Cholesterol Efflux Capacity Full Steam Ahead or a Bump in the Road

TLDR: Recent published outcomes trials involving the addition of niacin or dalcetrapib to standard low-density lipoprotein cholesterol reduction therapy failed to demonstrate clinical benefit despite increases in HDL-C, reinforcing the idea that changes in LDL-C levels are an inadequate surrogate for therapeutic use.

Abstract: High-density lipoprotein cholesterol (HDL-C) levels represent a robust and well-integrated biomarker of cardiovascular risk. The prevalence of low HDL-C is high and likely to increase in coming years in parallel with the epidemic of obesity and type 2 diabetes mellitus. However, the clinical efficacy of raising plasma HDL-C levels to achieve cardiovascular risk reduction has been difficult to prove. Recently published outcomes trials involving the addition of niacin or dalcetrapib to standard low-density lipoprotein cholesterol reduction therapy failed to demonstrate clinical benefit despite increases in HDL-C.1,2 Furthermore, genetic variants associated with increased HDL-C, thus conferring lifelong exposure to higher circulating levels, are not consistently associated with improved vascular outcomes.3 These findings have reinforced the idea that changes in HDL-C levels are an inadequate surrogate for therapeutic use. See accompanying article on page 1696 The notion of HDL functionality has circulated in the field for years based on known heterogeneity in lipid content, protein cargo, and size across HDL particles.4 For example, assays that quantify apoptotic pathway activation, endothelial vasomotor effects, and antioxidant properties have suggested HDL functional impairment in cardiometabolic disease states.5–7 Although the relative mechanistic contributions of HDL-mediated atheroprotection remain unclear, the role of HDL in macrophage reverse cholesterol transport is thought to play a key role. This pathway involves efflux of cholesterol from macrophages (such as those within atherosclerotic plaque) to HDL acceptor particles for ultimate return to the liver and biliary excretion.8 Animal studies have suggested that flux through this pathway is a better predictor of the atherosclerotic impact of various genetic and pharmacological perturbations than static, mass-based quantification of circulating HDL-C.9 Rothblat et al10 pioneered methodologies allowing assessment of the cholesterol efflux capacity of human serum or HDL, the basic premise of which is that …