New research reveals that tirzepatide and semaglutide both offer strong, early heart-protective effects.
A major new investigation from Mass General Brigham has directly compared the heart-protective effects of two popular diabetes medications, tirzepatide and semaglutide. The findings reveal that both drugs significantly lower the risk of heart attack, stroke, and death from any cause. The results were published in Nature Medicine and presented at the 2025 American Heart Association Scientific Sessions.
Earlier studies had already shown that semaglutide helps guard against cardiovascular events such as heart attacks and strokes. However, it remained uncertain whether tirzepatide, another widely used treatment for type 2 diabetes, offered the same protective advantages.
To explore this question, researchers analyzed national health claims data from nearly one million adults who were taking tirzepatide, semaglutide, or other medications prescribed for type 2 diabetes.
Real-World Data and Research Approach
“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 first author Nils Krüger, MD, a research fellow in the Division of Pharmacoepidemiology and Pharmacoeconomics in the Mass General Brigham Department of Medicine. “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. Moreover, we can study patients who reflect the reality of everyday clinical care, in contrast to the highly selected participants of randomized experiments.”
The analysis showed that both medications improved cardiovascular outcomes for people with type 2 diabetes who faced a higher risk of heart-related complications. Compared with sitagliptin, a diabetes drug known to have neutral effects on heart health, semaglutide reduced the combined risk of stroke and heart attack by 18 percent. Tirzepatide also showed a benefit, cutting the risk of stroke, heart attack, and death by 13 percent when compared with dulaglutide, another GLP-1 receptor agonist that has been in use for several years.
“Both drugs show strong cardioprotective effects. Our data also indicate that these benefits occur early, suggesting that their protective mechanisms go beyond weight loss alone,” said Krüger. The exact biological mechanisms underlying these protective effects remain unknown.
Comparing the Leading GLP-1 Agents
Because these medications have only recently become available, studies confirming their cardioprotective mechanisms—particularly those directly comparing the two dominant GLP-1 agents, tirzepatide and semaglutide—are still lacking.
“According to recently presented database analyses by the respective manufacturers, each company’s own drug appears to reduce cardiovascular risk much more effectively than the competitor’s,” said Krüger. “However, our study found only small differences between tirzepatide and semaglutide in cardiovascular protection among populations at risk of adverse events, underscoring that both agents provide protective benefit and could be integrated into clinical cardiovascular practice.”
“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,” said last author Shirley Wang, PhD, an associate epidemiologist in the Division of Pharmacoepidemiology and Pharmacoeconomics in the Mass General Brigham Department of Medicine.
Reference: “Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice” by Nils Krüger, Sebastian Schneeweiss, Rishi J. Desai, Sushama Kattinakere Sreedhara, Anna R. Kehoe, Kenshiro Fuse, Georg Hahn, Heribert Schunkert and Shirley V. Wang, 9 November 2025, Nature Medicine.
DOI: 10.1038/s41591-025-04102-x
This work was funded by the National Institutes of Health (R01-HL141505, R01-AR080194) and the German Heart Foundation (S/02/24, SRF-HF/24).
Disclosures: Schneeweiss reported personal fees from Aetion Inc, a software-enabled analytics company, and grants from Bayer, UCB, and Boehringer Ingelheim to Brigham and Women’s Hospital outside the submitted work. Schunkert reported personal fees from AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, MSD, Novartis, Pharmacosmos, Sanofi, Servier, Synlab, Amgen, and Amarin outside the submitted work. Wang reported personal fees from MITRE, a federally funded research and development center for the Centers for Medicare & Medicaid Services and personal fees from Cytel Inc during the conduct of the study. No other disclosures were reported.
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