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Cholesteryl Ester Transfer Protein Raises Serum High-Density Lipoprotein Cholesterol Levels as Monotherapy and Combined with a Statin

Patients with low levels of high-density lipoprotein (HDL) cholesterol showed marked increases in plasma HDL cholesterol while receiving torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, either alone or in combination with atorvastatin.

In this single-blind, placebo-controlled, study of 19 patients with HDL cholesterol levels less than 40 mg/dL, "Torcetrapib not only increased the levels of HDL cholesterol and apolipoprotein A-I, it also reduced the levels of LDL [low-density lipoprotein] cholesterol and apolipoprotein B," reports Margaret E. Brousseau, PhD, Division of Endocrinology, Metabolism, Diabetes, and Molecular Medicine, New England Medical Centre and Tufts University School of Medicine, Boston, Massachusetts, United States, and colleagues.

The patients, aged between 18 and 75 years old had - in addition to low HDL cholesterol - triglyceride levels below 400 mg/dL, LDL cholesterol levels of 160 mg/dL or less, and a body-mass index between 18 and 35. Patients were excluded according to childbearing potential, alcohol and cigarette use, treatment with any medication known to affect plasma lipid levels except a statin in the previous 6 weeks; and evidence or history of renal or endocrine disease, hepatic disease, cardiac disease within the previous 6 months, or illegal drug use.

After screening, 9 patients with LDL cholesterol above 160 mg/dL received 20 mg atorvastatin daily for 2 to 4 weeks to achieve stabilisation of LDL cholesterol levels. For the next 4 weeks, all 19 patients received placebo, followed by 4 weeks of daily torcetrapib at 120 mg. A subgroup of 6 patients who did not use atorvastatin continued a third phase of treatment with 120 mg torcetrapib twice daily for an additional 4 weeks.

Once daily torcetrapib increased plasma concentrations of HDL cholesterol by 61%, apolipoprotein A-I by 13% and A-II levels by 10%, and reduced plasma LDL cholesterol levels by 17%, and apolipoprotein B levels by 14% among patients receiving atorvastatin, relative to placebo. In patients taking once daily torcetrapib monotherapy, corresponding values increased 46%, 16%, 12%, and decreased 8% (not significant), and 10%, respectively. Among patients taking twice daily torcetrapib, levels of HDL, apolipoprotein A-I, and A-II, increased 106%, 36%, 21%, respectively, while levels of LDL and apolipoprotein reduced by non-significant values of 17% and 17%, respectively.

Patients reported 20 mild and 8 moderate adverse events, including headache, asthenia, pain, dyspepsia, herpes simples, herpes zoster, sweating, dyspepsia, amnesia, abnormal thinking, and dizziness, but none of the events were serious and no patients discontinued treatment due to adverse events.

"In conclusion, torcetrapib is a well-tolerated and effective CETP inhibitor that has pronounced effects on plasma lipoproteins in patients with low HDL cholesterol levels," the authors write.

N Engl J Med 2004;350:1505-15.

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