CETP inhibition in cardiovascular risk management: a critical appraisal

Dullaart, Robin P. F.; Dallinga‐Thie, Geesje M.; Wolffenbuttel, Bruce H. R.; Tol, Arie van

doi:10.1111/j.1365-2362.2007.01756.x

Cited by 51 publications

(45 citation statements)

References 76 publications

(111 reference statements)

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“…Accordingly, an inverse correlation of pre-b-HDL with intima media thickness, an established marker of subclinical atherosclerosis, was found recently (43). Nonetheless, the net effect of PLTP (46,47) and CETP action may be pro-atherogenic (48,49), much depending on metabolic circumstances like elevated plasma triglycerides (50).…”

Section: Metabolic Syndrome Absent (Nz94)mentioning

confidence: 95%

Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

Dullaart¹,

Groen

Dallinga‐Thie

et al. 2008

European Journal of Endocrinology

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Objective: We tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol. Design: In 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, we determined plasma (apo)lipoproteins, pre-b-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor. Results: Apo E, PLTP activity, EST, and CET were higher (PZ0.04 to !0.001), whereas adiponectin was lower in MetS subjects (P!0.01). Pre-b-HDL and pre-b-HDL formation were not different between subjects with and without MetS. Cellular cholesterol efflux to plasma from MetS subjects was slightly higher versus plasma from subjects without MetS (8.8G1.0 vs 8.5G0.9%, PZ0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-b-HDL formation, EST, PLTP activity, and apo E (P!0.05 for all by multiple linear regression analysis), without an independent association with MetS and diabetes status. Conclusions: The ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS.European Journal of Endocrinology 158 53-60

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Section: Metabolic Syndrome Absent (Nz94)mentioning

confidence: 95%

Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

Dullaart¹,

Groen

Dallinga‐Thie

et al. 2008

European Journal of Endocrinology

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“…The increase in HDL-C after GH replacement in glucocorticoid-treated hypopituitary patients homozygous for the K629 CETP CC allele may thus be explained in part by assuming that GH elicits a more pronounced decrease in circulating CETP levels in these patients. Although we did not measure serum CETP mass or activity in the present study, it is plausible that the GH-induced increase in HDL-C is attributable to CETP lowering, resulting in decreased transfer of cholesteryl esters out of HDL particles (11)(12)(13). Notably, it is likely that other mechanisms also contribute to the effects of glucocorticoids on HDL metabolism.…”

Section: Discussionmentioning

confidence: 83%

“…CETP transfers cholesteryl esters from HDL toward triglyceride-rich lipoproteins. Consequently, increased CETP activity results in a lower HDL-C (11)(12)(13). Common genetic variations have been identified in CETP (14,15), among which the K629 CETP COA promoter polymorphism (rs1800775) has been shown to regulate CETP transcriptional activity in vitro (16).…”

Section: Introductionmentioning

confidence: 99%

HDL cholesterol response to GH replacement is associated with common cholesteryl ester transfer protein gene variation (−629C>A) and modified by glucocorticoid treatment

Dullaart¹,

Berg²,

Knaap³

et al. 2010

European Journal of Endocrinology

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Objective: GH replacement lowers total cholesterol and low-density lipoprotein cholesterol (LDL-C) in GH-deficient adults, but effects on high-density lipoprotein (HDL) cholesterol (HDL-C) are variable. Both GH and glucocorticoids decrease cholesteryl ester transfer protein (CETP) activity, which is important in HDL metabolism. We determined the extent to which the changes in HDL-C in response to GH replacement are predicted by the K629COA CETP promoter polymorphism, and questioned whether this association is modified by concomitant glucocorticoid treatment. Design and methods: A total of 91 GH-deficient adults (63 receiving glucocorticoids) were genotyped for the K629 CETP COA polymorphism. Fasting serum lipids were measured before and after 1.2G0.4 years of GH treatment (Genotropin, Pfizer Inc., Stockholm, Sweden). Results: In the whole group, total cholesterol and LDL-C decreased (P!0.05) after GH treatment, but the changes in HDL-C were not significant. In CC carriers receiving glucocorticoids (nZ19), HDL-C rose by 0.15G0.25 mmol/l (PZ0.02; P!0.03 from unchanged HDL-C in K629 AACCA carriers on glucocorticoids and from CC homozygotes not receiving glucocorticoids). Multivariate regression analysis showed that individual changes in HDL-C were predicted by the CETP polymorphism (CC versus AACCC, PZ0.006) in glucocorticoid users, independently of baseline HDL-C and other variables including apolipoprotein E4 carrier status; an opposite association with the CETP polymorphism was found in patients not receiving glucocorticoids (PZ0.053). Conclusions: We suggest a common CETP variant-glucocorticoid treatment interaction concerning the effect of GH replacement on HDL-C. This may explain some of the reported variation in the HDL-C response to GH.

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“…The detailed crystal structure of CETP ( 24 ) provides compelling evidence for the shuttle model over the ternary complex model because it appears that the CETP molecule can bind to only one lipoprotein to CETP and prevents CETP-lipoprotein binding ( 7 ). Torcetrapib is more potent ( 8 ) and acts as a noncompetitive inhibitor by binding reversibly to CETP where the resulting complex can bind to lipoproteins and form an inactive complex that is unable to complete transfer of lipids ( 7 ). It is unclear, however, what the consequences of different inhibition mechanisms may be on CETP transfer activity and lipoprotein metabolism in general.…”

Section: Conceptual Model For Cetp Activitymentioning

confidence: 99%

“…In humans, CETP defi ciency has been associated with both increased and decreased CHD risk ( 3,5 ). The CETP inhibitors JTT-705 and torcetrapib have been shown to effectively reduce CETP activity in humans and raise HDL cholesterol, although the effect of this class of compounds on atherosclerosis and CHD risk is as yet unclear (6)(7)(8).…”

mentioning

confidence: 99%

Mechanism of inhibition defines CETP activity: a mathematical model for CETP in vitro

Potter

Sprecher

Walker

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org cludes the transfer of triglyceride (TG) from VLDL and LDL to HDL ( 1-3 ).The relationship between CETP and atherosclerosis/ coronary heart disease (CHD) is unclear, as is the importance of the net transfer of CE from HDL to apolipoprotein (apo)B-containing lipoproteins. CETP defi ciency and inhibition studies in animals and humans have produced confl icting results. Pharmacologic CETP inhibition has increased HDL cholesterol and reduced atherosclerosis in rabbit models ( 5 ). In humans, CETP defi ciency has been associated with both increased and decreased CHD risk ( 3, 5 ). The CETP inhibitors JTT-705 and torcetrapib have been shown to effectively reduce CETP activity in humans and raise HDL cholesterol, although the effect of this class of compounds on atherosclerosis and CHD risk is as yet unclear ( 6-8 ).Adding to this uncertainty is the termination of a Phase III torcetrapib study following an unexpected increase in deaths when dosed in combination with statin therapy versus statin therapy alone. "Off-target" activities of torcetrapib have been suggested as the reason for increased mortality and morbidity ( 9 ) and atherosclerotic plaque volume decreases were seen in the subset of patients having the greatest HDL changes ( 10 ). It is not yet known, however, if the increases in mortality and morbidity were caused entirely by the proposed mechanism or were in part due to changes in HDL subfractions or in functionality induced by CETP inhibition itself ( 11 ). Studies with other CETP inhibitors in development may shed light on whether this is a generalized phenomenon or specifi c to certain compounds, patient groups, or lipid phenotypes.The Cholesteryl ester transfer protein (CETP) plays a critical role in reverse cholesterol transport ( 1-3 ). CETP facilitates the net transfer of cholesterol ester (CE) from HDL to VLDL and LDL, which is followed by hepatic uptake of LDL via the LDL receptor ( 4 ). The CETP-mediated transfer of CE is part of a bidirectional exchange that also in-

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CETP inhibition in cardiovascular risk management: a critical appraisal

Abstract: In view of the cardioprotective effect of high-density lipoproteins (HDL)

Cited by 51 publications

References 76 publications

Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

HDL cholesterol response to GH replacement is associated with common cholesteryl ester transfer protein gene variation (−629C>A) and modified by glucocorticoid treatment

Mechanism of inhibition defines CETP activity: a mathematical model for CETP in vitro

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