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 alpha1-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 alpha1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) does not significantly influence fecal sterol excretion.
RCT Entities:
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 alpha1-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 alpha1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) does not significantly influence fecal sterol excretion.
Authors: E Reihnér; M Rudling; D Ståhlberg; L Berglund; S Ewerth; I Björkhem; K Einarsson; B Angelin Journal: N Engl J Med Date: 1990-07-26 Impact factor: 91.245
Authors: A Inazu; M L Brown; C B Hesler; L B Agellon; J Koizumi; K Takata; Y Maruhama; H Mabuchi; A R Tall Journal: N Engl J Med Date: 1990-11-01 Impact factor: 91.245
Authors: M L Brown; A Inazu; C B Hesler; L B Agellon; C Mann; M E Whitlock; Y L Marcel; R W Milne; J Koizumi; H Mabuchi Journal: Nature Date: 1989-11-23 Impact factor: 49.962
Authors: K Ikewaki; D J Rader; T Sakamoto; M Nishiwaki; N Wakimoto; J R Schaefer; T Ishikawa; T Fairwell; L A Zech; H Nakamura Journal: J Clin Invest Date: 1993-10 Impact factor: 14.808
Authors: Adriaan G Holleboom; Lily Jakulj; Remco Franssen; Julie Decaris; Menno Vergeer; Joris Koetsveld; Jayraz Luchoomun; Alexander Glass; Marc K Hellerstein; John J P Kastelein; G Kees Hovingh; Jan Albert Kuivenhoven; Albert K Groen; Scott M Turner; Erik S G Stroes Journal: J Lipid Res Date: 2013-05-06 Impact factor: 5.922
Authors: Ronald W Clark; David Cunningham; Yang Cong; Timothy A Subashi; George T Tkalcevic; David B Lloyd; James G Boyd; Boris A Chrunyk; George A Karam; Xiayang Qiu; Ing-Kae Wang; Omar L Francone Journal: J Lipid Res Date: 2009-10-21 Impact factor: 5.922
Authors: Eric J Niesor; Christine Magg; Naoto Ogawa; Hiroshi Okamoto; Elisabeth von der Mark; Hugues Matile; Georg Schmid; Roger G Clerc; Evelyne Chaput; Denise Blum-Kaelin; Walter Huber; Ralf Thoma; Philippe Pflieger; Makoto Kakutani; Daisuke Takahashi; Gregor Dernick; Cyrille Maugeais Journal: J Lipid Res Date: 2010-09-22 Impact factor: 5.922