Torcetrapib Significantly Increases HDL Cholesterol Levels

April 07, 2004

Yael Waknine

April 7, 2004 -- Torcetrapib alone and in combination with atorvastatin significantly increases high-density lipoprotein (HDL) cholesterol in patients with low HDL levels, according to the results of a single-blind, placebo-controlled, fixed-sequence study published in the April 8 issue of the New England Journal of Medicine.

"A low level of HDL cholesterol is the most common lipid abnormality observed in patients with known coronary heart disease," writes Margaret E. Brousseau, PhD, from the Lipid Research Laboratory at New England Medical Center and Tufts University School of Medicine in Boston, Massachusetts. "Statins have only moderate effects on HDL cholesterol levels, raising them by 5 to 10 percent."

According to the authors, another HDL-raising strategy involves the use of torcetrapib, a novel cholesteryl ester transfer protein (CETP) inhibitor. CETP is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from HDL cholesterol to apolipoprotein B–containing lipoproteins.

"Humans with CETP deficiency...have markedly elevated plasma levels of HDL cholesterol and apolipoprotein A-1, leading to the concept that CETP inhibition may increase HDL cholesterol levels," the authors point out.

The investigators recruited 19 subjects aged 18 to 70 years with an HDL cholesterol level less than 40 mg/dL, a triglyceride level less than 400 mg/dL, a low-density lipoprotein (LDL) cholesterol level of 160 mg/dL or less, and a body mass index between 18 and 35 kg/m 2.

During an introductory screening period of two to four weeks, nine subjects with LDL cholesterol levels higher than 160 mg/dL were stabilized on 20 mg atorvastatin daily. All subjects received placebo for the next four weeks followed by 120 mg torcetrapib daily for four weeks. Patients not receiving atorvastatin then went on to receive 120 mg torcetrapib twice daily for four weeks.

There were no serious adverse events or withdrawals due to adverse events.

Torcetrapib significantly reduced CETP trough activity compared with placebo in all subjects. Torcetrapib at a dose of 120 mg daily combined with 20 mg atorvastatin reduced CETP activity by 38% ± 22% ( P = .001). CETP activity was reduced by 28% ± 16% in the 120 mg torcetrapib group ( P = .003) and by 65% ± 16% in the group receiving 120 mg torcetrapib twice daily ( P = .01).

Reductions in CETP activity resulted in significantly increased HDL cholesterol concentrations. Torcetrapib at a dose of 120 mg daily increased HDL cholesterol levels by 61% compared with placebo in subjects also receiving atorvastatin (47 ± 10 mg/dL vs. 29 ± 4 mg/dL; P < .001) and by 46% in those receiving monotherapy (46 ± 14 mg/dL vs. 32 ± 7 mg/dL; P = .001).

The subgroup of subjects not taking atorvastatin who went on to take 120 mg torcetrapib twice daily showed a 106% increase in HDL cholesterol levels compared with placebo (70 ± 15 mg/dL vs. 34.5 ± 5 mg/dL; P < .001).

Torcetrapib in combination with atorvastatin resulted in reduced LDL cholesterol levels (by 17%; P = .02) and reduced apolipoprotein B levels (by 14%; P = .002) compared with placebo. Treatment with torcetrapib alone (120 mg) resulted in reduced LDL cholesterol (by 8%; not significant) and apolipoprotein B levels (by 10%; P = .004). Treatment with 120 mg torcetrapib twice daily was associated with nonsignificant reductions in LDL cholesterol and apolipoprotein B (17% and 17%, respectively).

"Even small increases in the HDL cholesterol level can significantly reduce the risk of coronary heart disease," the authors point out. "An increase in HDL cholesterol by 1 mg/dL is associated with a 2% to 4% reduction in the risk of cardiovascular events."

"Torcetrapib is a well-toleratedand effective CETP inhibitor that has pronounced effects on plasma lipoproteins in patients with low HDL cholesterol levels," the authors note. "Ultimately, the question of whether CETP inhibition is effective in reducing atherosclerotic cardiovascular disease will be resolved only by trials based on hard clinical evidence."

This study was supported in part by Pfizer and grants from the National Center for Research Resources and the National Heart, Lung, and Blood Institute. Dr. Rader is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and of a Doris Duke Distinguished Clinical Investigator Award. Drs. Schaefer and Rader report having received lecture fees, consulting fees, and grant support from AstraZeneca, KOS Pharmaceuticals, and Pfizer. Dr. Rader also reports having received grant support from Pfizer.

In an accompanying editorial, H. Bryan Brewer, Jr., MD, writes, "Despite the small number of patients, the results suggest that torcetrapib can effectively increase the HDL cholesterol level in subjects with low levels; moreover, the addition of torcetrapib to statin therapy is associated with a further reduction in the LDL cholesterol level."

Dr. Brewer concludes, "Given the available data, CETP inhibitors hold great promise as a new class of drugs that will be of major benefit in the treatment of cardiovascular disease."

Dr. Brewer reports having served as a consultant to and member of the speakers bureau of Pfizer, Esperion, and Lipid Sciences.

N Engl J Med. 2004;250:1491-1494, 1505-1515

Reviewed by Gary D. Vogin, MD

Yael Waknine is a freelance writer for Medscape.

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