Evolocumab is already known to significantly reduce the risk of major adverse cardiovascular events (MACE), but whether its benefits vary according to body weight has remained uncertain. This study addressed this gap by examining outcomes across BMI categories in 27,564 participants enrolled in the FOURIER trial, all of whom had stable atherosclerotic cardiovascular disease and were receiving optimized statin therapy. Participants were randomized to evolocumab or placebo and followed for a median of 2.2 years.
The primary endpoint included cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. This study focused first on the placebo arm to assess how BMI alone related to cardiovascular risk. The research evaluated whether BMI modified the treatment effect of evolocumab using interaction testing in Cox proportional hazards models.
About 40% of participants had a BMI of at least 30 kg/m², and 13% had severe obesity, defined as a BMI of 35 kg/m² or higher. In patients assigned to placebo, cardiovascular risk rose steadily with increasing BMI. After adjusting for other clinical predictors, each 5-unit increase in BMI above 30 kg/m² was associated with an 11% higher risk of experiencing a major cardiovascular event. This finding reinforces obesity as an independent driver of adverse cardiovascular outcomes.
Among patients with a BMI below 30 kg/m², evolocumab reduced the risk of the primary endpoint by 11%. The benefit was larger in those with class I obesity (BMI 30 to <35 kg/m²), with a 14% relative risk reduction. The most striking effect was seen in patients with severe obesity, where evolocumab lowered the risk of major cardiovascular events by 29%.
While relative risk reductions highlight proportional benefit, the absolute reductions, 1.4%, 1.8%, and 5.7% across increasing BMI categories, which highlight the substantial clinical impact in patients with the highest baseline risk. Overall, this analysis demonstrates that individuals with obesity face a significantly elevated risk of cardiovascular events, but also stand to gain the most from PCSK9 inhibition. Evolocumab not only lowers LDL cholesterol but meaningfully attenuates excess cardiovascular risk in patients with obesity, supporting its role in personalized risk-based prevention strategies.
Reference:
Kang, Y. M., Giugliano, R. P., Keech, A. C., López, J. A. G., Monsalvo, M. L., Ohman, E. M., Ran, X., Murphy, S. A., Sabatine, M. S., & O’Donoghue, M. L. (2025). Obesity-associated cardiovascular risk and benefit from PCSK9 Inhibition: A prespecified analysis from FOURIER. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2025.10.036
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