title: Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion.
abstract: 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.
  
  
  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.affiliation: Lipid Metabolism Laboratory, JM-USDA-HNRCA at Tufts University and Tufts-New England Medical Center, Boston, Mass 02111, USA. margaret.brousseau@tufts.edu
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Brousseau
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Diffenderfer
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Chorthip
authors.initials: C
authors.lastname: Nartsupha
authors.forename: Bela F
authors.initials: BF
authors.lastname: Asztalos
authors.forename: Francine K
authors.initials: FK
authors.lastname: Welty
authors.forename: Megan L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Bo
authors.initials: B
authors.lastname: Angelin
authors.forename: James P
authors.initials: JP
authors.lastname: Mancuso
authors.forename: Andres G
authors.initials: AG
authors.lastname: Digenio
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
mesh_terms: D000924:Anticholesteremic Agents / Q000008:administration & dosage; D016632:Apolipoprotein A-I / Q000378:metabolism*; D000069059:Atorvastatin; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000378:metabolism*; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism; D005243:Feces; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D011758:Pyrroles / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage*; D013261:Sterols / Q000097:blood / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001647:Bile Acids and Salts; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; D006538:Heptanoic Acids; D011758:Pyrroles; D011804:Quinolines; D013261:Sterols; C483909:torcetrapib; D000069059:Atorvastatin