Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study
Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study
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DOI：
10.1016/j.ahj.2011.11.017
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发表时间：
2012-03-01
影响因子：
4.8
通讯作者：
Stein, Evan A.
中科院分区：
文献类型：
--
作者：
Ballantyne, Christie M.;Miller, Michael;Stein, Evan A.
背景胆固醇酯转移蛋白(CETP)参与高密度脂蛋白(HDLE)的重塑和脂类在高密度脂蛋白颗粒与其他脂蛋白之间的转移。流行病学研究表明，高密度脂蛋白-胆固醇(HDL-C)升高和CETP活性降低均可降低心血管风险，使抑制或调节CETP成为潜在的治疗靶点。这项研究分析了达西曲布与普伐他汀联合应用时对低或中等高密度脂蛋白胆固醇患者脂蛋白谱、CETP活性和细胞胆固醇流出的影响。方法采用双盲方法将患者随机分为安慰剂或达西曲布300、600或900 mg，每天一次，持续12周。所有患者同时接受普伐他汀治疗，以达到低密度脂蛋白胆固醇的目标。用核磁共振波谱和聚丙烯酰胺梯度凝胶电泳法分析脂蛋白谱。在聚乙二醇沉淀后，对高密度脂蛋白组分的组成进行了评估。结果达西曲布与普伐他汀联合应用可增加高密度脂蛋白胆固醇(HDLC)、载脂蛋白(Apo)A-I和A-II以及CETP质量，降低CETP活性。观察到大的高密度脂蛋白和低密度脂蛋白亚颗粒比例的相对增加。高密度脂蛋白的组成与酯化胆固醇、游离胆固醇、磷脂、载脂蛋白A-I和载脂蛋白E的相关性增加。结论达西曲布在600 mg与普伐他汀联合应用时，可使高密度脂蛋白水平升高，并改变脂蛋白组成、高密度脂蛋白组成和高密度脂蛋白功能，900 mg时变化不大。对血脂异常患者心血管事件的影响正在评估中。(《美国心脏杂志》2012；163：515-521。E3。)
Background Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C.Methods Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells.Results Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5'-triphosphate-binding cassette A1- and scavenger receptor type BI-mediated cholesterol efflux increased.Conclusions Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated. (Am Heart J 2012; 163: 515-521. e3.)