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


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.
de Grooth
Greetje J
GJ
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
Kuivenhoven
Jan Albert
JA
Stalenhoef
Anton F H
AF
de Graaf
Jacqueline
J
Zwinderman
Aeilko H
AH
Posma
Jan L
JL
van Tol
Arie
A
Kastelein
John J P
JJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides; D001053:Apolipoproteins / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004952:Esters; D005260:Female; D006023:Glycoproteins; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D013438:Sulfhydryl Compounds / Q000009:adverse effects* / Q000627:therapeutic use*
D000577:Amides; D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D006023:Glycoproteins; D000960:Hypolipidemic Agents; D008055:Lipids; D008074:Lipoproteins; D013438:Sulfhydryl Compounds; C411602:dalcetrapib