Comparative 24-month cardiovascular outcomes and biomarker trajectories with semaglutide, empagliflozin, and sitagliptin in people with obesity and type 2 diabetes: a multicenter real-world study.

BACKGROUND: Comparative evidence on 24-month clinical outcomes and biomarker trajectories with semaglutide, empagliflozin, and sitagliptin in adults with type 2 diabetes (T2D) and obesity remains limited. OBJECTIVES: To compare 24-month clinical outcomes and longitudinal biomarker trajectories among semaglutide, empagliflozin, and sitagliptin in people with T2D and obesity. DESIGN: Multicenter retrospective cohort study. METHODS: Using TriNetX, we performed an active-comparator, new-user study with three prespecified 1:1 propensity score-matched contrasts: semaglutide versus empagliflozin, semaglutide versus sitagliptin, and empagliflozin versus sitagliptin. Follow-up was intention-to-treat for 24 months. Multiplicity was addressed with Benjamini-Hochberg false discovery rate correction within two prespecified families: (i) clinical time-to-event endpoints (all-cause mortality, MACE, heart failure, MAKE, MALO, atrial fibrillation, stroke) within each comparator pairing, and (ii) window-level laboratory contrasts within each biomarker at baseline, 6, 12, and 24 months. RESULTS: Versus empagliflozin, semaglutide was associated with lower all-cause mortality (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.51-0.69), major adverse cardiovascular events (MACE; HR 0.76, 95% CI 0.66-0.88), and heart failure (HR 0.62, 95% CI 0.54-0.70). Versus sitagliptin, semaglutide was associated with lower all-cause mortality (HR 0.34, 95% CI 0.27-0.42), MACE (HR 0.64, 95% CI 0.51-0.81), and heart failure (HR 0.54, 95% CI 0.43-0.67). Empagliflozin versus sitagliptin showed lower all-cause mortality (HR 0.48, 95% CI 0.40-0.58) and MACE (HR 0.74, 95% CI 0.59-0.92), whereas heart failure did not differ significantly. CONCLUSION: In matched cohorts with T2D and obesity, semaglutide was associated with lower 24-month mortality and heart failure risk than empagliflozin, and both semaglutide and empagliflozin were associated with lower mortality and MACE than sitagliptin. TRIAL REGISTRATION: Not applicable (retrospective cohort); Institutional Review Board approval CS2-24004, Chung Shan Medical University Hospital.