Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Dezima Pharma BV, Naarden, The Netherlands.
J Clin Lipidol. 2016 Sep-Oct;10(5):1137-1144.e3. doi: 10.1016/j.jacl.2016.06.006. Epub 2016 Jun 25.
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.
TA-8995 是一种强效的胆固醇酯转移蛋白（CETP）抑制剂，对脂质和脂蛋白有有益的影响。TA-8995 对胆固醇外排能力（CEC）的影响，CEC 是高密度脂蛋白（HDL）功能的一个衡量标准，以及 HDL 亚颗粒分布的影响在很大程度上尚不清楚。
评估 CETP 抑制剂 TA-8995 对 ABCA1 驱动和非-ABCA1 驱动的 CEC 以及对 HDL 颗粒分布的影响。
在 187 名轻度血脂异常患者中，使用 J774 细胞测量总、非-ABCA1 和 ABCA1 特异性 CEC，使用二维凝胶电泳测量 HDL 亚类分布，这些患者被随机分配至安慰剂、1mg、5mg、10mg TA-8995 或 10mg TA-8995 联合 10mg 瑞舒伐他汀治疗 12 周（NCT01970215）。
与安慰剂相比，随机接受 10mg TA-8995 治疗的患者的总、非-ABCA1 和 ABCA1 特异性 CEC 分别增加了 38%、72%和 28%，剂量依赖性增加。ABCA1 驱动胆固醇外排的主要受体 PreBeta-1 HDL 增加了 36%。这种 PreBeta-1 HDL 的增加与总 CEC 和 ABCA1 驱动的 CEC 增加显著相关，而高密度脂蛋白胆固醇（HDL-C）的增加则没有。
TA-8995 剂量依赖性地不仅增加了总 CEC 和非-ABCA1 特异性 CEC，而且还增加了 ABCA1 特异性 CEC 和 PreBeta-1 HDL 颗粒水平。这些发现表明，TA-8995 不仅增加了 HDL-C 水平，而且还促进了 HDL 颗粒的功能特性。这种 CETP 抑制剂驱动的 PreBeta-1 HDL 增加是 ABCA1 和总 CEC 增加的一个重要预测因素，独立于 HDL-C 增加。这些 HDL 颗粒组成和功能的变化是否对心血管结局有有益的影响，需要在心血管结局试验中进行正式检验。
