Published online before print March 10, 2005, doi: 10.1161/01.ATV.0000161928.16334.dd
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion
From the Lipid Metabolism Laboratory (M.E.B., M.R.D., C.N., B.F.A., E.J.S.), JM-USDA-HNRCA at Tufts University and Tufts-New England Medical Center, Boston, Mass; Department of Medicine and Center for Experimental Therapeutics (J.S.M., M.L.W., D.J.R.), University of Pennsylvania School of Medicine, Philadelphia; Division of Cardiology (F.K.W.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Medicine (M.R., I.B., B.A.), Center for Metabolism and Endocrinology and Center for Molecular Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Clinical Biostatistics (J.P.M.), Pfizer, Inc., Groton, Conn; and Department of Clinical Sciences (A.G.D.), Pfizer, Inc., New London, Conn.
Correspondence to Margaret E. Brousseau, PhD, Lipid Metabolism Laboratory, JM-USDA-HNRCA at Tufts University, 711 Washington St, Boston, MA 02111. E-mail margaret.brousseau{at}tufts.edu
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 
1-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 1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) does not significantly influence fecal sterol excretion.
The effects of cholesteryl ester transfer protein (CETP) inhibition on HDL apoA-I kinetics and surrogate markers of cholesterol synthesis and fecal sterol excretion were assessed in 19 subjects with low HDL. Our data indicate that CETP inhibition with with torcetrapib significantly increased HDL apoA-I pool size because of delayed catabolism, but did not alter fecal sterol excretion.
Key Words: apolipoprotein A-I • bile acids • cholesteryl ester transfer protein • CETP inhibition • high-density lipoproteins • kinetics
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