Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study

GJ de Grooth, JA Kuivenhoven, AFH Stalenhoef… - Circulation, 2002 - Am Heart Assoc
GJ de Grooth, JA Kuivenhoven, AFH Stalenhoef, J de Graaf, AH Zwinderman, JL Posma…
Circulation, 2002Am Heart Assoc
Background—Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral
lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL
cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705,
a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the
progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results
using this CETP inhibitor in humans. Methods and Results—In a randomized, double-blind …
Background Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans.
Methods and Results In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity (P<0.0001), a 34% increase in HDL cholesterol (P<0.0001), and a 7% decrease in LDL cholesterol (P=0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL2, HDL3, and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests.
Conclusions We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects (P=0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.
Am Heart Assoc