Cardiovascular and Kidney Outcomes of Tirzepatide versus Semaglutide in Stage 2 Cardiovascular-Kidney-Metabolic Syndrome: A Propensity Score-matched Cohort Study

Background Cardiovascular-kidney-metabolic (CKM) syndrome describes the overlapping burden of metabolic dysfunction, chronic kidney disease, and cardiovascular disease. Tirzepatide and semaglutide are both recommended for patients with type 2 diabetes and obesity, yet no randomized trial has directly compared their effect on hard cardiovascular and renal outcomes. Methods We conducted a retrospective, propensity score matched cohort study using the TriNetX Research Network (115 healthcare organizations queried). Adults with Stage 2 CKM syndrome and no established atherosclerotic, cerebrovascular, or heart failure disease were grouped by receipt of tirzepatide or semaglutide. Efficacy, safety, and exploratory outcomes were assessed over 1-year and 3-year windows. Cohorts were matched 1:1 (caliper 0.2 SD) on demographics, comorbidities, medications, and laboratory values, with a separate match performed for each analysis. Risk differences, risk ratios, odds ratios, hazard ratios (HR), and Kaplan–Meier survival analyses were calculated, and prespecified negative-control outcomes were used to test for residual confounding. Results After matching, cohorts ranged from 198,753 to 238,370 patients per group. Median observed follow-up was 163 days (tirzepatide) and 172 days (semaglutide) in the 3-year efficacy analysis. Compared with semaglutide, tirzepatide was associated with lower rates of major adverse cardiovascular events (1-year HR 0.83, 95% CI 0.77–0.90; 3-year HR 0.84, 0.78–0.91; 3-year risk difference −1.09 per 1,000 patients), all-cause mortality (1-year HR 0.75; 3-year HR 0.78), the cardiorenal composite, major adverse kidney events, end-stage kidney disease, and heart failure exacerbation at both time points. New atherosclerotic heart disease, acute kidney injury, and macroalbuminuria did not differ significantly. No prespecified safety outcome was more frequent with tirzepatide, and negative-control outcomes were null, although coronary artery calcium testing and HbA1c measurement were more frequent with tirzepatide, suggesting differential surveillance. Mean HbA1c was modestly lower with tirzepatide. Conclusion In this large real-world analysis with predominantly short observed follow-up, tirzepatide was associated with lower cardiovascular and renal event rates than semaglutide, with comparable safety. These findings are hypothesis-generating, may be affected by residual confounding, and require confirmation in randomized controlled trials.