Cardiovascular disease (CVD) is a significant concern for individuals with obesity, accounting for nearly two-thirds of obesity-related mortality.¹ Effective management of obesity, therefore, necessitates a focus on reducing cardiovascular risk.¹ At ESC Congress 2025, Professor Mamas A. Mamas from Keele University in the United Kingdom presented post hoc findings from the SURMOUNT-5 trial, which compared the predicted 10-year CVD risk reduction associated with tirzepatide vs. semaglutide in adults with obesity who do not have type 2 diabetes (T2D) or prior cardiovascular events.¹

The SURMOUNT-5 trial was a phase 3b, multicenter, open-label, randomized controlled study involving adults with obesity or overweight and at least one obesity-related complication, excluding those with T2D or prior CVD.¹ Participants were randomly assigned in a 1:1 ratio to receive either tirzepatide (at doses of 10mg or 15mg) or semaglutide (at doses of 1.7mg or 2.4mg) through weekly subcutaneous injections over a 72-week period.¹ This post hoc analysis specifically evaluated participants who completed the 72-week treatment regimen, utilizing the body mass index (BMI)-based Framingham risk score to estimate predicted 10-year CVD risk and assess changes from baseline to week 72.¹ Additionally, subgroup analyses were conducted based on sex, race, and BMI category to provide a comprehensive understanding of the treatment effects.¹ To estimate the broader public health implications, the findings were extrapolated to eligible populations in the United States (US) and Europe, applying the observed 10-year CVD risk reductions to the respective population sizes.¹

Of the 751 participants randomized in the trial, 576 without pre-existing CVD were included in this analysis, with 292 receiving tirzepatide and 284 receiving semaglutide.¹ The mean age of participants was 44.8 years, with a mean BMI of 39.5kg/m².¹ Approximately two-thirds of participants were female, 57.5% had prediabetes, and 37.2% were undergoing treatment for hypertension.¹ At baseline, the predicted 10-year CVD risk was 9.0% for the tirzepatide group and 9.5% for the semaglutide group.¹

The primary focus of this post hoc analysis was the change in predicted 10-year CVD risk from baseline to week 72, calculated using validated Framingham risk equations.¹ The results indicated that, at 72 weeks, tirzepatide achieved an absolute reduction in predicted 10-year CVD risk of 2.4%, compared to a 1.4% reduction in the semaglutide group (p<0.001).¹ This translated to a relative reduction of 23.7% from baseline with tirzepatide vs. 13.6% with semaglutide (p<0.001).¹ Notably, the beneficial effects of tirzepatide on predicted CVD risk were evident as early as week 12 and continued throughout the treatment period.¹

Subgroup analyses assessed treatment differences by sex, race, and baseline BMI, as well as projections of preventable CVD events over a decade among eligible populations in the US and Europe.¹ These analyses found that tirzepatide consistently yielded significantly greater reductions in predicted CVD risk across all categories.¹ For instance, among females, the risk reduction was 25.8% with tirzepatide compared to 15.4% with semaglutide; for males, the reductions were 19.8% vs. 9.8% (both p<0.001).¹ In White participants, the reductions were 26.2% for tirzepatide compared to 14.3% for semaglutide (p<0.001).¹ Furthermore, patients with a baseline BMI of less than 35kg/m² experienced reductions of 23.6% with tirzepatide vs. 15.7% with semaglutide (p<0.05), while those with a BMI of 35kg/m² or higher had reductions of 23.5% compared to 12.7% (p<0.001).¹

When these findings were extrapolated to an estimated 85 million adults in the US and 49 million in Europe eligible for treatment without prior CVD, the potential public health impact became apparent.¹ Tirzepatide could potentially prevent approximately 3.1 million cardiovascular events over the next decade, compared to 1.8 million events with semaglutide across the major countries analyzed.¹

In summary, the post hoc findings from the SURMOUNT-5 trial highlight the cardiovascular benefits of tirzepatide compared to semaglutide in adults with obesity.¹ These results underscore the importance of considering cardiovascular risk reduction in the management of obesity, particularly for individuals without T2D or prior cardiovascular events.¹ The potential to prevent cardiovascular events in the broader population further emphasizes the need for effective obesity treatments that address not only weight loss but also associated cardiovascular risks.¹