Effects of the cholesteryl ester transfer protein inhibitor, TA-8995, on cholesterol efflux capacity and high-density lipoprotein particle subclasses.
TA-8995 is a potent inhibitor of cholesteryl ester transfer protein (CETP) with beneficial effects on lipids and lipoproteins. The effect of TA-8995 on cholesterol efflux capacity (CEC), a measure of high-density lipoprotein (HDL) function, and HDL subparticle distribution is largely unknown.



To assess the effect of the CETP inhibitor TA-8995 on ABCA1- and non-ABCA1-driven CEC and on HDL particle distribution.



Total, non-ABCA1-, and ABCA1-specific CEC from J774 cells and HDL subclass distribution assessed by two-dimensional gel electrophoresis were measured at baseline and after 12-week treatment in 187 mild-dyslipidemic patients randomized to placebo, 1 mg, 5 mg, 10 mg TA-8995, or 10 mg TA-8995 combined with 10 mg rosuvastatin (NCT01970215).



Compared with placebo, total, non-ABCA1-, and ABCA1-specific CEC were increased dose dependently by up to 38%, 72%, and 28%, respectively, in patients randomized to 10 mg of TA-8995. PreBeta-1 HDL, the primary acceptor for ABCA1-driven cholesterol efflux, was increased by 36%. This increase in preBeta-1 HDL correlated significantly with the total and the ABCA1-driven CEC increase, whereas the high-density lipoprotein cholesterol (HDL-C) increase did not.



TA-8995 dose dependently increased not only total and non-ABCA1-specific CEC but also ABCA1-specific CEC and preBeta-1 HDL particle levels. These findings suggest that TA-8995 not only increases HDL-C levels but also promotes functional properties of HDL particles. This CETP inhibitor-driven preBeta-1 HDL increase is an important predictor of both ABCA1 and total CEC increase, independent of HDL-C increase. Whether these changes in HDL particle composition and functionality have a beneficial effect on cardiovascular outcome requires formal testing in a cardiovascular outcome trial.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Julian C
JC
van Capelleveen
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Dezima Pharma BV, Naarden, The Netherlands. Electronic address: j.s.jansen@amc.uva.nl.
John J P
JJ
Kastelein
Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands.
Aeilko H
AH
Zwinderman
Dezima Pharma BV, Naarden, The Netherlands; Department of Gastroenterology, Leiden University Medical Centre, Leiden, The Netherlands.
Sander J H
SJ
van Deventer
Vascular Strategies, Horsham, PA, USA.
Heidi L
HL
Collins
Vascular Strategies, Horsham, PA, USA.
Steven J
SJ
Adelman
Dezima Pharma BV, Naarden, The Netherlands; Xention Ltd, Cambridge, UK.
Patrick
P
Round
Dezima Pharma BV, Naarden, The Netherlands; Xention Ltd, Cambridge, UK.
John
J
Ford
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, PA, USA.
Daniel J
DJ
Rader
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
G Kees
GK
Hovingh
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000032:analysis / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000188:drug therapy*; D005260:Female; D053442:High-Density Lipoproteins, Pre-beta / Q000032:analysis; D006801:Humans; D008075:Lipoproteins, HDL / Q000032:analysis* / Q000145:classification; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D011804:Quinolines / Q000627:therapeutic use*; D000068718:Rosuvastatin Calcium / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D011804:Quinolines; C000597751:TA-8995; D014280:Triglycerides; D000068718:Rosuvastatin Calcium
CETP inhibitor; Cholesterol efflux capacity; HDL; Pre-Beta1 HDL; TA-8995