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As [[High-density lipoprotein|HDL]] can alleviate atherosclerosis and other [[cardiovascular disease]]s, and certain disease states such as the [[metabolic syndrome]] feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.<ref>{{cite journal | vauthors = Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR | title = Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis | journal = Arterioscler Thromb Vasc Biol | volume = 23 | issue = 2 | pages = 160–7 | date = February 2003 | pmid = 12588754 | doi = 10.1161/01.ATV.0000054658.91146.64 }}</ref> To be specific, in a 2004 study, the small molecular agent [[torcetrapib]] was shown to increase HDL levels, alone and with a [[statin]], and lower LDL when co-administered with a statin.<ref>{{cite journal | vauthors = Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ | title = Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol | journal = N Engl J Med | volume = 350 | issue = 15 | pages = 1505–15 | date = April 2004 | pmid = 15071125 | doi = 10.1056/NEJMoa031766 | url = http://content.nejm.org/cgi/content/full/350/15/1505 }}</ref> Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in [[lipid]] levels, most reported an increase in [[blood pressure]], no change in atherosclerosis,<ref>{{cite journal | vauthors = Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Lasala GP, Tuzcu EM | title = Effect of torcetrapib on the progression of coronary atherosclerosis | journal = N Engl J Med | volume = 356 | issue = 13 | pages = 1304–16 | date = March 2007 | pmid = 17387129 | doi = 10.1056/NEJMoa070635 | last11 = Illustrate | issn = 0028-4793 | first11 = Investigators | deadurl = no }}</ref><ref>{{cite journal | vauthors = Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML | title = Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia | journal = N Engl J Med | volume = 356 | issue = 16 | pages = 1620–30 | date = April 2007 | pmid = 17387131 | doi = 10.1056/NEJMoa071359 }}</ref> and, in a trial of a combination of torcetrapib and [[atorvastatin]], an increase in cardiovascular events and mortality.<ref name=FDA2006>{{cite press release |title=Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety |publisher=U.S. Food and Drug Administration |date=2006-12-03 |url=http://www.fda.gov/bbs/topics/news/2006/new01514.html}}</ref> |
As [[High-density lipoprotein|HDL]] can alleviate atherosclerosis and other [[cardiovascular disease]]s, and certain disease states such as the [[metabolic syndrome]] feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.<ref>{{cite journal | vauthors = Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR | title = Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis | journal = Arterioscler Thromb Vasc Biol | volume = 23 | issue = 2 | pages = 160–7 | date = February 2003 | pmid = 12588754 | doi = 10.1161/01.ATV.0000054658.91146.64 }}</ref> To be specific, in a 2004 study, the small molecular agent [[torcetrapib]] was shown to increase HDL levels, alone and with a [[statin]], and lower LDL when co-administered with a statin.<ref>{{cite journal | vauthors = Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ | title = Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol | journal = N Engl J Med | volume = 350 | issue = 15 | pages = 1505–15 | date = April 2004 | pmid = 15071125 | doi = 10.1056/NEJMoa031766 | url = http://content.nejm.org/cgi/content/full/350/15/1505 }}</ref> Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in [[lipid]] levels, most reported an increase in [[blood pressure]], no change in atherosclerosis,<ref>{{cite journal | vauthors = Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Lasala GP, Tuzcu EM | title = Effect of torcetrapib on the progression of coronary atherosclerosis | journal = N Engl J Med | volume = 356 | issue = 13 | pages = 1304–16 | date = March 2007 | pmid = 17387129 | doi = 10.1056/NEJMoa070635 | last11 = Illustrate | issn = 0028-4793 | first11 = Investigators | deadurl = no }}</ref><ref>{{cite journal | vauthors = Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML | title = Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia | journal = N Engl J Med | volume = 356 | issue = 16 | pages = 1620–30 | date = April 2007 | pmid = 17387131 | doi = 10.1056/NEJMoa071359 }}</ref> and, in a trial of a combination of torcetrapib and [[atorvastatin]], an increase in cardiovascular events and mortality.<ref name=FDA2006>{{cite press release |title=Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety |publisher=U.S. Food and Drug Administration |date=2006-12-03 |url=http://www.fda.gov/bbs/topics/news/2006/new01514.html}}</ref> |
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A compound related to torcetrapib, [[Dalcetrapib]] (investigative name JTT-705/R1658), was also studied, but trials have ceased.<ref>{{cite journal | vauthors = El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ | title = The role of CETP inhibition in dyslipidemia | journal = Curr Atheroscler Rep | volume = 9 | issue = 2 | pages = 125–33 | date = August 2007 | pmid = 17877921 | doi = 10.1007/s11883-007-0008-5 }}</ref> It increases HDL levels by 30%, as compared to 60% by torcetrapib.<ref>{{cite journal | vauthors = de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ | title = Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study | journal = Circulation | volume = 105 | issue = 18 | pages = 2159–65 | date = May 2002 | pmid = 11994249 | doi = 10.1161/01.CIR.0000015857.31889.7B | url = http://circ.ahajournals.org/cgi/content/full/circulationaha;105/18/2159 }}</ref> Two CETP inhibitors are currently under development. One is Merck's MK-0859 [[anacetrapib]], which in initial studies did not increase blood pressure.<ref>{{cite news |author=Reuters|title=Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes | url= |
A compound related to torcetrapib, [[Dalcetrapib]] (investigative name JTT-705/R1658), was also studied, but trials have ceased.<ref>{{cite journal | vauthors = El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ | title = The role of CETP inhibition in dyslipidemia | journal = Curr Atheroscler Rep | volume = 9 | issue = 2 | pages = 125–33 | date = August 2007 | pmid = 17877921 | doi = 10.1007/s11883-007-0008-5 }}</ref> It increases HDL levels by 30%, as compared to 60% by torcetrapib.<ref>{{cite journal | vauthors = de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ | title = Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study | journal = Circulation | volume = 105 | issue = 18 | pages = 2159–65 | date = May 2002 | pmid = 11994249 | doi = 10.1161/01.CIR.0000015857.31889.7B | url = http://circ.ahajournals.org/cgi/content/full/circulationaha;105/18/2159 }}</ref> Two CETP inhibitors are currently under development. One is Merck's MK-0859 [[anacetrapib]], which in initial studies did not increase blood pressure.<ref>{{cite news |author=Reuters|title=Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes | url=https://www.reuters.com/article/inPlayBriefing/idUSIN20071004163052MRK20071004 |publisher=Reuters, Inc. |date=2007-10-04 |deadurl=no |accessdate=26 November 2013}}</ref> The other is Eli Lilly's evacetrapib, which failed in Phase 3 trials. |
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==Interactive pathway map== |
==Interactive pathway map== |
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.
The CETP gene is located on the sixteenth chromosome (16q21).
Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis.[3] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity [4] and to metabolic response to nutritional intervention.[5] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[6] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[3]
Elaidic acid, a major component of trans fat, increases CETP activity.[7]
AsHDL can alleviate atherosclerosis and other cardiovascular diseases, and certain disease states such as the metabolic syndrome feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.[8] To be specific, in a 2004 study, the small molecular agent torcetrapib was shown to increase HDL levels, alone and with a statin, and lower LDL when co-administered with a statin.[9] Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in blood pressure, no change in atherosclerosis,[10][11] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[12]
A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased.[13] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[14] Two CETP inhibitors are currently under development. One is Merck's MK-0859 anacetrapib, which in initial studies did not increase blood pressure.[15] The other is Eli Lilly's evacetrapib, which failed in Phase 3 trials.
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
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Lipids: lipoprotein particle metabolism
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Lipoprotein particle classes and subclasses |
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Lipid transfer proteins |
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Cell surface receptors |
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ATP-binding cassette transporter |
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