Abstract
<title>Abstract</title> <p> <bold>Background/Objectives:</bold> 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. <bold>Subjects/Methods:</bold> 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. <bold>Results:</bold> 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. <bold>Conclusions:</bold> 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. </p>