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Cardiovascular and Cerebrovascular Outcomes Risk Reduction Associated With Semaglutide vs Tirzepatide: A Target Trial
Ahmed Y Azzam1, Muhammed Amir Essibayi2, Pranjal Rai3
1Department of Neuroradiology, WVU Rockefeller Neuroscience Institute, West Virginia University, Morgantown, West Virginia, USA.
JACC. Advances
|July 23, 2026
Summary
Tirzepatide showed better cardiovascular outcomes than semaglutide for both diabetic and nondiabetic patients. Diabetes status influenced treatment effects, with tirzepatide demonstrating greater risk reduction in certain groups.
Area of Science:
- Cardiovascular medicine
- Endocrinology
- Pharmacology
Background:
- Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) offer cardiovascular benefits.
- Head-to-head trials comparing semaglutide and tirzepatide are limited.
- The impact of diabetes status on these comparisons is not well-established.
Purpose of the Study:
- To compare cardiovascular outcomes between semaglutide and tirzepatide.
- To assess if treatment effects differ based on type 2 diabetes status.
- To utilize a target trial emulation approach for robust comparison.
Main Methods:
- A target trial emulation study using the TARGET framework.
- Included 217,920 adults initiating semaglutide or tirzepatide.
- Matched patients 1:1 based on diabetes status (diabetic and nondiabetic) with 3-year follow-up.
Main Results:
- Tirzepatide demonstrated lower risk for atrial fibrillation, heart failure, and myocardial infarction at 1 and 3 years.
- Significant effect modification by diabetes status was observed for key cardiovascular outcomes.
- Risk reduction with tirzepatide appeared to strengthen over the 3-year follow-up.
Conclusions:
- Tirzepatide showed more favorable cardiovascular risk reduction compared to semaglutide.
- Treatment effects varied significantly between diabetic and nondiabetic populations.
- Differential treatment associations suggest personalized approaches may be beneficial.
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