Semaglutide shows superior 24-month cardiovascular and mortality benefits over empagliflozin and sitagliptin in T2D with obesity.

While newer glucose-lowering agents like GLP-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors have demonstrated cardiovascular benefits in clinical trials, real-world comparative evidence on their long-term clinical outcomes and biomarker trajectories against older agents like DPP-4 inhibitors remains limited. Type 2 diabetes (T2D) and obesity are major drivers of cardiovascular disease (CVD), leading to significant morbidity and mortality. Understanding these differences over 24 months is crucial for optimizing treatment strategies and improving patient outcomes in this high-risk population.

This multicenter retrospective cohort study utilized the TriNetX network to compare 24-month outcomes. Researchers performed an active-comparator, new-user study with three 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 using Benjamini-Hochberg false discovery rate correction for clinical time-to-event endpoints (all-cause mortality, MACE, heart failure, MAKE, MALO, atrial fibrillation, stroke) and window-level laboratory contrasts at baseline, 6, 12, and 24 months.