Department of Cardiology, Imperial College Healthcare NHS Trust, London, UK.
Department of Primary Care and Public Health, Imperial College, London, UK.
Heart. 2017 Nov;103(21):1670-1679. doi: 10.1136/heartjnl-2016-310844. Epub 2017 Jun 8.
Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo. The development programme for a third humanised monoclonal antibody, bococizumab, was terminated early due to the presence of neutralising antibodies reducing its efficacy over time. Results from the first cardiovascular outcomes trial, FOURIER, have demonstrated significant reductions in cardiovascular events in a population with stable cardiovascular disease over a 2-year period. The ODYSSEY OUTCOMES trial comparing alirocumab to placebo is expected to report in 2018 and provide cardiovascular outcome data in a post acute coronary syndrome population. Monoclonal antibodies have an injection burden of 12-26 injections per year. An alternative approach to reducing PCSK9 is to inhibit translation of the messenger RNA for PCSK9. The phase II ORION-1 study using inclisiran, a small interference RNA to PCSK9, suggested that two doses of inclisiran produced time averaged reductions in LDL cholesterol of 50% over 9 months. The ORION-4 cardiovascular outcome trial will assess the cardiovascular benefits of two injections per year using inclisiran. With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies.
在这篇综述中，我们探讨了前蛋白转化酶枯草溶菌素/糜蛋白酶 9（PCSK9）抑制剂在预防动脉粥样硬化性心血管疾病方面的潜力是否与所产生的兴奋相符。目前，有两种针对 PCSK9 的全人源单克隆抗体已在美国和欧盟获得临床应用许可：依洛尤单抗（evolocumab）和阿利西尤单抗（alirocumab）。这两种药物在多种人群中可使 LDL 胆固醇降低 50%以上，且总体安全性与安慰剂相当。第三种人源化单克隆抗体——波西珠单抗（bococizumab）的开发项目因中和抗体的存在而提前终止，这些抗体随着时间的推移降低了其疗效。首个心血管结局试验 FOURIER 的结果表明，在 2 年内，稳定型心血管疾病患者的心血管事件显著减少。预计 2018 年将报告比较阿利西尤单抗与安慰剂的 ODYSSEY OUTCOMES 试验结果，为急性冠状动脉综合征患者提供心血管结局数据。单克隆抗体每年的注射负担为 12-26 次。降低 PCSK9 的另一种方法是抑制 PCSK9 信使 RNA 的翻译。使用小干扰 RNA 抑制 PCSK9 的 ORION-1 Ⅱ期研究表明，inclisiran（一种 PCSK9 的小干扰 RNA）的两剂治疗可在 9 个月内使 LDL 胆固醇平均降低 50%。ORION-4 心血管结局试验将评估每年使用inclisiran 进行两次注射的心血管获益。随着更多的试验结果公布，考虑到这些治疗方法的药物成本更高，因此患者的选择应更加谨慎。
