Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease.
Innovative pharmacological approaches to raise anti-atherogenic high-density lipoprotein-cholesterol (HDL-C) are currently of considerable interest, particularly in atherogenic dyslipidemias characterized by low levels of HDL-C, such as type 2 diabetes, the metabolic syndrome, and mixed dyslipidemia, but equally among individuals with or at elevated risk for premature cardiovascular disease (CVD). Epidemiological and observational studies first demonstrated that HDL-C was a strong, independent predictor of coronary heart disease (CHD) risk, and suggested that raising HDL-C levels might afford clinical benefit. Accumulating data from clinical trials of pharmacological agents that raise HDL-C levels have supported this concept. In addition to the pivotal role that HDL-C plays in reverse cholesterol transport and cellular cholesterol efflux, HDL particles possess a spectrum of anti-inflammatory, anti-oxidative, anti-apoptotic, anti-thrombotic, vasodilatory and anti-infectious properties, all of which potentially contribute to their atheroprotective nature. Significantly, anti-atherogenic properties of HDL particles are attenuated in common metabolic diseases that are characterized by subnormal HDL-C levels, such as type 2 diabetes and metabolic syndrome. Inhibition of cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism and transport, constitutes an innovative target for HDL-C raising. In lipid efficacy trials, 2 CETP inhibitors-JTT-705 and torcetrapib-induced marked elevation in HDL-C levels, with torcetrapib displaying greater efficacy. Moreover, both agents attenuate aortic atherosclerosis in cholesterol-fed rabbits. Clinical trial data demonstrating the clinical benefits of these drugs on atherosclerosis and CHD are eagerly awaited.
Chapman
M John
MJ
Dyslipoproteinemia and Atherosclerosis Research Unit (UMR-551), National Institute for Health and Medical Research (INSERM), France. chapman@chups.jussieu.fr
D000577:Amides; D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood* / Q000502:physiology; D003327:Coronary Disease / Q000517:prevention & control*; D004952:Esters; D006706:Homeostasis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007249:Inflammation / Q000517:prevention & control; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists; D047494:PPAR delta / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D011804:Quinolines / Q000627:therapeutic use; D013438:Sulfhydryl Compounds / Q000627:therapeutic use
D000577:Amides; D008076:Cholesterol, HDL; D004952:Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D011804:Quinolines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; C483909:torcetrapib; D002784:Cholesterol