Cardiovascular Outcomes of Tirzepatide vs Semaglutide in Obesity Without Type 2 Diabetes: A Matched Cohort Study
Tirzepatide may be associated with lower risks of major cardiovascular events compared to semaglutide in adults with obesity without type 2 diabetes, but further randomized trials are needed to confirm these findings.
Where it sits
this study against the rest of the semaglutide corpusSummary and findings
This study compared cardiovascular outcomes between tirzepatide and semaglutide in adults with obesity without type 2 diabetes. The primary outcome was major adverse cardiovascular events (MACE), assessed at 12 and 18 months. Tirzepatide was associated with lower MACE compared to semaglutide.
Abstract
Abstract Background/Objectives: Tirzepatide, a dual GIP/GLP-1 receptor agonist, achieves greater weight loss than semaglutide in adults with obesity without type 2 diabetes (T2D), but no randomised trial has directly compared their cardiovascular outcomes in this population. We compared major adverse cardiovascular events (MACE) and other cardiorenal outcomes between the two agents. Subjects/Methods: We conducted an active-comparator, propensity score–matched cohort study in the TriNetX Global Collaborative Network (178 healthcare organisations). Adults aged 18–80 years with obesity (BMI ≥30 kg/m²) initiating tirzepatide or subcutaneous semaglutide in 2024, with no prior T2D (ICD-10 E11.x or HbA1c ≥6.5%), were eligible. After 1:1 propensity score matching, outcomes were assessed under a 6-month landmark at 6–12 and 6–18 months after the index date. The primary outcome was 3-point MACE (acute myocardial infarction, ischaemic stroke, or all-cause mortality). Secondary outcomes included incident atrial fibrillation (AF) and a chronic kidney disease (CKD) progression composite. Two prespecified negative controls and E-values assessed residual confounding. Results: After matching, 54,978 pairs were analysed (mean age 46.6 years; 74.0% female; mean BMI 39.5 kg/m²). Tirzepatide was associated with lower MACE at 12 months (hazard ratio [HR] 0.80; 95% CI 0.69–0.92) and 18 months (HR 0.84; 95% CI 0.75–0.94). Significant reductions were also observed for incident AF (HR 0.83–0.84) and CKD progression (HR 0.82–0.84) at both horizons. All-cause mortality and acute MI showed directionally concordant but non-significant reductions. Negative controls were null; the primary MACE E-value was 1.81 (point estimate) and 1.39 (upper confidence limit). BMI-stratified sensitivity analyses confirmed consistency across obesity classes I–III. Conclusions: In adults with obesity without T2D, tirzepatide was associated with lower risks of MACE, incident AF, and CKD progression compared with semaglutide. These findings generate the hypothesis that dual GIP/GLP-1 receptor agonism may confer cardiovascular benefits beyond selective GLP-1 receptor agonism, warranting confirmation in randomised trials.