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Erik S.g. Stroes - One of the best experts on this subject based on the ideXlab platform.
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Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity A Pooled Analysis of the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) Trials
2016Co-Authors: Erik S.g. StroesAbstract:Background—Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of Torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results—Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or Torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving Torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.00760.0011 versus 0.00250.0011 mm/y; P0.0014). Subjects treated with Torcetrapib plus atorvastatin displayed higher postrandomiza-tion systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving Torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-densit
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dalcetrapib no off target toxicity on blood pressure or on genes related to the renin angiotensin aldosterone system in rats
British Journal of Pharmacology, 2009Co-Authors: Erik S.g. Stroes, Roger G Clerc, J J P Kastelein, Agnes Benardeau, O Kuhlmann, Denise Blum, Luciana A Campos, Eric J NiesorAbstract:Background and purpose: The association between Torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and Torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model. Experimental approach: Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving Torcetrapib 10, 40 or 80 mg·kg−1·day−1; dalcetrapib 100, 300 or 500 mg−1·kg·day−1; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days' treatment with Torcetrapib 40 mg·kg−1·day−1, dalcetrapib 500 mg·kg−1·day−1 or vehicle was measured by quantitative polymerase chain reaction. Key results: Torcetrapib transiently increased mean AP in normotensive rats (+3.7 ± 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 ± 0.6 mmHg with 40 mg·kg−1·day−1 at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas. Conclusions and implications: In contrast to Torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of Torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.
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cholesteryl ester transfer protein inhibitor Torcetrapib and off target toxicity a pooled analysis of the rating atherosclerotic disease change by imaging with a new cetp inhibitor radiance trials
Circulation, 2008Co-Authors: Menno Vergeer, Sander I Van Leuven, Eric J.g. Sijbrands, Anton F H Stalenhoef, Michiel L. Bots, Gregory W Evans, D. C. G. Basart, Diederick E Grobbee, Frank L.j. Visseren, Erik S.g. StroesAbstract:BACKGROUND: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor [corrected] (RADIANCE) trials, which assessed the impact of Torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. METHODS AND RESULTS: Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or Torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving Torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076+/-0.0011 versus 0.0025+/-0.0011 mm/y; P=0.0014). Subjects treated with Torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving Torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. CONCLUSIONS: These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving Torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that Torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.
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cholesteryl ester transfer protein inhibitor Torcetrapib and off target toxicity a pooled analysis of the rating atherosclerotic disease change by imaging with a new cetp inhibitor radiance trials
Circulation, 2008Co-Authors: Menno Vergeer, Eric J.g. Sijbrands, Anton F H Stalenhoef, Michiel L. Bots, Gregory W Evans, D. C. G. Basart, Diederick E Grobbee, Frank L.j. Visseren, Sander I Van Leuven, Erik S.g. StroesAbstract:Background—Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of Torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results—Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or Torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving Torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P=0.0014). Subjects treated with Torcetrapib plus atorvastatin dis...
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cholesteryl ester transfer protein inhibitor Torcetrapib and off target toxicity a pooled analysis of the rating atherosclerotic disease change by imaging with a new cetp inhibitor radiance trials
Circulation, 2008Co-Authors: Menno Vergeer, Eric J.g. Sijbrands, Anton F H Stalenhoef, Michiel L. Bots, Gregory W Evans, D. C. G. Basart, Diederick E Grobbee, Frank L.j. Visseren, Sander I Van Leuven, Erik S.g. StroesAbstract:Background— Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of Torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results— Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or Torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving Torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P =0.0014). Subjects treated with Torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving Torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. Conclusions— These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving Torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that Torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.
Eric J Niesor - One of the best experts on this subject based on the ideXlab platform.
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Abstract 508: Plasma Kinetics of 3H-Cholesterol from Labeled Macrophages in Hamsters Treated with Dalcetrapib, Torcetrapib and Anacetrapib
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Eric J Niesor, Cyrille MaugeaisAbstract:Introduction: A model using hamsters injected intraperitoneally with cholesterol-labeled macrophages has been developed for the study of reverse cholesterol transport following treatment with compounds affecting CETP activity e.g., the CETP modulator dalcetrapib or the CETP inhibitors Torcetrapib and anacetrapib. Hypothesis: Contrary to Torcetrapib and anacetrapib, dalcetrapib allows CETP-induced remodeling of HDL and the formation of pre-β-HDL in vitro ; these compounds may differentially alter the kinetics of efflux of 3 H-cholesterol ( 3 H-C) from macrophages to plasma HDL and elimination from plasma HDL. Methods: Male Golden Syrian hamsters were fed a chow diet and received dalcetrapib 150 mg/kg bid, n=10; Torcetrapib 30 mg/kg qd, n=10; anacetrapib 30 mg/kg qd, n=10; or vehicle (0.5% HPMC), n=8, for 10 days. On Day 7, all animals were administered ip 3 H-C-labeled J774 macrophages and treated as above for a further 3 days. The appearance of 3 H-C in plasma HDL (24, 48 and 72 h), liver and in feces was measured and 3 H-C specific activity (SA) calculated. Results: Compared to vehicle, Torcetrapib and dalcetrapib raised plasma total cholesterol by 14% and anacetrapib by 21% with a similar trend for HDL-C. At 24, 48 and 72 h, HDL 3 H-C SA was -22.3, +4.9 and -0.5% (p 3 H-C in fecal cholesterol was +19.8, +0.5 and +44.8% (NS, NS, p Conclusions: The SA of HDL 3 H-C from labeled macrophages is significantly higher for dalcetrapib at 24 and 48 h but lower for Torcetrapib and anacetrapib at 24 h in treated hamsters compared to vehicle. A comparable SA to vehicle at later time points suggests an active mechanism of 3 H-C removal from macrophages and elimination for dalcetrapib, while 3 H-C for Torcetrapib and anacetrapib is initially diluted in the HDL-C pool followed by attainment of equilibrium in this pool.
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modulating cholesteryl ester transfer protein activity maintains efficient pre β hdl formation and increases reverse cholesterol transport
Journal of Lipid Research, 2010Co-Authors: Eric J Niesor, Hiroshi Okamoto, Christine Magg, Naoto Ogawa, Elisabeth Von Der Mark, Hugues Matile, Georg Schmid, Roger G Clerc, Evelyne Chaput, Denise BlumkaelinAbstract:The mechanism by which cholesteryl ester transfer protein (CETP) activity affects HDL metabolism was investigated using agents that selectively target CETP (dalcetrapib, Torcetrapib, anacetrapib). In contrast with Torcetrapib and anacetrapib, dalcetrapib requires cysteine 13 to decrease CETP activity, measured as transfer of cholesteryl ester (CE) from HDL to LDL, and does not affect transfer of CE from HDL3 to HDL2. Only dalcetrapib induced a conformational change in CETP, when added to human plasma in vitro, also observed in vivo and correlated with CETP activity. CETP-induced pre-β-HDL formation in vitro in human plasma was unchanged by dalcetrapib ≤3 µM and increased at 10 µM. A dose-dependent inhibition of pre-β-HDL formation by Torcetrapib and anacetrapib (0.1 to 10 µM) suggested that dalcetrapib modulates CETP activity. In hamsters injected with [3H]cholesterol-labeled autologous macrophages, and given dalcetrapib (100 mg twice daily), Torcetrapib [30 mg once daily (QD)], or anacetrapib (30 mg QD), only dalcetrapib significantly increased fecal elimination of both [3H]neutral sterols and [3H]bile acids, whereas all compounds increased plasma HDL-[3H]cholesterol. These data suggest that modulation of CETP activity by dalcetrapib does not inhibit CETP-induced pre-β-HDL formation, which may be required to increase reverse cholesterol transport.
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Different Binding Modes of Compounds Affecting CETP Activity: Dalcetrapib and Torcetrapib
Biophysical Journal, 2010Co-Authors: Christine Magg, Georg Schmid, Cyrille Maugeais, Gregor Dernick, Walter Huber, Elisabeth Von Der Mark, Ralf Thoma, Eric J NiesorAbstract:Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein in plasma and facilitates the exchange of neutral lipids between various lipoproteins resulting in a net transport of cholesteryl ester from HDL to LDL. Decrease in CETP activity leads to an increase of HDL cholesterol which potentially reduces cardiovascular risk.Human recombinant CETP (rhCETP) was purified to homogeneity by hydrophobic interaction chromatography and size exclusion chromatography (SEC). The protein showed an extraordinarily high thermodynamic stability against thermal as well as denaturant-induced unfolding.The effects of CETP on lipoprotein profiles were characterized after in-vitro incubation of plasma with rhCETP followed by SEC and reverse phase protein arrays. Monitoring the distribution of apolipoproteins and the cholesterol profiles confirmed the transfer of cholesteryl ester from HDL to LDL induced by CETP. In the presence of the potent CETP inhibitor Torcetrapib (1 µM) added CETP is bound to lipoproteins while free CETP can still be detected in presence of dalcetrapib (3 µM), a compound from a different chemical class.14C-Torcetrapib and 14C-dalcetrapib were bound to CETP immobilized on sepharose and incubated with excess of unlabelled compounds. 14C-dalcetrapib bound as Dalcetrapib-thiol could only be displaced in the presence of reducing agent by an excess of unlabeled dalcetrapib but not by Torcetrapib. Dalcetrapib did not compete for binding of 14C-Torcetrapib.Interaction studies with Surface Plasmon Resonance confirmed reversible covalent binding of dalcetrapib-thiol and different binding sites for dalcetrapib and Torcetrapib. In agreement with literature cysteine 13 of CETP was identified as attachment point of dalcetrapib-thiol. All data suggested that Torcetrapib and dalcetrapib bind to different sites on CETP which may be related to differences observed in their pharmacological profiles.
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dalcetrapib no off target toxicity on blood pressure or on genes related to the renin angiotensin aldosterone system in rats
British Journal of Pharmacology, 2009Co-Authors: Erik S.g. Stroes, Roger G Clerc, J J P Kastelein, Agnes Benardeau, O Kuhlmann, Denise Blum, Luciana A Campos, Eric J NiesorAbstract:Background and purpose: The association between Torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and Torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model. Experimental approach: Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving Torcetrapib 10, 40 or 80 mg·kg−1·day−1; dalcetrapib 100, 300 or 500 mg−1·kg·day−1; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days' treatment with Torcetrapib 40 mg·kg−1·day−1, dalcetrapib 500 mg·kg−1·day−1 or vehicle was measured by quantitative polymerase chain reaction. Key results: Torcetrapib transiently increased mean AP in normotensive rats (+3.7 ± 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 ± 0.6 mmHg with 40 mg·kg−1·day−1 at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas. Conclusions and implications: In contrast to Torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of Torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.
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RESEARCH PAPER Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats
2009Co-Authors: J J P Kastelein, Roger G Clerc, O Kuhlmann, Denise Blum, Eric J NiesorAbstract:Background and purpose: The association between Torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and Torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model. Experimental approach: Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving Torcetrapib 10, 40 or 80 mg·kg -1 ·day -1 ; dalcetrapib 100, 300 or 500 mg -1 ·kg·day -1 ; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days’ treatment with Torcetrapib 40 mg·kg -1 ·day -1 , dalcetrapib 500 mg·kg -1 ·day -1 or vehicle was measured by quantitative polymerase chain reaction. Key results: Torcetrapib transiently increased mean AP in normotensive rats (+3.7 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 0.6 mmHg with 40 mg·kg -1 ·day -1
Philip J Barter - One of the best experts on this subject based on the ideXlab platform.
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Effects of Torcetrapib and Statin Treatment on ApoC-III and Apoprotein-Defined Lipoprotein Subclasses (from the ILLUMINATE Trial)
The American journal of cardiology, 2017Co-Authors: John Bagdade, Philip J Barter, Carmen Quiroga, Pierre AlaupovicAbstract:In the ILLUMINATE Trial, treatment with the cholesteryl ester transfer protein inhibitor Torcetrapib resulted in a significant increase in both atherosclerotic cardiovascular disease events and total mortality which was not explained by changes in the routinely measured plasma lipids. To determine whether alterations in lipoproteins defined by their apoprotein content that are not estimated with conventional laboratory methods contributed to these unexpected events, we measured the apoB- and apoA-containing subclasses in a subgroup of ILLUMINATE participants. We find that Torcetrapib treatment significantly increased the high-density lipoprotein subclasses LpA-I and LpA-I:A-II equally (p
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Relationship between atorvastatin dose and the harm caused by Torcetrapib
Journal of lipid research, 2012Co-Authors: Philip J Barter, Kerry-anne Rye, Mohan Beltangady, William C. Ports, William T. Duggan, S. Matthijs Boekholdt, David A. Demicco, John J.p. Kastelein, Charles L ShearAbstract:Development of the cholesteryl ester transfer protein (CETP) inhibitor, Torcetrapib, was halted after the ILLUMINATE trial revealed an increase in both all-cause mortality (ACM) and major cardiovascular events (MCVEs) associated with its use. We now report that the harm caused by Torcetrapib was confi ned to those in the 10 mg atorvasta- tin subgroup for both ACM (hazard ratio (HR) = 2.68, 95% CI (1.58, 4.54), P < 0.0001) and MCVEs (HR = 1.41, 95% CI (1.14, 1.74), P = 0.002), with no evidence of harm when Torcetrapib was coadministered with higher doses of ator- vastatin. In the atorvastatin 10 mg subgroup, age, prior heart failure and stroke were signifi cantly associated with ACM, independent of Torcetrapib treatment, whereas low apoA-I, smoking, hypertension, heart failure, myocardial infarction, and stroke were independently associated with MCVEs. After adjusting for these factors, the HR associated with Torcetrapib treatment in the 10 mg atorvastatin subgroup remained elevated for both ACM (HR = 2.67, 95% CI (1.57, 4.54), P < 0.001) and MCVE (HR = 1.36, 95% CI (1.10, 1.69), P = 0.005). Thus, the harm caused by Torcetrapib was con- fi ned to individuals taking atorvastatin 10 mg. The harm could not be explained by Torcetrapib-induced changes in lipid levels, blood pressure, or electrolytes. It is conceiv- able that higher doses of atorvastatin protected against the harm caused by Torcetrapib .—Barter, P. J., K-A. Rye, M. S. Beltangady, W. C. Ports, W. T. Duggan, S. M. Boekholdt, D. A. DeMicco, J. J. P. Kastelein, and C. L. Shear. Relationship between atorvastatin dose and the harm caused by torce- trapib. J. Lipid Res . 2012. 53: 2436-2442.
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Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk
Journal of Lipid Research, 2012Co-Authors: Philip J BarterAbstract:Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor Torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by Torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than Torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of Torcetrapib.
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Thematic Review Series: New Lipid and Lipoprotein Targets for the Treatment of Cardiometabolic Diseases Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk
2012Co-Authors: Philip J Barter, Kerry-anne RyeAbstract:Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass trans- fers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proathero- genic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor Torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clin- ical outcome trial. The precise explanation for the harm caused by Torcetrapib is unknown but may relate to docu- mented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhib- itor dalcetrapib, which raises HDL levels less effectively than Torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibi- tors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of Torcetrapib. — Barter, P. J., and K.-A. Rye. Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. J. Lipid Res. 2012. 53: 1755-1766.
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Cholesteryl ester transfer protein inhibition to reduce cardiovascular risk: where are we now?
Trends in pharmacological sciences, 2011Co-Authors: Philip J Barter, Kerry-anne RyeAbstract:Elevated low-density lipoprotein-cholesterol (LDL-C) and reduced high-density lipoprotein-cholesterol (HDL-C) are major risk factors for the development of cardiovascular disease. One approach to raising HDL-C is to inhibit the cholesteryl ester transfer protein (CETP), a plasma protein that promotes transfer of cholesteryl esters from HDL and other lipoprotein fractions. Drugs that inhibit CETP increase HDL-C and some lower LDL-C. However, the development of Torcetrapib, the first CETP inhibitor to be tested in a human clinical outcomes trial, was terminated because it caused an excess of deaths and cardiovascular events. There is evidence, however, that Torcetrapib had adverse off-target effects unrelated to CETP inhibition. This has opened the way for retesting of the hypothesis that CETP inhibitors will be anti-atherogenic in studies conducted with agents such as dalcetrapib and anacetrapib that do not share the off-target effects of Torcetrapib. Clinical outcome trials with dalcetrapib and anacetrapib are currently under way.
Margaret E. Brousseau - One of the best experts on this subject based on the ideXlab platform.
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Effects of the cholesteryl ester transfer protein inhibitor Torcetrapib on VLDL apolipoprotein E metabolism
Journal of lipid research, 2007Co-Authors: John S Millar, Margaret R Diffenderfer, Megan L Wolfe, Francine K Welty, Margaret E. Brousseau, Chorthip Nartsupha, P. Hugh R. Barrett, Jeffrey S. Cohn, Aisha Wilson, Peter M. SchaeferAbstract:Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor Torcetrapib on VLDL apolipoprotein E (apoE) metabolism. Subjects, pretreated with atorvastatin (n = 9) or untreated (n = 10), received placebo followed by Torcetrapib (4 weeks each). After each treatment, subjects underwent a primed-constant infusion of D 3 -leucine to determine the VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib alone reduced the VLDL apoE pool size (PS) (-28%) by increasing the VLDL apoE FCR (77%) and leaving the VLDL apoE PR unchanged. In subjects pretreated with atorvastatin, Torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Used alone, Torcetrapib reduces the VLDL apoE PS by increasing the apoE FCR while leaving the VLDL apoE content unchanged. In contrast, Torcetrapib added to atorvastatin treatment increases both the VLDL apoE FCR and PR, leaving the VLDL apoE PS unchanged. Adding Torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL.
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Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans
Arteriosclerosis thrombosis and vascular biology, 2006Co-Authors: John S Millar, Andres Digenio, Margaret R Diffenderfer, Megan L Wolfe, Francine K Welty, Margaret E. Brousseau, Chorthip Nartsupha, P. Hugh R. Barrett, Aisha Faruqi, James P MancusoAbstract:Objective— Cholesteryl ester transfer protein (CETP) inhibition with Torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. Methods and Results— Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg Torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg Torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg Torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg Torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. Conclusions— These data indicate that when used alone, Torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, Torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.
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effects of cholesteryl ester transfer protein inhibition on high density lipoprotein subspecies apolipoprotein a i metabolism and fecal sterol excretion
Arteriosclerosis Thrombosis and Vascular Biology, 2005Co-Authors: Margaret E. Brousseau, Margaret R Diffenderfer, Megan L Wolfe, Bela F Asztalos, Francine K Welty, Chorthip Nartsupha, Ingemar Bjorkhem, Mats Rudling, John S Millar, Bo AngelinAbstract:Objective— Pharmacological inhibition of the cholesteryl ester transfer protein (CETP) in humans increases high-density lipoprotein (HDL) cholesterol (HDL-C) levels; however, its effects on apolipoprotein A-I (apoA-I) containing HDL subspecies, apoA-I turnover, and markers of reverse cholesterol transport are unknown. The present study was designed to address these issues. Methods and Results— Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor Torcetrapib (120 mg QD) for 4 weeks. In 6 subjects from the nonatorvastatin cohort, the everyday regimen was followed by a 4-week period of Torcetrapib (120 mg BID). At the end of each phase, subjects underwent a primed-constant infusion of (5,5,5-2H3)-l-leucine to determine the kinetics of HDL apoA-I. The lipid data in this study have been reported previously. Relative to placebo, 120 mg daily Torcetrapib increased the amount of apoA-I in α1-migrating HDL in the atorvastatin (136%; P <0.001) and nonatorvastatin (153%; P <0.01) cohorts, whereas an increase of 382% ( P <0.01) was observed in the 120 mg twice daily group. HDL apoA-I pool size increased by 8±15% in the atorvastatin cohort ( P =0.16) and by 16±7% ( P <0.0001) and 34±8% ( P <0.0001) in the nonatorvastatin 120 mg QD and BID cohorts, respectively. These changes were attributable to reductions in HDL apoA-I fractional catabolic rate (FCR), with Torcetrapib reducing HDL apoA-I FCR by 7% ( P =0.10) in the atorvastatin cohort, by 8% ( P <0.001) in the nonatorvastatin 120 mg QD cohort, and by 21% ( P <0.01) in the nonatorvastatin 120 mg BID cohort. Torcetrapib did not affect HDL apoA-I production rate. In addition, Torcetrapib did not significantly change serum markers of cholesterol or bile acid synthesis or fecal sterol excretion. Conclusions— These data indicate that partial inhibition of CETP via Torcetrapib in patients with low HDL-C: (1) normalizes apoA-I levels within α1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) does not significantly influence fecal sterol excretion.
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Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion
Arteriosclerosis Thrombosis and Vascular Biology, 2005Co-Authors: Margaret E. Brousseau, Margaret R Diffenderfer, Megan L Wolfe, Bela F Asztalos, Francine K Welty, Chorthip Nartsupha, Ingemar Bjorkhem, Mats Rudling, John S Millar, Bo AngelinAbstract:Objective— Pharmacological inhibition of the cholesteryl ester transfer protein (CETP) in humans increases high-density lipoprotein (HDL) cholesterol (HDL-C) levels; however, its effects on apolipoprotein A-I (apoA-I) containing HDL subspecies, apoA-I turnover, and markers of reverse cholesterol transport are unknown. The present study was designed to address these issues. Methods and Results— Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor Torcetrapib (120 mg QD) for 4 weeks. In 6 subjects from the nonatorvastatin cohort, the everyday regimen was followed by a 4-week period of Torcetrapib (120 mg BID). At the end of each phase, subjects underwent a primed-constant infusion of (5,5,5-2H3)-l-leucine to determine the kinetics of HDL apoA-I. The lipid data in this study have been reported previously. Relative to placebo, 120 mg daily Torcetrapib increased the amount of apoA-I in α1-migrating HDL in the atorvastatin (136%; P
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effects of an inhibitor of cholesteryl ester transfer protein on hdl cholesterol
The New England Journal of Medicine, 2004Co-Authors: Margaret E. Brousseau, Andres Digenio, Ronald W Clark, James P Mancuso, Megan L Wolfe, Leanne T Bloedon, Daniel J. RaderAbstract:background Decreased high-density lipoprotein (HDL) cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL cholesterol levels. methods We conducted a single-blind, placebo-controlled study to examine the effects of Torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol (<40 mg per deciliter [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of Torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of Torcetrapib twice daily for four weeks. results Treatment with 120 mg of Torcetrapib daily increased plasma concentrations of HDL cholesterol by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL cholesterol by 106 percent (P<0.001). Torcetrapib also reduced low-density lipoprotein (LDL) cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, Torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort.
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Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial.
Journal of the American Heart Association, 2019Co-Authors: Anirudh Kumar, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Am Lincoff, Divyang Patel, Govinda J. Weerakkody, Kathy Wolski, Danielle M. Brennan, Stephen J NichollsAbstract:Background The failure of cholesteryl ester transfer protein inhibitor Torcetrapib was associated with an off‐target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib ...
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CETP Inhibition in CVD Prevention: an Actual Appraisal.
Current Cardiology Reports, 2016Co-Authors: Belinda A. Di Bartolo, Kohei Takata, My Ngan Duong, Stephen J NichollsAbstract:By virtue of their effects on low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and cellular cholesterol efflux, there is considerable interest in the potential use of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) as a novel approach for cardiovascular disease prevention. This is supported by observations from genetic and animal studies suggesting that less CETP activity has favorable cardiovascular effects. Despite the adverse effects of the first CETP inhibitor to move forward in clinical development, Torcetrapib, there remains considerable interest in developing alternative CETP inhibitors without the off-target effects of Torcetrapib. The clinical development programs leading to a number of promising CETP inhibitors will be reviewed.
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cholesteryl ester transfer protein inhibition high density lipoprotein raising and progression of coronary atherosclerosis insights from illustrate investigation of lipid level management using coronary ultrasound to assess reduction of atheroscleros
Circulation, 2008Co-Authors: Stephen J Nicholls, Danielle M. Brennan, Jean-claude Tardif, Murat E Tuzcu, Steven E NissenAbstract:Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor Torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis. Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to Torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, Torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P =0.02), and lowered serum potassium (0.11±0.02 mmol/L, P <0.0001). Despite substantial increases in HDL-C, no effect was found of Torcetrapib on percent atheroma volume. In Torcetrapib-treated patients, an inverse relationship was observed between changes in HDL-C and percentage atheroma volume ( r =−0.17, P <0.001). Participants with regression had greater increases in HDL-C (mean±SE, 62.9±37.4% versus 54.0±39.1%, P =0.002). Compared with the lowest quartile, Torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (−0.31±0.27 versus 0.88±0.27%, P =0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (−0.69±0.27%, P =0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression ( P =0.001). Conclusions— The majority of Torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression. Received May 5, 2008; accepted September 12, 2008. # CLINICAL PERSPECTIVE {#article-title-2}
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Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atheroscl
Circulation, 2008Co-Authors: Stephen J Nicholls, Danielle M. Brennan, Jean-claude Tardif, E. Murat Tuzcu, Steven E NissenAbstract:Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor Torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis. Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to Torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, Torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P =0.02), and lowered serum potassium (0.11±0.02 mmol/L, P
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Effect of Torcetrapib on the Progression of Coronary Atherosclerosis
The New England journal of medicine, 2007Co-Authors: Steven E Nissen, Stephen J Nicholls, Charles L Shear, James H Revkin, William T. Duggan, Jean-claude Tardif, Witold Rużyłło, William Bachinsky, Gregory P. Lasala, E. Murat TuzcuAbstract:Background Levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, increases HDL cholesterol levels, but the functional effects associated with this mechanism remain uncertain. Methods A total of 1188 patients with coronary disease underwent intravascular ultrasonography. After treatment with atorvastatin to reduce levels of low-density lipoprotein (LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of Torcetrapib daily. After 24 months, disease progression was measured by repeated intravascular ultrasonography in 910 patients (77%). Results After 24 months, as compared with atorvastatin monotherapy, the effect of Torcetrapib–atorvastatin therapy was an approximate 61% relative increase in HDL cholesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of L...
