HDL-C may no longer be cardioprotective at very high concentrations

Study results have raised questions regarding the merit of pharmacologically raising the level of high-density lipoprotein cholesterol (HDL-C), with the finding that large HDL particles and elevated plasma HDL-C concentrations may no longer be cardioprotective in certain circumstances. Concentrations of HDL-C have been shown to be independently and inversely proportional to the risk of developing coronary artery disease (CAD). These findings have led to the development of agents that elevated HDL-C levels by inhibiting the cholesteryl ester transfer protein (CETP); however, clinical studies using a novel CETP inhibitor have not demonstrated regression of atherosclerosis despite large increases in plasma HDL-C. In the current study, van der Steeg et al. conducted a post-hoc analysis of two prospective studies — the IDEAL trial and the EPIC-Norfolk study — to investigate the effect of plasma HDL-C, HDL particle size and apolipoprotein (apo) A-I on CAD. The IDEAL trial compared the efficacy of high-dose to usual-dose statin therapy for the secondary prevention of cardiovascular events. The EPIC-Norfolk case-control study included men and women and investigated dietary and other determinants of various diseases including CAD. The occurrence of a major coronary event was defined as an outcome variable for the current analysis. Data from 8564 IDEAL study participants were included in the current analysis, and 1133 cases and 2237 control patients were included from the EPIC-Norfolk study. Following adjustment for apoA-I, and apoB, very high levels of HDL-C (>70 mg/dL) were found to be positively associated with major coronary events in the IDEAL study. A similar pattern was observed in the EPIC-Norfolk study, with large HDL particle size found to be associated with major coronary events, particularly among the highest categories of distribution. In contrast, no positive relationship was exhibited between apoA-I and major coronary events in any model, implying that apoA-I may not be a significant risk factor at high concentration. The authors surmised that “cardiovascular risk management may be more accurate if risk assessment relies on more precise measurements of HDL metabolism than HDL-C.” The results of this post-hoc analysis suggested that very high plasma concentrations of HDL-C and very large HDL particle size may actually represent increased risk of CAD when levels of apoA-I and apoB remain constant. In a related editorial, Dr Jacques Genest, stated that a potential clinical implication of “this apparently counterintuitive finding,” was that naturally occurring high levels of HDL-C may not actually protect against heart disease. “The finding that apoA-I, even when corrected for HDL-C and apoB, remains cardioprotective, suggests that the means by which HDL particles are increased may be far more important that the cholesterol mass in HDL particles ... the measurement of apoA-I will be an absolute necessity in clinical trials” he stated. Reference...