Dalcetrapib
JTT-705 raises HDL cholesterol but fails to reduce aortic atherosclerosis in rabbits with severe hypercholesterolaemia (Clin Sci 2002)
Original title: Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia
Researchers tested whether the CETP inhibitor JTT-705 reduces atherosclerosis in Japanese white rabbits fed a high-cholesterol diet. After 4 weeks on 0.25% cholesterol chow, animals received low-dose (100 mg/kg) or high-dose (300 mg/kg) JTT-705 and were monitored through week 12. The high dose significantly raised HDL cholesterol from 21 plus or minus 3 to 50 plus or minus 7 mg/dL (p < 0.0001) versus a rise from 21 plus or minus 2 to 27 plus or minus 2 mg/dL in controls, but the atheromatous area was similar between groups, 60 plus or minus 9% with JTT-705 versus 58 plus or minus 9% in controls. Correlation analysis showed triacylglycerol and non-HDL cholesterol levels, not CETP activity or HDL cholesterol, tracked with atherosclerosis development, suggesting JTT-705 alone has limited anti-atherogenic benefit in a severe hypercholesterolaemia model where non-HDL lipoproteins dominate risk.
Original abstract
Cholesteryl ester transfer protein (CETP) is a major determinant of plasma levels of high-density lipoprotein-cholesterol (HDL-C) in humans. The anti-atherogenic effect of lowering CETP levels is dependent not only on HDL-C levels but also on a metabolic background of increased low-density lipoprotein or very-low-density lipoprotein. Here we investigated the effects of JTT-705, a chemical inhibitor of CETP, on the development of atherosclerosis in Japanese white rabbits fed on a high cholesterol diet. After 4 weeks on a diet of 0.25% cholesterol-containing chow, 100 mg/kg (low dose) or 300 mg/kg (high dose) JTT-705 was given, and the animals were monitored at weeks 0, 4, 8 and 12. Aortic atherosclerotic lesions were determined at the end of this period. JTT-705 induced a significant increase in HDL-C in the high-dose group [from 21+/-3 to 50+/-7 mg/dl (mean+/-S.E.M.); P <0.0001] compared with the control group (from 21+/-2 to 27+/-2 mg/dl). The atheromatous area was 60+/-9% in the high-dose group and 58+/-9% in the control group. Moreover, correlation analysis showed that triacylglycerol and non-HDL-C levels had a direct relationship with the development of atherosclerosis, but CETP activity and HDL-C levels did not. Thus the CETP inhibitor JTT-705 alone did not have an anti-atherogenic effect in our rabbit model, of severe hypercholesterolaemia suggesting a relatively minor effect of HDL-elevating therapy as compared with decreases in non-HDL-C (or triacylglycerol) levels in patients with severe hypercholesterolaemia, such as familial hypercholesterolaemia.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.