title: Cholesteryl ester transfer protein (CETP) deficiency and CETP inhibitors.
abstract: Epidemiologic studies have shown that low-density lipoprotein cholesterol (LDL-C) is a strong risk factor, whilst high-density lipoprotein cholesterol (HDL-C) reduces the risk of coronary heart disease (CHD). Therefore, strategies to manage dyslipidemia in an effort to prevent or treat CHD have primarily attempted at decreasing LDL-C and raising HDL-C levels. Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL and LDL. We have published the first report indicating that a group of Japanese patients who were lacking CETP had extremely high HDL-C levels, low LDL-C levels and a low incidence of CHD. Animal studies, as well as clinical and epidemiologic evidences, have suggested that inhibition of CETP provides an effective strategy to raise HDL-C and reduce LDL-C levels. Four CETP inhibitors have substantially increased HDL-C levels in dyslipidemic patients. This review will discuss the current status and future prospects of CETP inhibitors in the treatment of CHD. At present anacetrapib by Merck and evacetrapib by Eli Lilly are under development. By 100mg of anacetrapib HDL-C increased by 138%, and LDL-C decreased by 40%. Evacetrapib 500 mg also showed dramatic 132% increase of HDL-C, while LDL-C decreased by 40%. If larger, long-term, randomized, clinical end point trials could corroborate other findings in reducing atherosclerosis, CETP inhibitors could have a significant impact in the management of dyslipidemic CHD patients. Inhibition of CETP synthesis by antisense oligonucleotide or small molecules will produce more similar conditions to human CETP deficiency and may be effective in reducing atherosclerosis and cardiovascular events. We are expecting the final data of prospective clinical trials by CETP inhibitors in 2015.
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.affiliation: Laboratory Science, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D002986:Clinical Trials as Topic; D003327:Coronary Disease / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy / Q000378:metabolism; D023303:Oxazolidinones / Q000494:pharmacology*
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D023303:Oxazolidinones; D001569:Benzodiazepines; C568301:evacetrapib; D002784:Cholesterol; C530884:anacetrapib
keywords: CETP deficiency; HDL & LDL; cholesteryl ester transfer protein (CETP); hyper-HDL-cholesterolemia; inhibitors of CETP