Open AccessJournal Article
CETP inhibition in cardiovascular risk management: a critical appraisal (vol 37, pg 90, 2007)
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TLDR
In this paper, the effect of cholesteryl ester transfer protein (CETP) on HDL cholesterol was investigated in a large-scale phase III clinical trial, with torcetrapib being only evaluated in combination therapy with atorvastatin.Abstract:
In view of the cardioprotective effect of high‐density lipoproteins (HDL) and the limited effects of statin and fibrate therapy on HDL cholesterol, it is clinically relevant to test whether pharmacological treatment aimed at raising HDL lowers cardiovascular risk. Cholesteryl ester transfer protein (CETP) is a new therapeutic target, because the cholesteryl ester transfer process lowers HDL cholesterol and contributes to an atherogenic lipoprotein profile, particularly when plasma triglycerides are high. Clinical evidence suggests that coronary artery calcification as well as intima media thickness is positively related to plasma cholesteryl ester transfer, and that high plasma CETP concentration is associated with increased cardiovascular risk in hypertriglyceridaemia. However, CETP could also have anti‐atherogenic potential, since it provides a potentially beneficial route for delivery of HDL‐derived cholesteryl esters to the liver. In addition, CETP could also favourably stimulate peripheral cell cholesterol removal and enhance hepatic cholesterol uptake. Recent evidence suggests that a high CETP level may confer lower cardiovascular risk in the context of low triglycerides. At maximal doses, the CETP inhibitors JTT‐705 and torcetrapib elicit a marked rise in HDL cholesterol of up to 34% and 91–106%, respectively. The effectiveness of these drugs on (intermediate) clinical outcome measures is currently being tested in large‐scale phase III clinical trials, with torcetrapib being only evaluated in combination therapy with atorvastatin. When and how to use CETP inhibitors, e.g. in combination with a statin or a fibrate, is a major challenge. We propose that low HDL cholesterol in the context of high triglycerides, such as found in type 2 diabetes mellitus, could become an important indication area for this new class of drugs.read more
Citations
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Journal ArticleDOI
Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk
Alexander M. W. Cargill Thompson,Emanuele Di Angelantonio,Nadeem Sarwar,Sebhat Erqou,Danish Saleheen,Robin P. F. Dullaart,Bernard Keavney,Zheng Ye,John Danesh +8 more
TL;DR: Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk.
Journal ArticleDOI
Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.
Michiel L. Bots,Frank L.J. Visseren,Gregory W. Evans,Ward A. Riley,James H. Revkin,Charles H. Tegeler,Charles L. Shear,William T. Duggan,Ralph M Vicari,Diederick E. Grobbee,John J.P. Kastelein +10 more
TL;DR: Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments.
Journal ArticleDOI
CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction.
Jakub J. Regieli,J. Wouter Jukema,Diederick E. Grobbee,John J. P. Kastelein,Jan Albert Kuivenhoven,Aeilko H. Zwinderman,Yolanda van der Graaf,Michiel L. Bots,Pieter A. Doevendans +8 more
TL;DR: In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality, suggesting that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels.
Journal ArticleDOI
Design of the DEFINE trial: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib
Christopher P. Cannon,Hayes M. Dansky,Michael H. Davidson,Antonio M. Gotto,Eliot A. Brinton,A. Lawrence Gould,Michael Stepanavage,Sherry Xueyu Liu,Sukrut Shah,Joseph Rubino,Patrice H. Gibbons,Anne Hermanowski-Vosatka,Bruce Binkowitz,Yale B. Mitchel,Philip J. Barter +14 more
TL;DR: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib is a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHD risk equivalents.
Journal ArticleDOI
Apple polyphenols inhibit plasma CETP activity and reduce the ratio of non-HDL to HDL cholesterol
TL;DR: It was concluded that AP favorably improved distribution of cholesterol in lipoproteins, most likely, by its inhibition on CETP activity.
References
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Journal ArticleDOI
Genetic Cholesteryl Ester Transfer Protein Deficiency Is Extremely Frequent in the Omagari Area of Japan: Marked Hyperalphalipoproteinemia Caused by CETP Gene Mutation Is Not Associated With Longevity
Ken-ichi Hirano,Shizuya Yamashita,Norimichi Nakajima,Takeshi Arai,Takao Maruyama,Yu Yoshida,Masato Ishigami,Naohiko Sakai,Kaoru Kameda-Takemura,Yuji Matsuzawa +9 more
TL;DR: It is indicated for the first time that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome, suggesting the importance of reevaluation of the clinical significance and pathophysiology of amarked HALP.
Journal ArticleDOI
Remodelling of high density lipoproteins by plasma factors
TL;DR: This review documents what is currently known about the interaction of HDL with plasma factors and presents an overview of the remodelling of HDL which occurs as a consequence of those interactions.
Journal ArticleDOI
Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene.
Tony Hayek,L. Masucci-Magoulas,Xian Jiang,Annemarie Walsh,Edward M. Rubin,Jan L. Breslow,Alan R. Tall +6 more
TL;DR: CETP expression inhibits the development of early atherosclerotic lesions but only in hypertriglyceridemic mice, and is found to cause an increased susceptibility to dietary atherosclerosis in nonhypertrig triglyceridemic CETP transgenic mice compared to controls.
Journal ArticleDOI
Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin : cholesterol acyltransferase and lipid transfer proteins
TL;DR: This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus.
Journal ArticleDOI
Prevalence of risk factors in men with premature coronary artery disease.
Jacques Genest,Jacques Genest,Judith R. McNamara,Judith R. McNamara,Deeb N. Salem,Deeb N. Salem,Ernst J. Schaefer,Ernst J. Schaefer +7 more
TL;DR: The prevalence of modifiable cardiovascular risk factors was markedly higher in the patients with CAD than in Framingham Offspring Study subjects, whereas the prevalence of LDL cholesterol greater than or equal to 160 mg/dl was not significantly different between Patients with CAD and Framinghamoffspring Study subjects.
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