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依泽替米贝单药治疗或与他汀类药物联合治疗对高密度脂蛋白胆固醇和低密度脂蛋白胆固醇的影响：一项随机对照试验。

Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial.

机构信息

Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH 44195, USA.

出版信息

JAMA. 2011 Nov 16;306(19):2099-109. doi: 10.1001/jama.2011.1649.

DOI:10.1001/jama.2011.1649

PMID:22089718

Abstract

CONTEXT

Interest remains high in cholesteryl ester transfer protein (CETP) inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins.

OBJECTIVE

To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia.

DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe.

INTERVENTIONS

Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks.

MAIN OUTCOME MEASURES

The co-primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment.

RESULTS

The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of -0.7 mg/dL (-3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of -20.5 to -51.4 mg/dL (-13.6% to -35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of -67.1 to -75.8 mg/dL (-11.2% to -13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed.

CONCLUSIONS

Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT01105975.

摘要

背景

人们对胆固醇酯转移蛋白（CETP）抑制剂作为心脏保护剂的兴趣仍然很高。很少有研究记录 CETP 抑制剂与常用的他汀类药物联合使用的疗效和安全性。

目的

研究 evacetrapib 作为单药治疗以及与他汀类药物联合治疗血脂异常患者的生化效应、安全性和耐受性。

设计、地点和参与者：这是一项于 2010 年 4 月至 2011 年 1 月在美国和欧洲的社区和学术中心进行的随机对照试验，共纳入了 398 例低密度脂蛋白胆固醇（LDL-C）升高或高密度脂蛋白胆固醇（HDL-C）水平低的患者。

干预措施

在饮食引导期后，患者被随机分配接受安慰剂（n = 38）；evacetrapib 单药治疗，30 mg/d（n = 40）、100 mg/d（n = 39）或 500 mg/d（n = 42）；或他汀类药物治疗（n = 239）（辛伐他汀，40 mg/d；阿托伐他汀，20 mg/d；或瑞舒伐他汀，10 mg/d）联合或不联合 evacetrapib，100 mg/d，治疗 12 周。

主要终点

主要终点是治疗 12 周后 HDL-C 和 LDL-C 与基线相比的百分比变化。

结果

平均基线 HDL-C 水平为 55.1（SD，15.3）mg/dL，平均基线 LDL-C 水平为 144.3（SD，26.6）mg/dL。作为单药治疗，evacetrapib 使 HDL-C 分别增加 30.0 至 66.0 mg/dL（53.6%至 128.8%），与安慰剂相比降低 0.7 mg/dL（-3.0%；所有与安慰剂相比的 P 值均<.001），与安慰剂相比 LDL-C 降低 20.5 至 51.4 mg/dL（-13.6%至-35.9%）。与安慰剂相比，所有与安慰剂相比的 P 值均<.001）。与他汀类药物联合治疗时，evacetrapib，100 mg/d，使 HDL-C 分别增加 42.1 至 50.5 mg/dL（78.5%至 88.5%；所有与他汀类药物单药治疗相比的 P 值均<.001）和 LDL-C 降低 67.1 至 75.8 mg/dL（-11.2%至-13.9%；所有与他汀类药物单药治疗相比的 P 值均<.001）。与他汀类药物单药治疗相比，他汀类药物与 evacetrapib 的联合治疗导致 LDL-C 降低更多（P<.001），但 HDL-C 增加无差异（P=.39）。尽管该研究的效力不足，但未观察到不良反应。