NEW YORK (Reuters Health) Mar 17 - Torcetrapib, a newly developed inhibitor of cholesteryl ester transfer protein (CETP), increases HDL cholesterol up to 91% while significantly lowering LDL cholesterol, phase I trial results show.

Another CETP inhibitor raised HDL levels in mildly hyperlipidemic subjects. However, animal studies showed no associated reduction in atherosclerotic lesion formation, suggesting that more potent inhibition of CETP will be required to lower the risk of heart disease, Dr. Ronald W. Clark and colleagues explain in the March issue of Arteriosclerosis, Thrombosis and Vascular Biology.

Dr. Clark's group at Pfizer Global Research and Development in Groton, Connecticut, tested torcetrapib in healthy volunteers, who were randomly assigned to placebo or torcetrapib 10, 30, 60 or 120 mg daily or 120 mg b.i.d. for 14 days.

HDL levels rose significantly after 2 weeks, ranging from 16% in the 10-mg group to 91% in the 120-mg b.i.d. group, with reciprocal decreases in non-HDL cholesterol. LDL decreased up to 42% at the highest dose.

The LDL-to-HDL ratio decreased significantly at doses of 30 mg or higher.

In an accompanying editorial, Dr. H. Bryan Brewer Jr. notes that complete CETP inhibition promotes atherogenesis by causing accumulation of very large dysfunctional HDL and abnormal LDL. Torcetrapib's partial inhibition appears to prevent these gross abnormalities while promoting an anti-atherogenic shift from low-density to high-density lipoprotein.

Dr. Brewer, a researcher at the National Institutes of Health in Bethesda, Maryland, concludes, "The ultimate evaluation of the potential protection against atherosclerosis with torcetrapib will require clinical trials using surrogate end points, including coronary intravascular ultrasound and carotid IMT as well as hard clinical endpoints."

Arterioscler Thromb Vasc Biol 2004;24:490-497.

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