Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport

Low levels of HDL-C are a major independent risk factor for atherosclerotic cardiovascular disease and events, even in patients who are aggressively treated for LDL-C reduction. Although existing drugs have modest effects on HDL-C levels, this area remains a major unmet medical need in cardiovascular medicine. HDL metabolism is exceedingly complex, and because the protective ability of HDL may relate to the flux of cholesterol through the RCT pathway and to other aspects of HDL functionality, the plasma level of HDL-C alone is almost certainly not an adequate predictor of the potential clinical benefit of an HDL-targeted therapy. Some interventions that raise HDL-C may not reduce atherosclerosis or cardiovascular events; conversely, other interventions may not raise HDL-C but through effects on RCT or HDL function may have major effects on atherosclerosis or cardiovascular events. There is a great need for the development of novel biomarkers and kinetic methods to assess the effects of novel interventions on RCT and HDL function. Despite the challenges, a large number of HDL-targeted therapies are in various stages of preclinical and clinical development. Because CETP inhibition is the furthest along, it will provide the first information about whether a therapy specifically targeted to raising HDL-C levels will reduce atherosclerosis and cardiovascular events. This issue is one of the most critical questions for the field of HDL and atherosclerosis in the next couple of years. Many additional important questions in the area of HDL therapeutics will be addressed in the next several years. Will parenteral administration of apoA-I Milano, apoA-I mimetic peptides, or large unilamellar vesicles in ACS patients regress atherosclerosis and/or reduce cardiovascular events, thus supporting the concept of "acute induction therapy" for atherosclerosis? Do PPAR agonists actually promote macrophage cholesterol efflux and RCT in vivo, and what is the optimal "mix" of PPAR-modulating activities for effects on RCT and atherosclerosis? Will LXR agonists or modulators enter into clinical development, and, if so, will they have the same effects on hepatic lipogenesis and RCT as in preclinical models? Will we see new compounds specifically targeted to the niacin receptor, and will they increase HDL-C levels in humans? Will EL-specific inhibitors be discovered and enter into clinical development? Will phospholipid-based therapies advance in clinical development? There will undoubtedly be further advances in drug development as more is discovered through basic and translational research with regard to the multiple mechanisms of HDL action and the effects of altering HDL metabolism. Much as the last 2 decades have seen a revolution in our ability to reduce LDL-C and thus cardiovascular events, the next 2 decades are likely to witness major advances in the development of novel therapeutics targeted to HDL metabolism and RCT with the goal of inhibition and even regression of atherosclerosis and a further substantial reduction in cardiovascular events. © 2006 American Heart Association, Inc.