Tirzepatide Shows Lower Mortality and Better Cardiorenal Outcomes than Semaglutide in Coronary Artery Disease and Obesity: AHJ Study, December 2025

In patients with coronary artery disease (CAD) and obesity, tirzepatide was associated with lower mortality and reduced cardiovascular and renal complications compared to semaglutide, suggesting differences in cardiorenal protection between these incretin-based therapies.

This study abstract is published in American Heart Journal in December 2025.

Background of the Study

A new real-world analysis from the TriNetX Research Network provides important comparative insight into two of the most widely used incretin medications—tirzepatide and semaglutide—specifically in individuals living with both obesity and established CAD. This population is at exceptionally high risk for cardiovascular events, hospitalizations, and long-term complications. While both medications have shown significant benefits in clinical trials, direct comparisons in routine clinical practice have been limited. This study fills a critical evidence gap at a time when incretin therapies are rapidly reshaping obesity and cardiovascular care.

About the Study

Researchers used TriNetX’s research network to identify adults with CAD and a body mass index (BMI) of 30 kg/m² who were prescribed either tirzepatide or semaglutide. The initial sample included over 150,000 patients, with 43,023 receiving tirzepatide and 110,544 receiving semaglutide. After propensity score matching to ensure both groups were clinically comparable, 43,019 patients remained in each cohort. The primary outcome assessed was all-cause mortality, while secondary outcomes included heart failure, arrhythmias, renal complications, pulmonary outcomes, and cerebrovascular disease.

Key Findings of the Study

• The researchers found that tirzepatide was associated with a significantly lower mortality rate than semaglutide (1.1% vs 1.7%), representing a 35% relative reduction.
• The dual incretin therapy also demonstrated reduced risks of heart failure, atrial fibrillation, cardiogenic shock, and acute kidney injury.
• These benefits extended to pulmonary embolism, pulmonary edema, and cerebrovascular complications, suggesting a broad pattern of cardiopulmonary and renal protection.
• Although the mechanisms behind these differences were not directly analyzed, tirzepatide’s combined GIP and GLP-1 agonism and its greater impact on weight loss and metabolic parameters may play a role.

However, the authors note that real-world data, while powerful, are subject to limitations such as potential unmeasured confounders and variations in medication adherence or dosing. Despite these considerations, the large sample size and consistency of the findings strengthen the reliability of the conclusions. As the landscape of cardiometabolic therapy continues to evolve, further comparative studies will help clarify these differences and guide optimal treatment strategies.

Potential Clinical Implications

Clinically, these findings carry significant implications. For patients with CAD and obesity, both incretin therapies offer meaningful cardiometabolic benefits, but tirzepatide may provide an additional margin of protection. Cardiology and obesity specialists who manage high-risk patients may increasingly view tirzepatide as a preferred option, especially for long-term cardiovascular risk reduction. Because this study reflects real-world prescribing patterns, medication use outside the controlled trial environment, and outcomes across diverse clinical settings, it provides practical evidence that can inform daily decision-making.