraction (HFrEF) and HF with non-reduced ejection fraction (HFnonrEF). Propensity score matching was performed across demographic, clinical, medication, and laboratory covariates. Outcomes included all-cause mortality, hospitalization, HF exacerbation, and major adverse cardiovascular events (MACE). After matching, 8,956 patients were included in each group. Tirzepatide therapy was associated with a lower hazard of all-cause mortality (HR 0.32, 95% CI 0.25-0.42), hospitalizations (HR 0.53, 95% CI 0.48-0.57), HF exacerbation (HR 0.37, 95% CI 0.33-0.42) and MACE (HR 0.79, 95% CI 0.73-0.84). Sub-group analyses for HFrEF and HFnonrEF demonstrated similar trends. In conclusion, among patients with T2DM and HF, treatment with tirzepatide was associated with markedly lower hazards of mortality, hospitalization, HF exacerbation, and MACE compared to DPP-4 inhibitors.
