Pharmacy Department, Jackson Memorial Hospital, Miami, FL, USA.
Ann Pharmacother. 2011 Jan;45(1):84-94. doi: 10.1345/aph.1P446. Epub 2011 Jan 4.
To evaluate the role of cholesteryl ester transfer protein (CETP) in the cholesterol transport system and review the pharmacology, pharmacokinetic properties, efficacy, and adverse effects of the CETP inhibitors, anacetrapib and dalcetrapib, for the treatment of dyslipidemia.
A literature search was conducted in Ovid/MEDLINE (1950 to week 4 December 2010), PubMed/MEDLINE (up to December 2010), EMBASE (2000 to December 2010), and International Pharmaceutical Abstracts (1970 to December 2010) using the MeSH terms and key words anacetrapib, MK 0859, dalcetrapib, and JTT 705. The search was limited to publications in English.
Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of anacetrapib and dalcetrapib for the treatment of dyslipidemia were included. Clinical reviews evaluating the characterization of CETP and its inhibition as a mechanism for reducing cardiovascular risk were also included.
Anacetrapib and dalcetrapib represent a novel treatment option for patients who have dyslipidemia and low levels of high-density lipoprotein cholesterol (HDL-C). Anacetrapib and dalcetrapib increase HDL-C by inhibiting CETP-mediated transfer of cholesteryl ester and triglyceride. Studies evaluating the safety and efficacy of anacetrapib and dalcetrapib concluded that both agents safely and effectively augment HDL-C. Their mechanism of action, potential for significant raising of HDL-C, once-daily dosing regimen, and favorable lipid-altering effects when added to hydroxymethylglutaryl-CoA reductase inhibitors are key elements. Anacetrapib and dalcetrapib are well tolerated, with mild gastrointestinal complaints reported more than with placebo. Although another CETP inhibitor, torcetrapib, was withdrawn from clinical development secondary to increased morbidity and mortality, neither anacetrapib nor dalcetrapib has demonstrated the adverse off-target effects portrayed with torcetrapib.
Inhibition of CETP by anacetrapib and dalcetrapib represents an encouraging development in the management of dyslipidemia, particularly in patients with low HDL-C levels. Results of future trials are much anticipated, as these will clarify the role of anacetrapib and dalcetrapib in reduction of cardiovascular disease.
评估胆固醇酯转移蛋白（CETP）在胆固醇转运系统中的作用，并综述CETP 抑制剂——依泽替米贝和达塞曲匹——治疗血脂异常的药理学、药代动力学特性、疗效和不良反应。
在 Ovid/MEDLINE（1950 年至 2010 年 12 月第 4 周）、PubMed/MEDLINE（截至 2010 年 12 月）、EMBASE（2000 年至 2010 年 12 月）和国际药学文摘（1970 年至 2010 年 12 月）中使用 MeSH 术语和关键词依泽替米贝、MK0859、达塞曲匹和 JTT705 进行文献检索。检索仅限于英语出版物。
纳入评估依泽替米贝和达塞曲匹治疗血脂异常的药理学、药代动力学、安全性和疗效的研究。还纳入了评估 CETP 及其抑制作用作为降低心血管风险机制的临床综述。
依泽替米贝和达塞曲匹为患有血脂异常和低水平高密度脂蛋白胆固醇（HDL-C）的患者提供了一种新的治疗选择。依泽替米贝和达塞曲匹通过抑制 CETP 介导的胆固醇酯和甘油三酯转移来增加 HDL-C。评估依泽替米贝和达塞曲匹安全性和疗效的研究得出结论，这两种药物均安全有效地增加了 HDL-C。其作用机制、显著提高 HDL-C 的潜力、每日一次的给药方案以及与羟甲基戊二酰基辅酶 A 还原酶抑制剂联合使用时的有利脂质改变作用是关键因素。依泽替米贝和达塞曲匹耐受性良好，与安慰剂相比，报告的胃肠道轻度不适更多。虽然另一种 CETP 抑制剂——托彻普替泊因增加发病率和死亡率而从临床开发中撤出，但依泽替米贝和达塞曲匹均未表现出与托彻普替泊因相关的不良脱靶作用。
依泽替米贝和达塞曲匹对 CETP 的抑制作用代表了血脂异常管理方面令人鼓舞的进展，尤其是在 HDL-C 水平较低的患者中。未来试验的结果备受期待，因为这些结果将阐明依泽替米贝和达塞曲匹在降低心血管疾病方面的作用。
