Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease.
Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors-torcetrapib and JTT-705-are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events.
Barter
Philip J
PJ
The Heart Research Institute, Camperdown, Sydney, Australia. p.barter@hri.org.au
Kastelein
John J P
JJ
D000577:Amides; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D004952:Esters; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D011804:Quinolines / Q000627:therapeutic use; D012307:Risk Factors; D013438:Sulfhydryl Compounds / Q000627:therapeutic use; D014612:Vaccines
D000577:Amides; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004952:Esters; D006023:Glycoproteins; D011804:Quinolines; D013438:Sulfhydryl Compounds; D014612:Vaccines; C411602:dalcetrapib; C483909:torcetrapib