Real-World Data Points to Greater Impact of Semaglutide Over Tirzepatide in Reducing Heart Attack, Stroke Risk

Ludovic Helfgott

Recently presented data from the real-world STEER study showed that treatment with semaglutide (Wegovy; Novo Nordisk), an FDA-approved glucagon-like peptide-1 receptor agonist (GLP-1 RA), led to more lowered risk for heart attack, stroke, and cardiovascular-related death than tirzepatide, another GLP-1 RA. Overall, these data point to potential cardiovascular benefits of semaglutide for those living with obesity and cardiovascular disease, without diabetes.¹

In this retrospective, observational study, investigators assessed the efficacy of semaglutide 2.4 mg (n = 10,625) vs tirzepatide (n = 10,625) for the prevention of MACE in adults with overweight or obesity and established cardiovascular disease (CVD) with no prior history of diabetes. The trial used a revised 5-point MACE (heart attack, stroke, hospitalization for heart failure, coronary revascularization, and death from any cause) and revised 3-point MACE (heart attack, stroke, and death from any cause) as the primary outcome measure.

When compared with tirzepatide, results revealed a 57% greater risk reduction with semaglutide for heart attack, stroke, and cardiovascular-related death or death from any cause. During an average follow-up of 3.8 months with semaglutide and 4.3 months with tirzepatide, 15 cardiovascular events (0.1%) occurred in the semaglutide group compared with 39 events (0.4%) in the tirzapatide group.

"Our landmark trial, SELECT, showed that Wegovy® is associated with a significant 20% risk reduction of cardiovascular events, backed up with even greater risk reductions in the real-world studies SCORE and STEER. The results are clear – STEER demonstrates that Wegovy® cuts the risk of heart attack, stroke or death by 57% compared to tirzepatide," Ludovic Helfgott, executive vice president and head of Product & Portfolio Strategy at Novo Nordisk, said in a statement. "This data confirms that semaglutide stands apart as the only available GLP-1-based medication with proven cardiovascular benefits for people living with obesity and cardiovascular disease, without diabetes."

Presented at the European Society of Cardiology (ESC) Congress in Madrid, Spain, treatment with semaglutide resulted in a significant 29% lowered risk for heart attack, stroke, and death for treated people, regardless of any gaps in their treatment, when compared with tirzepatide. These findings were collected over an average follow-up of 8.3 months for semaglutide and 8.6 months for tirzepatide.

As Helfgott noted, semaglutide was previously studied in the real-world SCORE and SELECT trials. SELECT (NCT03574597) was a randomized, double-blind, placebo-controlled trial testing semaglutide vs placebo for reducing MACE in adults at least 45 years with overweight or obesity and established cardiovascular disease, but no diabetes. In contrast, the SCORE study assessed similar outcomes in a real-world U.S. population of semaglutide users and non-users meeting comparable inclusion criteria.

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SELECT, published in the New England Journal of Medicine, included 17,604 patients with preexisting cardiovascular disease who were randomly assigned 1:1 to either semaglutide or placebo for a mean follow-up of 39.8 months. Overall, the primary cardiovascular end point, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in 569 patients (6.5%) in the semaglutide group and in 701 patients (8.0%) in the placebo (HR, 0.80; 95% CI, 0.72-0.90; P <.001).²

Data from SCORE, presented earlier this year at the American College of Cardiology Annual Scientific Session and Expo, revealed a 57% (HR, 0.43; 95% CI, 0.31-0.61; P <.0001) lowered risk of revised MACE-3 composite end point with semaglutide 2.4 mg. Overall, revised MACE-3 occurred in 42 (0.45%) of the 9,321 patients in the semaglutide 2.4 mg group and 175 (0.94% ) of the 18,642 patients in the non-user group. In the study, patients were followed for a mean duration of 7.1 months for semaglutide users and 6.4 months for non-users.³

Additional data from SCORE revealed that use of semaglutide 2.4 mg was associated with a 45% lower risk of the revised MACE-5 composite endpoint—consisting of heart attack, stroke, hospitalization for heart failure (HF), coronary revascularization, or all-cause death—compared with non-users (HR, 0.55; 95% CI: 0.43–0.70; p < 0.001). Revised MACE-5 events occurred in 88 patients (0.94%) of the 9,321 treated with semaglutide 2.4 mg, compared with 288 patients (1.54%) of the 18,642 in the non-user group. These results were consistent across a range of cardiovascular outcomes, as semaglutide use was also linked to significantly reduced risks of hospitalization for HF, cardiovascular-related death, and all-cause death.

REFERENCES
1. Novo Nordisk’s Wegovy® cuts risk of heart attack, stroke or death by 57% compared to tirzepatide in real-world study of people with obesity and cardiovascular disease. News release. Novo Nordisk. August 31, 2025. Accessed September 2, 2025. https://www.globenewswire.com/news-release/2025/08/31/3141900/0/en/Novo-Nordisk-s-Wegovy-cuts-risk-of-heart-attack-stroke-or-death-by-57-compared-to-tirzepatide-in-real-world-study-of-people-with-obesity-and-cardiovascular-disease.html
2. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. SCORE analysis of semaglutide 2.4 mg demonstrated reduction in cardiovascular events in a real-world setting. NEJM. 2023;389;2221-2232. doi:10.1056/NEJMoa2307563
3. SCORE analysis of semaglutide 2.4 mg demonstrated reduction in cardiovascular events in a real-world setting. News release. Novo Nordisk. March 30, 2025. Accessed September 2, 2025. https://www.prnewswire.com/news-releases/score-analysis-of-semaglutide-2-4-mg-demonstrated-reduction-in-cardiovascular-events-in-a-real-world-setting-302414812.html