How can cholesterol efflux capacity be used as a risk factor for atherosclerotic cardiovascular disease?

High-density lipoprotein cholesterol (HDL-C) has long been regarded as 'good cholesterol,' but clinical trials and epidemiological studies have demonstrated that simply raising HDL-C levels does not reduce cardiovascular events. Attention has therefore shifted from HDL-C quantity to HDL functionality. This review summarizes evidence from PubMed and Web of Science (2011-2024) on cholesterol efflux capacity (CEC), the most widely studied HDL functionality. CEC reflects the ability of HDL to remove cholesterol from macrophages, representing the first step of reverse cholesterol transport. Cohort and case-control studies consistently indicate that CEC provides incremental predictive value for atherosclerotic cardiovascular disease (ASCVD) beyond traditional lipid parameters. However, results vary across familial hypercholesterolemia cohorts, highlighting the influence of assay methods, treatment exposure, and HDL remodeling. The review also addresses lifestyle and genetic factors (e.g. alcohol consumption, ALDH2 polymorphisms), oxidative stress, and methodological challenges that complicate CEC measurement and standardization. While CEC is a promising surrogate marker, it remains a phenomenon rather than a therapeutic target, and there is no conclusive evidence that increasing CEC reduces ASCVD events. Future research should focus on disease-specific molecules, such as FABP5 and ORM1, that impair HDL function. Identifying these pathways may yield novel biomarkers and therapeutic targets, offering a more precise approach to residual cardiovascular risk beyond HDL-C levels.