Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apolipoprotein A-II metabolism.
This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (-9.4%, P < 0.003) and nonatorvastatin once- (-9.9%, P = 0.02) and twice- (-13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in alpha-3-migrating HDL, with mean reductions of -14% (P = 0.23), -18% (P < 0.02), and -18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.
Brousseau
Margaret E
ME
Cardiovascular Research Laboratory, Tufts University School of Medicine, Boston, MA, USA. margaret.brousseau@novartis.com
Millar
John S
JS
Diffenderfer
Margaret R
MR
Nartsupha
Chorthip
C
Asztalos
Bela F
BF
Wolfe
Megan L
ML
Mancuso
James P
JP
Digenio
Andres G
AG
Rader
Daniel J
DJ
Schaefer
Ernst J
EJ
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000097:blood; D016633:Apolipoprotein A-II / Q000378:metabolism*; D000069059:Atorvastatin; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D010919:Placebos / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006538:Heptanoic Acids; D010919:Placebos; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin