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
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 I...
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| Published in | Circulation (New York, N.Y.) Vol. 118; no. 24; pp. 2515 - 2522 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Hagerstown, MD
Lippincott Williams & Wilkins
09.12.2008
|
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
|---|---|
| AbstractList | 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. 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.BACKGROUNDTorcetrapib, 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.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.METHODS AND RESULTSData 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.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.CONCLUSIONSThese 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. 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. 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. 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. |
| Author | Evans, Gregory W. Kastelein, John J.P. Bots, Michiel L. Visseren, Frank L. Vergeer, Menno Sijbrands, Eric J. Grobbee, Diederick E. Stalenhoef, Anton F. van Leuven, Sander I. Basart, Dick C. Stroes, Erik S. |
| Author_xml | – sequence: 1 givenname: Menno surname: Vergeer fullname: Vergeer, Menno organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 2 givenname: Michiel L. surname: Bots fullname: Bots, Michiel L. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 3 givenname: Sander I. surname: van Leuven fullname: van Leuven, Sander I. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 4 givenname: Dick C. surname: Basart fullname: Basart, Dick C. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 5 givenname: Eric J. surname: Sijbrands fullname: Sijbrands, Eric J. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 6 givenname: Gregory W. surname: Evans fullname: Evans, Gregory W. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 7 givenname: Diederick E. surname: Grobbee fullname: Grobbee, Diederick E. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 8 givenname: Frank L. surname: Visseren fullname: Visseren, Frank L. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 9 givenname: Anton F. surname: Stalenhoef fullname: Stalenhoef, Anton F. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 10 givenname: Erik S. surname: Stroes fullname: Stroes, Erik S. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest – sequence: 11 givenname: John J.P. surname: Kastelein fullname: Kastelein, John J.P. organization: From the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M.V., S.I.v.L., E.S.S., J.J.P.K.); Julius Center for Health Sciences and Primary Care (M.L.B., D.E.G.) and Department of Vascular Medicine (F.L.V.), University Medical Center Utrecht, Utrecht, The Netherlands; Westfries Gasthuis, Hoorn, The Netherlands (D.C.B.); Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands (E.J.S.); Division of Public Health Sciences, Wake Forest |
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| Keywords | Vascular disease Torcetrapib Toxicity drugs Atherosclerosis Lipids Cardiovascular disease imaging Cholesterol Antilipemic agent |
| Language | English |
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Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a... Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant... |
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| SubjectTerms | Adult Anticholesteremic Agents - adverse effects Anticholesteremic Agents - therapeutic use Atherosclerosis (general aspects, experimental research) Atherosclerosis - drug therapy Atorvastatin Calcium Biological and medical sciences Blood and lymphatic vessels Blood Pressure - drug effects Cardiology. Vascular system Cholesterol Ester Transfer Proteins - antagonists & inhibitors Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Female Heptanoic Acids - administration & dosage Humans Male Medical sciences Middle Aged Mineralocorticoids Pyrroles - administration & dosage Quinolines - administration & dosage Quinolines - toxicity |
| Subtitle | A Pooled Analysis of the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) Trials |
| Title | Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity |
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