The Heart Research Institute, Sydney, New South Wales, 2042, Australia.
J Lipid Res. 2012 Sep;53(9):1755-66. doi: 10.1194/jlr.R024075. Epub 2012 May 22.
Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib.
人和兔血浆中含有一种胆固醇酯转移蛋白（CETP），可促进胆固醇酯从高密度脂蛋白（HDL）向其他血浆脂蛋白部分的净质量转移。如预测的那样，CETP 在人和兔中的抑制作用增加了潜在保护性 HDL 部分中胆固醇的浓度，同时降低了潜在促动脉粥样硬化的非 HDL 部分中的胆固醇浓度。CETP 在兔中的抑制作用也抑制了饮食诱导的动脉粥样硬化的发展。然而，CETP 抑制剂 torcetrapib 在人类中的使用并没有减少三项成像试验中的动脉粥样硬化斑块，并且在一项大型临床结局试验中导致了过多的死亡和心血管事件。torcetrapib 造成的伤害的确切解释尚不清楚，但可能与抑制 CETP 无关的已记录的潜在有害影响有关。最近，一项使用弱 CETP 抑制剂 dalcetrapib 的试验因无效而提前终止，dalcetrapib 升高 HDL 水平的效果不如 torcetrapib，并且不会降低非 HDL 脂蛋白水平。在该试验中没有证据表明 dalcetrapib 造成了伤害。尽管存在这些挫折，但 CETP 抑制剂在人类中具有抗动脉粥样硬化作用的假设仍在 anacetrapib 和 evacetrapib 的研究中进行测试，这两种 CETP 抑制剂比 dalcetrapib 强得多，并且没有 torcetrapib 的脱靶不良影响。
