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Papers In Press, published online ahead of print February 26, 2007
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Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Res and Dev., Groton, CT 06340
Corresponding Author: lee.a.morehouse{at}pfizer.com
Cholesteryl ester transfer protein (CETP) inhibitors increase HDL-C in animals and humans, but whether CETP inhibition will be anti-atherogenic is still uncertain. We tested the CETP-inhibitor torcetrapib in rabbits fed an atherogenic diet at a dose sufficient to raise HDL-C by at least 3 fold (207 ± 32 mg/dL vs 57 ± 6 mg/dL in controls at 16 wk). CETP activity was inhibited by 70-80% throughout the study. Non-HDL-C increased in both groups, but there with no difference apparent by study’s end (207 ± 32 mg/dL vs 57 ± 6 mg/dL in controls). At 16 wk aortic atherosclerosis was 60% lower in torcetrapib-treated animals (16.4 ± 3.4% vs 39.8 ± 5.4% in controls) and aortic cholesterol content was reduced proportionally. Sera from a separate group of rabbits administered torcetrapib effluxed 48% more cholesterol from Fu5AH cells than did sera from control animals, possibly explaining the reduced aortic cholesterol content. Regression analyses indicated that lesion area in the torcetrapib-treated group was strongly correlated with the ratio of TPC to HDL-C, but not with changes in other lipid or lipoprotein levels. Conclusion: CETP inhibition with torcetrapib retards atherosclerosis in rabbits, and the reduced lesion area is associated with elevated levels of HDL-C.
Revised on February 9, 2007
Accepted on February 26, 2007
Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in NZW rabbits
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