Authors: Chen, Liu, Huang
Journal: Therapeutic advances in endocrinology and metabolism (2026 07)
Abstract
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. To compare 24-month clinical outcomes and longitudinal biomarker trajectories among semaglutide, empagliflozin, and sitagliptin in people with T2D and obesity. Multicenter retrospective cohort study. 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. 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. 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. Not applicable (retrospective cohort); Institutional Review Board approval CS2-24004, Chung Shan Medical University Hospital. Semaglutide, empagliflozin, and sitagliptin in adults with type 2 diabetes and obesity: 24 month outcomes and biomarker patterns People with type 2 diabetes and obesity often need medicines that address both metabolic control and long term cardiovascular and kidney risks.
Comparative evidence from routine care is still limited, especially when clinical outcomes and laboratory patterns are evaluated together. We studied adults who newly started semaglutide, empagliflozin, or sitagliptin to describe how these treatments were associated with outcomes and biomarker changes over time. We used deidentified electronic health records from the TriNetX US Collaborative Network. Among 3,981,497 eligible individuals, we constructed three active comparator cohorts and applied one to one propensity score matching.
Patients were followed for up to 24 months using an intention to treat approach. Clinical outcomes included all cause mortality, major adverse cardiovascular events, heart failure, and a kidney composite outcome. Laboratory markers were summarized in prespecified windows around 6, 12, and 24 months, including glycemic measures, lipids, inflammatory markers, cardiac stress markers, and liver and kidney function. Mean corpuscular volume was processed as a negative control laboratory marker to help evaluate residual confounding.
Across matched cohorts, semaglutide compared with empagliflozin was associated with lower risks of all cause mortality, major adverse cardiovascular events, and heart failure over 24 months. When compared with sitagliptin, both semaglutide and empagliflozin were associated with lower risks of mortality and major adverse cardiovascular events. The kidney composite outcome showed a different pattern than the cardiovascular outcomes, supporting interpretation in terms of domain specific profiles. This observational study describes associations and may be influenced by unmeasured factors and incomplete laboratory capture.
