Predicted cardiovascular risk reduction with tirzepatide vs. semaglutide: interpretative considerations from the SURMOUNT-5 post hoc analysis

This correspondence refers to ‘Tirzepatide compared with semaglutide and 10-year cardiovascular disease risk reduction in obesity: post-hoc analysis of the SURMOUNT-5 trial’, by M.A. Mamas et al., https://doi.org/10.1093/ehjopen/oeaf117. The recent post hoc analysis of the SURMOUNT-5 trial comparing tirzepatide with semaglutide for predicted 10-year cardiovascular disease (CVD) risk reduction in individuals with obesity and without diabetes or established CVD addresses an important and timely question in preventive cardiology.1 The authors should be commended for undertaking the first head-to-head evaluation of two highly effective obesity pharmacotherapies using patient-level longitudinal data and for attempting to contextualize cardiometabolic risk modification at a population level. However, several interpretative considerations merit discussion, particularly regarding the implication of cardiovascular benefit superiority associated with tirzepatide. First, the analysis is based on modelled cardiovascular risk rather than observed cardiovascular events. The body mass index (BMI)–based Framingham risk equation used in this study explicitly incorporates BMI and systolic blood pressure as key determinants of predicted risk.2 Consequently, greater weight loss and blood pressure reduction will, by design, translate into a larger estimated reduction in cardiovascular risk. While this approach is appropriate for evaluating risk-factor modification, it inherently limits causal inference about differential cardiovascular outcomes between therapies and should not be interpreted as evidence of superiority in reducing major adverse cardiovascular events. Second, these findings should be interpreted in the context of randomized cardiovascular outcomes trials and meta-analyses of glucagon-like peptide-1 receptor agonists (GLP-1RAs). Across outcome-driven trials, GLP-1RAs have demonstrated consistent reductions in cardiovascular events that appear largely independent of baseline body weight and the magnitude of weight loss achieved.3 Meta-regression analyses have not identified weight loss as a dominant mediator of cardiovascular benefit, supporting the role of pleiotropic mechanisms—including anti-inflammatory, anti-atherosclerotic, and direct vascular effects—in cardiovascular risk reduction.4 Notably, in the SURPASS-CVOT programme, tirzepatide and dulaglutide demonstrated comparable cardiovascular outcomes despite substantial differences in weight loss, reinforcing the conceptual separation between adiposity reduction and cardiovascular protection.5 These observations suggest that post hoc risk modelling should be interpreted as complementary to, rather than overriding, randomized outcome evidence. Third, the baseline cardiovascular risk of the SURMOUNT-5 population was relatively low, with a mean predicted 10-year risk of 9.3%. Although relative reductions in predicted risk appear numerically meaningful, the absolute risk reductions at an individual level remain modest. Consequently, the clinical relevance for near-term cardiovascular prevention in individual patients may be limited. In addition, population-level projections of prevented cardiovascular events depend heavily on assumptions regarding long-term treatment persistence, durability of cardiometabolic improvements, and real-world adherence, all of which remain uncertain. Fourth, the greater reductions in systolic blood pressure and antihypertensive use observed with tirzepatide are noteworthy but closely parallel the degree of weight loss and are similarly embedded within the risk prediction model. This limits the ability to disentangle weight-mediated effects from potential direct cardiometabolic actions of dual GIP/GLP-1 receptor agonism. Although early divergence of predicted risk trajectories raises the hypothesis of weight-independent mechanisms, such inference remains speculative without event-driven outcome data. In summary, the SURMOUNT-5 post hoc analysis provides valuable insights into comparative cardiometabolic risk-factor modification with tirzepatide and semaglutide in a primary prevention obesity population. However, caution is warranted in framing these findings as evidence of cardiovascular superiority. Modelled risk reduction should not be conflated with demonstrated cardiovascular outcome benefit. Ongoing and future event-driven trials will be essential to determine whether differences in predicted risk translate into meaningful differences in cardiovascular morbidity and mortality. No funding was received for this research letter. The authors have no conflict of interest to declare.