title: 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.
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 [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.
  
  
  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.
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Vergeer
authors.forename: Michiel L
authors.initials: ML
authors.lastname: Bots
authors.forename: Sander I
authors.initials: SI
authors.lastname: van Leuven
authors.forename: Dick C
authors.initials: DC
authors.lastname: Basart
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sijbrands
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Evans
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
authors.forename: Frank L
authors.initials: FL
authors.lastname: Visseren
authors.forename: Anton F
authors.initials: AF
authors.lastname: Stalenhoef
authors.forename: Erik S
authors.initials: ES
authors.lastname: Stroes
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy*; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D008901:Mineralocorticoids; D011758:Pyrroles / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D006538:Heptanoic Acids; D008901:Mineralocorticoids; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin