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J Clin Lipidol. 2016 Sep-Oct;10(5):1137-1144.e3. doi: 10.1016/j.jacl.2016.06.006. Epub 2016 Jun 25.

Effects of the cholesteryl ester transfer protein inhibitor, TA-8995, on cholesterol efflux capacity and high-density lipoprotein particle subclasses.

Author information

1
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
2
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Dezima Pharma BV, Naarden, The Netherlands. Electronic address: j.s.jansen@amc.uva.nl.
3
Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands.
4
Dezima Pharma BV, Naarden, The Netherlands; Department of Gastroenterology, Leiden University Medical Centre, Leiden, The Netherlands.
5
Vascular Strategies, Horsham, PA, USA.
6
Dezima Pharma BV, Naarden, The Netherlands; Xention Ltd, Cambridge, UK.
7
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, PA, USA.

Abstract

BACKGROUND:

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.

OBJECTIVE:

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

METHODS:

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).

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

CETP inhibitor; Cholesterol efflux capacity; HDL; Pre-Beta1 HDL; TA-8995

PMID:
27678430
DOI:
10.1016/j.jacl.2016.06.006
[Indexed for MEDLINE]

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