Tirzepatide Predicted to Prevent Nearly Twice as Many Heart Disease Events as Semaglutide Over 10 Years

What the researchers found

In participants with obesity and no prior cardiovascular disease, the average baseline 10-year CVD risk score was 9.3%. After 72 weeks of treatment:

- Tirzepatide reduced predicted 10-year CVD risk by 2.4% (absolute reduction from baseline)

- Semaglutide reduced predicted 10-year CVD risk by 1.4% (absolute reduction from baseline)

- The difference was statistically significant (P < 0.001)

Projected to the ~85 million treatment-eligible Americans without prior CVD, tirzepatide could potentially prevent ~2 million CVD events over 10 years, compared to ~1.15 million with semaglutide.

Why it matters

About two-thirds of obesity-related deaths are from cardiovascular disease. This head-to-head comparison suggests tirzepatide may offer meaningfully greater cardiovascular protection than semaglutide in obesity, which could influence treatment decisions for millions of people and potentially save hundreds of thousands of additional lives.

How the study worked

This was a post-hoc analysis of the SURMOUNT-5 trial, a Phase 3b open-label randomized trial comparing tirzepatide (10 or 15 mg) with semaglutide (1.7 or 2.4 mg) via weekly subcutaneous injection over 72 weeks. Predicted 10-year CVD risk scores were calculated at baseline and post-treatment. Population-level impact was estimated by extrapolating risk reductions to the eligible US population.

What this study cannot tell us

This is a post-hoc analysis using predicted CVD risk scores, not actual observed cardiovascular events. The SURMOUNT-5 trial was open-label, which could introduce bias. The population projections assume that trial results would generalize to the entire US eligible population. The CVD risk prediction model may not fully capture the mechanisms through which these drugs reduce cardiovascular risk. The 72-week treatment period may not reflect long-term real-world medication adherence.

How to read the evidence

This is a post-hoc analysis of a Phase 3b randomized trial — reasonably strong evidence from a head-to-head comparison, but limited by its post-hoc nature, open-label design, and use of predicted rather than actual cardiovascular events.

When this study was published

Published in 2025 in European Heart Journal Open, this is among the first analyses from the SURMOUNT-5 trial comparing these two blockbuster drugs head-to-head.

The bigger picture

This is one of the first head-to-head comparisons of tirzepatide and semaglutide for cardiovascular risk reduction. It adds to mounting evidence that tirzepatide's dual GLP-1/GIP receptor mechanism may provide advantages over GLP-1-only drugs. However, these are predicted rather than observed cardiovascular events, and confirmation with actual outcome trials is needed.

Questions still open

• Will dedicated cardiovascular outcome trials confirm tirzepatide's superior CVD risk reduction over semaglutide?
• How much of the difference between tirzepatide and semaglutide is driven by greater weight loss versus other metabolic effects?
• Would the projected population-level benefits hold up when accounting for real-world medication adherence and discontinuation rates?

Common questions

Read the original research

Tirzepatide compared with semaglutide and 10-year cardiovascular disease risk reduction in obesity: post-hoc analysis of the SURMOUNT-5 trial.

European heart journal open, 5(5), oeaf117

Citation

Mamas, Mamas A; Bays, Harold; Li, Runjia; Upadhyay, Navneet; Irani, Tanya; Senyucel, Cagri; Dunn, Julia P; Liu-Seifert, Hong. (2025). Tirzepatide compared with semaglutide and 10-year cardiovascular disease risk reduction in obesity: post-hoc analysis of the SURMOUNT-5 trial.. European heart journal open, 5(5), oeaf117. https://doi.org/10.1093/ehjopen/oeaf117