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bococizumab降脂效果的变异性和抗药抗体的产生
Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab


Paul M Ridker ... 心脑血管疾病 • 2017.04.20
相关阅读
• LDL究竟应降到多低 • 通过抑制PCSK9减少心血管事件 • 高危患者使用bococizumab的心血管疗效和安全性 • 抗药抗体生成是否为PCSK9治疗中面临的问题

新型降脂药PCSK9抑制剂bococizumab为何失败

 

陈晨,郭小梅*

华中科技大学附属同济医院心血管内科

*通讯作者

 

低密度脂蛋白胆固醇(LDL-C)升高是动脉粥样硬化(AS)最重要的危险因素,众多大规模临床试验均证实,应用他汀类药物进行一级预防或二级预防可以显著降低动脉粥样硬化性心血管疾病(ASCVD)事件1-4。为进一步强化降低LDL-C和防控ASCVD,新一代降脂药物前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂应运而生。PCSK9抑制剂是一类新型强效降胆固醇药物,通过减少PCSK9调控的LDL受体降解,增加肝细胞LDL受体水平,进而显著降低LDL-C水平5

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摘要


背景

bococizumab,一种抗前蛋白转化酶枯草溶菌素9(PCSK9)人源化单克隆抗体,可降低低密度脂蛋白(LDL)胆固醇水平。然而,这一效果的变异性和持久性还不确定。

 

方法

我们进行了6项平行、多国的降脂试验,纳入了4,300例高脂血症患者,这些患者被随机分配接受每2周一次皮下注射bococizumab 150 mg或安慰剂,并且随访最长12个月;96%的患者入组时正在接受他汀治疗。我们评估了这些患者血脂随时间的变化,根据治疗期间是否检测到抗药抗体进行分层。

 

结果

12周时,与接受安慰剂的患者LDL胆固醇升高1.0%相比,接受bococizumab的患者LDL胆固醇水平相对于基线降低了54.2%(组间绝对差异,-55.2个百分点)。总胆固醇、非高密度脂蛋白胆固醇、载脂蛋白B和脂蛋白(a)也存在组间显著差异(全部比较的P<0.001)。然而,有相当一部分接受bococizumab的患者产生高滴度的抗药抗体,这明显减小了LDL胆固醇水平降低的幅度并缩短了持久性。另外,在没有抗药抗体的患者中,LDL胆固醇水平的降幅在12周和52周都有较大变异性。发生主要心血管事件的患者在bococizumab组有57例(2.5%),安慰剂组有55例(2.7%)(风险比,0.96;95%置信区间[CI],0.66~1.39;P=0.83)。接受bococizumab的患者中最常见的不良事件是注射部位反应(12.7/100人年)。

 

结论

在6项评价bococizumab的多国试验中,抗药抗体出现在一大部分患者体内,并且显著减小了LDL胆固醇水平的降幅。在没有产生抗药抗体的患者中,我们也观察到胆固醇水平的降幅有较大变异性(由辉瑞公司[Pfizer]资助;SPIRE在ClinicalTrials.gov注册号为NCT01968954、NCT01968967、NCT01968980、NCT02100514、NCT02135029和NCT02458287)。





作者信息

Paul M Ridker, M.D., Jean-Claude Tardif, M.D., Pierre Amarenco, M.D., William Duggan, Ph.D., Robert J. Glynn, Sc.D., J. Wouter Jukema, M.D., John J.P. Kastelein, M.D., Albert M. Kim, M.D., Ph.D., Wolfgang Koenig, M.D., Steven Nissen, M.D., James Revkin, M.D., Lynda M. Rose, M.S., Raul D. Santos, M.D., Ph.D., Pamela F. Schwartz, Ph.D., Charles L. Shear, Dr.P.H., and Carla Yunis, M.D., for the SPIRE Investigators*
From Brigham and Women’s Hospital, Harvard Medical School, Boston (P.M.R., R.J.G., L.M.R.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Pierre et Marie Curie University, Paris (P.A.); Pfizer, New York (W.D., A.M.K., J.R., P.F.S., C.L.S., C.Y.); Leiden University Medical Center, Leiden (J.W.J.), and Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.) — both in the Netherlands; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Center for Cardiovascular Research), Munich Heart Alliance, Munich, Germany (W.K.); Cleveland Clinic Foundation, Cleveland (S.N.); and the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital, São Paulo (R.D.S.). Address reprint requests to Dr. Ridker at the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave., Boston, MA 02215, or at pridker@partners.org; or to Dr. Tardif at the Montreal Heart Institute, 5000 Belanger St., Montreal, QC H1T 1C8, Canada, or at jean-claude.tardif@icm-mhi.org. A complete list of the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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