Phenotype-Specific Mortality Outcomes with Dipeptidyl Peptidase-4 Inhibitors in Heart Failure and Diabetes: Real-World Evidence from a Retrospective Single-Center Cohort Study

Background/Objectives: Type 2 diabetes mellitus (DM) commonly coexists with heart failure (HF) and is associated with increased cardiovascular (CV) morbidity and mortality. Although dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used for glycemic control, their CV safety in patients with established HF, particularly across HF phenotypes, remains uncertain. To evaluate the association between DPP-4 inhibitor use and 6-month CV mortality in patients with DM and HF, and to assess whether this association differs across HF phenotypes: HF with preserved ejection fraction (HFpEF), HF with mildly reduced ejection fraction (HFmrEF), HF with reduced ejection fraction (HFrEF). Methods: We conducted a retrospective cohort study at King Abdulaziz Medical City from January 2017 to December 2024 that included adults with DM and echocardiographically confirmed HF. Patients receiving DPP-4 inhibitors were compared with non-users. The primary outcome was 6-month CV mortality. Propensity score overlap weighting targeting the average treatment effect in the overlap population was applied to balance baseline characteristics. Weighted logistic regression with interaction terms was used to assess effect modification by HF phenotype. Results: Among 3435 patients (median age 69 years; 51.3% female), 1921 (55.9%) received a DPP-4 inhibitor, predominantly sitagliptin. In unadjusted analyses, CV mortality was numerically lower among DPP-4 inhibitor users across HF phenotypes. However, after overlap weighting, CV mortality was similar between users and non-users within HFpEF (7.1% vs. 8.0%; OR 0.88, 95% CI 0.51–1.52; p = 0.646), HFmrEF (2.6% vs. 5.0%; OR 0.50, 95% CI 0.09–2.86; p = 0.436), and HFrEF (6.4% vs. 6.4%; OR 1.00, 95% CI 0.48–2.07; p = 0.992). No significant interaction was observed between DPP-4 inhibitor use and HF phenotype (interaction p > 0.05). Conclusions: In this large real-world cohort of patients with DM and established HF, DPP-4 inhibitor use was not associated with increased or reduced 6-month CV mortality after robust adjustment. The neutral association was consistent across HF phenotypes, supporting the CV safety of DPP-4 inhibitors, predominantly sitagliptin, in contemporary HF management.