Cardiovascular disease risk reduction by raising HDL cholesterol--current therapies and future opportunities

Abstract

Since the first discovery of an inverse correlation between high-density lipoprotein-cholesterol (HDL-C) levels and coronary heart disease in the 1950s the life cycle of HDL, its role in atherosclerosis and the therapeutic modification of HDL-C levels have been major research topics. The Framingham study and others that followed could show that HDL-C is an independent cardiovascular risk factor and that the increase of HDL-C of only 10 mg·L(-1) leads to a risk reduction of 2-3%. While statin therapy and therefore low-density lipoprotein-cholesterol (LDL-C) reduction could lower coronary heart disease considerably; cardiovascular morbidity and mortality still occur in a significant portion of subjects already receiving therapy. Therefore, new strategies and therapies are needed to further reduce the risk. Raising HDL-C was thought to achieve this goal. However, established drug therapies resulting in substantial HDL-C increase are scarce and their effect is controversial. Furthermore, it is becoming increasingly evident that HDL particle functionality is at least as important as HDL-C levels since HDL particles not only promote reverse cholesterol transport from the periphery (mainly macrophages) to the liver but also exert pleiotropic effects on inflammation, haemostasis and apoptosis. This review deals with the biology of HDL particles, the established and future therapeutic options to increase HDL-C and discusses the results and conclusions of the most important studies published in the last years. Finally, an outlook on future diagnostic tools and therapeutic opportunities regarding coronary artery disease is given.

Figure 1

An overview of the HDL life cycle and where the therapeutic options mentioned earlier come into action. Statins raise HDL-C levels mainly by inhibiting CETP. Fibrates induce RCT via ABCA1 and ABCG1 up-regulation, inhibit CETP and induce ApoA-I production. Niacin induces RCT via ABCA1 and ABCG1, block CETP and inhibit clearance of HDL particles in the liver. PPARα/γ/δ agonists mainly raise HDL-C through ABCA1 and ABCG1 and consecutive induction of RCT. LXR agonists activate RCT via ABCA1 and ABCG1, promote transport of cholesterol esters from the liver to the intestines, inhibit intestinal cholesterol absorption and up-regulate excretion of cholesterol.