Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.
BACKGROUND
Decreased high-density lipoprotein (HDL) cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL cholesterol levels.


METHODS
We conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol (<40 mg per deciliter [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for four weeks.


RESULTS
Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL cholesterol by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL cholesterol by 106 percent (P<0.001). Torcetrapib also reduced low-density lipoprotein (LDL) cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort.


CONCLUSIONS
In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.
Brousseau
Margaret E
ME
Lipid Research Laboratory, Division of Endocrinology, Metabolism, Diabetes, and Molecular Medicine, New England Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA. margaret.brousseau@tufts.edu
Schaefer
Ernst J
EJ
Wolfe
Megan L
ML
Bloedon
LeAnne T
LT
Digenio
Andres G
AG
Clark
Ronald W
RW
Mancuso
James P
JP
Rader
Daniel J
DJ
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000097:blood; D016633:Apolipoprotein A-II / Q000097:blood; D000069059:Atorvastatin; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006023:Glycoproteins; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use; D011804:Quinolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016037:Single-Blind Method; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006023:Glycoproteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011804:Quinolines; D014280:Triglycerides; C483909:torcetrapib; D000069059:Atorvastatin