Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels

• Published in: Journal of the American College of Cardiology Vol. 48; no. 9; pp. 1774 - 1781
• Main Authors: Davidson, Michael H., McKenney, James M., Shear, Charles L., Revkin, James H.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 07.11.2006; Elsevier Science; Elsevier Limited
• Subjects: Adult; Atherosclerosis - blood; Atherosclerosis - drug therapy; Automation; Biological and medical sciences; Blood pressure; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Cholesterol; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol Ester Transfer Proteins - blood; Cholesterol, HDL - blood; Confidence intervals; Demographics; Disorders of blood lipids. Hyperlipoproteinemia; Double-Blind Method; Female; Humans; Hypothesis testing; Kinases; Lipids; Lipoproteins; Male; Medical sciences; Metabolic diseases; Middle Aged; NMR; Nuclear magnetic resonance; Proteins; Quinolines - adverse effects; Quinolines - pharmacology; Quinolines - therapeutic use; Studies; Triglycerides; CVD; HDL-C; SBP; apo; CETP; CE; NMR; DBP; AE; LDL-C; VLDL-C; CHD; cardiovascular disease; apolipoprotein; cholesteryl ester transfer protein; low-density lipoprotein cholesterol; adverse event; nuclear magnetic resonance; systolic blood pressure; very low-density lipoprotein cholesterol; diastolic blood pressure; high-density lipoprotein cholesterol; coronary heart disease; cholesteryl ester; High; Human; Protein inhibitor; Toxicity; Metabolic diseases; Lipids; Hyperlipoproteinemia; Lipoprotein; Protein A; Density; Phlebology; Cholesterol; Ester; Hypercholesterolemia; Torcetrapib; Efficiency; Individual; Transfer; Complication; Level; Circulatory system; Safety; Dyslipemia; Cardiology
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2006.06.067

Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels Michael H. Davidson, James M. McKenney, Charles L. Shear, James H. Revkin Evidence suggests that high-density lipoprotein cholesterol (HDL-C) is atheroprotective. One mechanism for increasing the level of HDL-C is the inhibition of cholesteryl ester transfer protein (CETP). Subjects with below-average HDL-C were randomized to treatment with the CETP inhibitor torcetrapib (10, 30, 60, or 90 mg/day) or placebo. The percent change from baseline to Week 8 with torcetrapib (least-squares mean difference from placebo) was dose-dependent and ranged from 9.0% to 54.5% for HDL-C and from 3.0% to −16.5% for low-density lipoprotein cholesterol. There were no dose-related increases in the frequency of adverse events. Significant blood pressure increases were noted in 2 of 140 subjects. This study was designed to evaluate the efficacy and safety of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in subjects with low high-density lipoprotein cholesterol (HDL-C) levels. Evidence suggests HDL-C is atheroprotective. A proven mechanism for increasing the level of HDL-C is the inhibition of CETP. A total of 162 subjects with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were not taking lipid-modifying therapy were randomized to double-blind treatment with torcetrapib 10, 30, 60, or 90 mg/day or placebo (∼30 subjects per group). The percent change from baseline to Week 8 with torcetrapib (least-squares mean difference from placebo) was dose-dependent and ranged from 9.0% to 54.5% for HDL-C (p ≤ 0.0001 for 30 mg and higher doses) and from 3.0% to −16.5% for low-density lipoprotein cholesterol (LDL-C) (p < 0.01 for 90-mg dose). Low-density lipoprotein cholesterol lowering was less in subjects with higher (>150 mg/dl) versus lower levels of baseline triglycerides; at 60 mg, the change in LDL-C was 0.1% versus −22.2% (p < 0.0001), respectively. Particle size for both HDL and LDL increased with torcetrapib. There were no dose-related increases in the frequency of adverse events. Significant blood pressure increases were noted in 2 of 140 subjects. Torcetrapib resulted in substantial dose-dependent elevations in HDL-C, accompanied by moderate decreases in LDL-C at the higher doses. Torcetrapib was generally well tolerated.