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
Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study
Greetje J. de Grooth,Jan Albert Kuivenhoven,Anton F. H. Stalenhoef,Jacqueline de Graaf,Aeilko H. Zwinderman,J. L. Posma,Arie van Tol,John J.P. Kastelein +7 more
TL;DR: The use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects, and further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.
Journal ArticleDOI
Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein
Keith R. Marotti,Christine K. Castle,Timothy P. Boyle,Alice H. Lin,Robert W. Murray,George W. Melchior +5 more
TL;DR: It is reported here that transgenic mice expressing CETP had much worse atherosclerosis than did non-expressing controls, and it is suggested that the increase in lesion severity was due largely to CETP-induced alterations in the lipoprotein profile.
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
Dyslipidemia and Hyperglycemia Predict Coronary Heart Disease Events in Middle-Aged Patients With NIDDM
TL;DR: Evidence is provided that dyslipidemia and poor glycemic control predict CHD mortality and morbidity in patients with NIDDM, and a 7-year follow-up study on risk factors for CHD provides evidence.
Journal ArticleDOI
Raising High-Density Lipoprotein in Humans Through Inhibition of Cholesteryl Ester Transfer Protein: An Initial Multidose Study of Torcetrapib
Ronald W. Clark,Tamara Sutfin,Roger B. Ruggeri,Ann T. Willauer,Eliot Sugarman,Magnus-Aryitey George Tetteh,Patricia G. Cosgrove,Thomas Sand,Wester Ronald Thure,John A. Williams,Michael Ellis Perlman,Mark J. Bamberger +11 more
TL;DR: These effects of CETP inhibition resemble those observed in partial CETP deficiency, and serve as a prelude to further studies in subjects with low HDL, or combinations of dyslipidemia, in assessing the role of CETp in atherosclerosis.
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