The EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study supports the reduction in the risk of atherosclerotic cardiovascular disease (ASCVD) events with ezetimibe without statin therapy in persons aged ≥75 years without a history of coronary artery disease. This evidence has also been incorporated into the 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. What might then be the potential explanations for the observed benefit of ezetimibe to prevent ASCVD in the EWTOPIA 75 study? First, cholesterol absorption efficiency generally increases with age. Therefore, cholesterol absorption-lowering medications, such as ezetimibe, are particularly beneficial in individuals aged 75 years and older, in whom low cholesterol absorption has been associated with fewer recurrent ASCVD events. It is also worth noting that ezetimibe may be more effective than a particular statin in reducing non-high-density lipoprotein cholesterol (non-HDL-C), which includes lipoprotein remnant particles. Therefore, the benefits of the achieved low-density lipoprotein cholesterol (LDL-C) levels are not directly comparable between ezetimibe and statin therapy. It remains to be verified in future studies whether ezetimibe monotherapy would be helpful, specifically in older patients. If so, one possible explanation is that, even in the absence of clinical ASCVD, ezetimibe slows and stabilizes the atherosclerotic process that is still advancing. Finally, a trade-off between a less effective LDL-C lowering but a low frequency of adverse effects and drug interactions could lead to better long-term adherence in the setting of primary prevention.
Vuorio et al. (Tue,) studied this question.