Real-world data show tirzepatide and semaglutide offer comparable cardiovascular protection 

A large real-world analysis from Mass General Brigham comparing nearly one million patients finds that tirzepatide and semaglutide deliver similar cardiovascular benefits in routine clinical practice, reinforcing trial evidence and highlighting the growing role of real-world data in cardiometabolic research. 

A new study from Mass General Brigham using real-world data (RWD) provides the first direct comparison of tirzepatide and semaglutide for cardiovascular protection in clinical practice. The findings, published simultaneously in Nature Medicine and presented at the American Heart Association Scientific Sessions 2025, suggest that both GLP-1–based therapies reduce major cardiovascular events in patients with type 2 diabetes and elevated cardiovascular risk. 

Using national US claims databases, the researchers analyzed nearly one million adults taking either tirzepatide, semaglutide, or other type 2 diabetes treatments. The aim was twofold: to compare the cardiovascular performance of the two incretin-based therapies and to assess how their effectiveness in real-world settings aligns with results from established cardiovascular outcome trials. As the authors noted, “As the landscape of cardiometabolic therapeutics evolves rapidly, real-world evidence may serve as a critical tool to generate comparative insights beyond trials that is essential for clinical decision-making and regulatory evaluation.” They added that as dozens of novel agents are now pursuing additional indications, it is worth questioning whether “the traditional practice of two confirmatory trials for every indication expansion remains justified,” particularly when trial emulation studies have shown strong agreement with earlier randomized evidence. 

While randomized controlled trials have already demonstrated that semaglutide can reduce cardiovascular events such as heart attack and stroke, evidence for tirzepatide has been more limited. The study addressed this evidence limitation by emulating two benchmark trials –SUSTAIN-6 for semaglutide and SURPASS-CVOT for tirzepatide – before extending the analysis to broader clinical-practice populations that better represent routine care. 

“Randomized controlled trials are often considered the reference standard in the medical evidence generation process. However, not all questions can be answered using this time- and resource-intensive method,” said study author Nils Krüger, a research fellow in the Division of Pharmacoepidemiology and Pharmacoeconomics. “Data generated in clinical practice and used secondarily for research allow us to address a wide range of clinically relevant questions time- and resource-effectively—when applied correctly.” 

To validate their methodology, the researchers first emulated SUSTAIN-6 and SURPASS-CVOT using sitagliptin and dulaglutide as placebo proxies. The emulations showed “high agreement” with the original randomized trials across most endpoints, except all-cause mortality in SUSTAIN-6, providing confidence in the analytic strategy for subsequent head-to-head analyses. 

The expanded real-world cohort, drawn from three large US administrative claims databases and including almost 300,000 patients, produced results consistent with randomized evidence. Semaglutide was associated with an 18% reduction in heart attack and stroke compared with sitagliptin (hazard ratio 0.82). Tirzepatide reduced the composite of stroke, heart attack, and all-cause mortality by 13% relative to dulaglutide (hazard ratio 0.87). 

“Both drugs show strong cardioprotective effects,” said Krüger. “Our data also indicate that these benefits occur early, suggesting that their protective mechanisms go beyond weight loss alone.” 

In the direct comparison, the hazard ratio for tirzepatide versus semaglutide was 1.06, indicating broadly comparable cardiovascular benefits. Krüger highlighted that while recent sponsor-led database analyses have suggested larger differences between the two drugs, the present study “found only small differences between tirzepatide and semaglutide in cardiovascular protection among populations at risk of adverse events.” 

The authors acknowledged several limitations typical of RWD studies, including non-randomized treatment allocation and potential residual confounding, reliance on administrative claims with variable accuracy, and limited insight into long-term treatment persistence. They noted that findings may generalize mainly to the US context and that assuming neutral cardiovascular effects for sitagliptin was based on prior evidence. 

Co-author Shirley Wang, PhD, associate epidemiologist in the Division of Pharmacoepidemiology and Pharmacoeconomics, emphasized the significance of the study and team’s commitment to transparency: 

“We hope that our study will help clinicians better understand how these new medications work in clinical practice. Our transparent and open science practices, including pre-registration of a public protocol and shared analytic code, are designed to support scientific discussion.”