title: New horizons for cholesterol ester transfer protein inhibitors.
abstract: High-density lipoprotein (HDL) cholesterol levels bear an inverse relationship to cardiovascular risk. To date, however, no intervention specifically targeting HDL has been demonstrated to reduce cardiovascular risk. Cholesterol ester transfer protein (CETP) mediates transfer of cholesterol ester from HDL to apolipoprotein B-containing particles. Most, but not all observational cohort studies indicate that genetic polymorphisms of CETP associated with reduced activity and higher HDL cholesterol levels are also associated with reduced cardiovascular risk. Some, but not all studies indicate that CETP inhibition in rabbits retards atherosclerosis, whereas transgenic CETP expression in mice promotes atherosclerosis. Torcetrapib, the first CETP inhibitor to reach phase III clinical development, was abandoned due to excess mortality associated with increases in aldosterone and blood pressure. Two other CETP inhibitors have entered phase III clinical development. Anacetrapib is a potent inhibitor of CETP that produces very large increases in HDL cholesterol and large reductions in low-density lipoprotein (LDL) cholesterol, beyond those achieved with statins. Dalcetrapib is a less potent CETP inhibitor that produces smaller increases in HDL cholesterol with minimal effect on LDL cholesterol. Both agents appear to allow efflux of cholesterol from macrophages to HDL in vitro, and neither agent affects blood pressure or aldosterone in vivo. Two large cardiovascular outcomes trials, one with anacetrapib and one with dalcetrapib, should provide a conclusive test of the hypothesis that inhibition of CETP decreases cardiovascular risk.
authors.affiliation: VA Medical Center and University of Colorado, Denver, CO 80220, USA. Gregory.Schwartz@va.gov
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood* / Q000187:drug effects; D006801:Humans; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL
references.citation: Circulation. 2010 Jan 26;121(3):366-74
references.pmid: 20065167
references.citation: Circulation. 2009 Dec 15;120(24):2414-20
references.pmid: 19948972
references.citation: N Engl J Med. 2007 Nov 22;357(21):2109-22
references.pmid: 17984165
references.citation: Circ Cardiovasc Genet. 2009 Feb;2(1):26-33
references.pmid: 20031564
references.citation: Expert Opin Ther Targets. 2008 Aug;12(8):937-48
references.pmid: 18620517
references.citation: J Lipid Res. 2010 Dec;51(12):3443-54
references.pmid: 20861162
references.citation: Circulation. 2008 Dec 9;118(24):2506-14
references.pmid: 19029466
references.citation: Curr Med Res Opin. 2011 Jan;27(1):141-50
references.pmid: 21128879
references.citation: JAMA. 2008 Jun 18;299(23):2777-88
references.pmid: 18560005
references.citation: J Cardiovasc Pharmacol. 2010 May;55(5):459-68
references.pmid: 20051879
references.citation: Eur Heart J. 2010 Feb;31(4):480-8
references.pmid: 20097702
references.citation: Circulation. 2009 Apr 21;119(15):2103-11
references.pmid: 19349317
references.citation: J Am Assoc Lab Anim Sci. 2010 Jul;49(4):464-71
references.pmid: 20819394
references.citation: Am J Cardiol. 2009 Jul 1;104(1):82-91
references.pmid: 19576325
references.citation: Bioorg Med Chem Lett. 2004 May 17;14(10):2589-91
references.pmid: 15109658
references.citation: Eur Heart J. 2008 Nov;29(22):2792-9
references.pmid: 18957472
references.citation: Nature. 2000 Jul 13;406(6792):203-7
references.pmid: 10910363
references.citation: J Lipid Res. 2011 Nov;52(11):1965-73
references.pmid: 21841206
references.citation: Circulation. 2011 Aug 2;124(5):555-62
references.pmid: 21804130
references.citation: Am J Cardiol. 2009 Nov 16;104(10 Suppl):39E-45E
references.pmid: 19895943
references.citation: J Hypertens. 2010 Aug;28(8):1676-86
references.pmid: 20498617
references.citation: Ann Pharmacother. 2011 Jan;45(1):84-94
references.pmid: 21205945
references.citation: Lancet. 2005 Oct 8;366(9493):1279-89
references.pmid: 16214598
references.citation: N Engl J Med. 2010 Apr 29;362(17):1563-74
references.pmid: 20228404
references.citation: J Lipid Res. 2010 Sep;51(9):2739-52
references.pmid: 20458119
references.citation: Clin Genet. 2004 May;65(5):412-8
references.pmid: 15099350
references.citation: Circulation. 2008 Dec 9;118(24):2515-22
references.pmid: 19029469
references.citation: Lancet. 2005 Nov 26;366(9500):1849-61
references.pmid: 16310551
references.citation: Lancet. 2005 Oct 8;366(9493):1267-78
references.pmid: 16214597
references.citation: Thromb Res. 2009;123(3):460-5
references.pmid: 18789492
references.citation: Am J Cardiol. 2010 Aug 15;106(4):451-6
references.pmid: 20691300
references.citation: Clin Pharmacol Ther. 2008 Dec;84(6):679-83
references.pmid: 18580870
references.citation: Atherosclerosis. 2002 May;162(1):131-5
references.pmid: 11947906
references.citation: Eur Heart J. 2008 Jan;29(1):104-12
references.pmid: 18063597
references.citation: Endocrinology. 2009 May;150(5):2211-9
references.pmid: 19164467
references.citation: Am Heart J. 2009 Dec;158(6):896-901.e3
references.pmid: 19958854
references.citation: N Engl J Med. 2010 Dec 16;363(25):2406-15
references.pmid: 21082868
references.citation: N Engl J Med. 2004 Apr 8;350(15):1505-15
references.pmid: 15071125
references.citation: J Lipid Res. 2007 Jun;48(6):1263-72
references.pmid: 17325387
references.citation: J Am Coll Cardiol. 2006 Nov 7;48(9):1782-90
references.pmid: 17084250
references.citation: Br J Pharmacol. 2008 Aug;154(7):1465-73
references.pmid: 18536749
references.citation: Am Heart J. 2011 Aug;162(2):214-221.e2
references.pmid: 21835280
references.citation: Br J Clin Pharmacol. 2009 Oct;68(4):535-45
references.pmid: 19843057
references.citation: Am Heart J. 2009 Feb;157(2):352-360.e2
references.pmid: 19185645