Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update
Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update
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DOI：
10.2174/157488412800228884
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发表时间：
2012-01-01
影响因子：
3.2
通讯作者：
Ghosh, Samhati Mondal
中科院分区：
文献类型：
--
作者：
Ghosh, Raktim Kumar;Ghosh, Samhati Mondal
简介：HDL-C和心血管疾病风险之间的负相关关系表明，增加HDL-C可能会降低疾病风险。胆固醇逆向转运被认为是HDL-C发挥其抗动脉粥样硬化作用的主要机制。RCT的一个关键调节因子是胆固醇酯转移蛋白（CETP）。涵盖领域：抑制CETP已被确定为大幅增加HDL-C水平的可能策略，CETP抑制剂已在初步临床试验中证明了临床疗效。当torcetrapib（首个CETP抑制剂）的主要III期试验由于心血管和非心血管死亡率增加而提前终止时，这种新型药物的开发遭受了重大挫折。随后的动物和临床研究表明，torcetrapib报告的心血管死亡率增加是分子特异性的，与其CETP抑制作用无关。其他两个CETP抑制剂，即dalcetrapib和anacetrapib耐受性良好，在I期和II期临床试验，不像torcetrapib，不影响血压和aldosterone levels.In这篇综述文章中，作者讨论了torcetrapib失败的教训和重要的临床前和临床CETP抑制剂的发展及其在管理高脂血症和心血管风险降低的作用。
Introduction: The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP).Areas Covered: Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels.In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.