University of Milano, Department of Pharmacological Sciences, Milano, Italy.
Expert Opin Investig Drugs. 2011 Nov;20(11):1543-54. doi: 10.1517/13543784.2011.614946. Epub 2011 Oct 1.
Reverse cholesterol transport (RCT) is a function of high-density lipoproteins (HDL) in humans and higher species. It is enabled by the cholesteryl ester transfer protein (CETP), a high molecular weight protein exchanging cholesteryl esters in HDL for triglycerides in very low-density lipoproteins (VLDL). Inhibition of CETP may provide a useful strategy to raise HDL, the protective lipoprotein fraction in plasma.
Evaluation based on clinical and experimental findings of the three drugs developed or in advanced development for CETP inhibition.
Inhibition of CETP, both inherited and drug induced, at times leads to dramatic elevations of HDL-cholesterol (HDL-C) levels. Epidemiological data presently available do not, however, provide convincing evidence that reduced CETP levels or activity due to genetic factors and associated with HDL-C elevations, reduce cardiovascular risk. Indeed, the opposite may be true in some instances. All the three CETP inhibitors were the object of experimental and clinical evaluation. Large clinical trials with torcetrapib led to very negative findings, that is, raised cardiovascular morbidity and mortality in addition to raised risk of cancer and sepsis. Off-target effects of the drug, such as aldosterone retention and raised blood pressure, were believed to provide an explanation for these negative findings. The two newer agents, dalcetrapib and anacetrapib, do not exert off-target effects. The two drugs differ because anacetrapib has a more dramatic effect on HDL cholesterolemia (+139%) versus more moderate effects of dalcetrapib (+20-30%). Anacetrapib, however, may impair formation of pre-β HDL, that is, the primary particles in the process of cholesterol removal. The initial large trial with anacetrapib (DEFINE study) in coronary patients on statin treatment, appeared to confirm a remarkable HDL raising property, together with some reduction in vascular end points, in particular coronary procedures. The issue of other potentially harmful effects of CETP inhibition (sepsis and others) has yet to be clarified. Large clinical end-point trials, however, will be necessary to provide convincing evidence that, in addition to raising HDL-C, CETP inhibitors provide a valid additional treatment, for example, to statins in patients with coronary heart disease (CHD) or at high risk of CHD.
在人类和高等生物中，胆固醇逆向转运（RCT）是高密度脂蛋白（HDL）的功能。它由胆固醇酯转移蛋白（CETP）实现，CETP 是一种高分子量蛋白，可将 HDL 中的胆固醇酯交换为极低密度脂蛋白（VLDL）中的甘油三酯。抑制 CETP 可能是提高 HDL（血浆中保护性脂蛋白）的有用策略。
基于三种开发或处于开发后期的 CETP 抑制剂的临床和实验研究结果进行评估。
CETP 的抑制，无论是遗传性的还是药物诱导的，有时会导致 HDL-胆固醇（HDL-C）水平的显著升高。然而，目前现有的流行病学数据并未提供令人信服的证据表明，由于遗传因素导致的 CETP 水平或活性降低与 HDL-C 升高相关，可降低心血管风险。事实上，在某些情况下可能恰恰相反。所有三种 CETP 抑制剂都经过了实验和临床评估。托彻普比的大型临床试验得出了非常负面的结果，即心血管发病率和死亡率升高，以及癌症和败血症风险升高。该药物的脱靶效应，如醛固酮潴留和血压升高，被认为是这些负面结果的解释。两种较新的药物，达塞曲匹和阿昔单抗，没有脱靶效应。这两种药物的不同之处在于，阿昔单抗对 HDL 胆固醇的作用更为显著（增加 139%），而达塞曲匹的作用则更为温和（增加 20-30%）。然而，阿昔单抗可能会损害前-β HDL 的形成，即胆固醇清除过程中的主要颗粒。在接受他汀类药物治疗的冠心病患者中进行的阿昔单抗（DEFINE 研究）初始大型试验似乎证实了其显著的升高 HDL 特性，同时在血管终点方面也有一定程度的降低，特别是在冠状动脉介入治疗方面。CETP 抑制的其他潜在有害影响（败血症等）的问题仍有待澄清。然而，需要进行大型临床终点试验，以提供令人信服的证据，证明除了升高 HDL-C 外，CETP 抑制剂还为冠心病（CHD）或有 CHD 高风险的患者提供了一种有效的附加治疗方法，例如他汀类药物。
