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

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


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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • Adolescent
  • Adult
  • Aged
  • Anticholesteremic Agents / therapeutic use*
  • Cell Line
  • Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
  • Cholesterol Ester Transfer Proteins / metabolism
  • Cholesterol, HDL / analysis
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Double-Blind Method
  • Drug Therapy, Combination
  • Dyslipidemias / drug therapy*
  • Female
  • High-Density Lipoproteins, Pre-beta / analysis
  • Humans
  • Lipoproteins, HDL / analysis*
  • Lipoproteins, HDL / classification
  • Male
  • Middle Aged
  • Placebo Effect
  • Quinolines / therapeutic use*
  • Rosuvastatin Calcium / therapeutic use
  • Triglycerides / blood
  • Young Adult


  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Anticholesteremic Agents
  • Cholesterol Ester Transfer Proteins
  • Cholesterol, HDL
  • Cholesterol, LDL
  • High-Density Lipoproteins, Pre-beta
  • Lipoproteins, HDL
  • Quinolines
  • TA-8995
  • Triglycerides
  • Rosuvastatin Calcium

Associated data

  • ClinicalTrials.gov/NCT01970215