Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Curr Pharm Des. 2013;19(17):3143-9. doi: 10.2174/1381612811319170022.
There is a strong need to reduce the risk of cardiovascular disease (CVD) beyond the use of statins that lower low-density lipoprotein cholesterol (LDL-C). The inverse relationship of high-density lipoprotein cholesterol (HDL-C) with cardiovascular disease suggests HDL-C raising therapy as a novel target. This review discusses the role of HDL-C in atherogenesis as well as the promise of cholesteryl ester transfer protein (CETP) inhibition in CVD prevention. While genetic studies show conflicting results on correlations between HDL-C and CVD, experimental studies have yielded sufficient encouraging data to proceed with the development of HDL-C raising strategies. CETP inhibition has been shown to successfully increase HDL-C levels in man. However, the first CETP inhibitor tested in phase III trials increased mortality possibly due to torcetrapib-specific vasopressor effects. More recently, dalcetrapib did not show an effect on CVD outcome while raising HDL-C by 30%, thereby refuting the HDL-C hypothesis. Anacetrapib and evacetrapib are currently tested in phase III clinical trials and have not shown adverse effects thus far. Both compounds not only increase HDL-C by 129-151%, they also decrease LDL-C (36-41%) and anacetrapib lowers Lp(a) (17%). Combined, these effects are anticipated to decrease CVD risk and the results will be revealed in 2017.
需要降低心血管疾病（CVD）风险，超越降低低密度脂蛋白胆固醇（LDL-C）的他汀类药物的使用。高密度脂蛋白胆固醇（HDL-C）与心血管疾病呈负相关，提示 HDL-C 升高治疗作为一种新的靶点。这篇综述讨论了 HDL-C 在动脉粥样硬化形成中的作用，以及胆固醇酯转移蛋白（CETP）抑制在 CVD 预防中的作用。虽然遗传研究显示 HDL-C 与 CVD 之间的相关性存在相互矛盾的结果，但实验研究已经产生了足够令人鼓舞的数据，可以继续开发升高 HDL-C 的策略。CETP 抑制已被证明能成功地增加人类的 HDL-C 水平。然而，在 III 期临床试验中测试的第一个 CETP 抑制剂增加了死亡率，可能是由于 torcetrapib 特有的血管加压作用。最近，dalcetrapib 升高 HDL-C 30%，但并未显示对 CVD 结局有影响，从而反驳了 HDL-C 假说。anacetrapib 和 evacetrapib 目前正在 III 期临床试验中进行测试，迄今为止尚未显示出不良反应。这两种化合物不仅将 HDL-C 升高 129-151%，还降低 LDL-C（36-41%），anacetrapib 降低 Lp(a)（17%）。联合这些作用有望降低 CVD 风险，结果将于 2017 年公布。
