Although the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and development of therapeutic antagonists represent a major triumph of modern clinical medicine, efforts to implement PCSK9 inhibitors (PCSK9i) in patient care have been sobering. This practical guide examines the barriers and opportunities for the successful application of pharmacological inhibition of PCSK9 in clinical practice through introduction of a new model of care delivery—the PCSK9i clinic. Historically, the foundation of primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has consisted of therapeutic lifestyle changes in combination with pharmacological therapy focused on lipid modulation, specifically low-density lipoprotein cholesterol (LDL-C) lowering.1 In 2015, the Food and Drug Administration (FDA) approved a new class of cholesterol-lowering medications, PCSK9i, to great anticipation. The seminal discovery in 2003 by Abifadel et al2 linked gain-of-function mutations in the PCSK9 gene with autosomal dominant hypercholesterolemia. This finding uncovered PCSK9 as a key player in cholesterol homeostasis, a circulating protein with the strongest influence on plasma LDL-C concentration.3 PCSK9 directly interacts with the low-density lipoprotein receptor and enhances its degradation by targeting it for destruction by the lysosome and halting its efficient recycling. Because PCSK9 causes degradation of the low-density lipoprotein receptor, inhibiting its action prolongs the lifespan of the low-density lipoprotein receptor and leads to profound reductions in plasma LDL-C levels. The ultimate culmination of this work was the regulatory approval of 2 monoclonal antibody inhibitors of PCSK9 (alirocumab and evolocumab). More recently, the randomized, placebo-controlled trial, FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), demonstrated improved ASCVD outcomes when evolocumab was added to background treatment with a statin. The combination of statin plus evolocumab resulted in a significant absolute and relative risk reduction in both the primary composite end point (cardiovascular death, myocardial infarction, stroke, and hospitalization …

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PCSK9抑制剂在实践中的应用

尽管前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）的发现和治疗性拮抗剂的开发代表了现代临床医学的主要成就，但是在患者护理中实施PCSK9抑制剂（PCSK9i）的努力却令人清醒。本实用指南通过引入新的护理提供模式PCSK9i诊所，探讨了PCSK9药理抑制在临床实践中成功应用的障碍和机遇。从历史上看，一级预防和二级预防动脉粥样硬化性心血管疾病（ASCVD）的基础是治疗性生活方式的改变与侧重于脂质调节（尤其是降低低密度脂蛋白胆固醇（LDL-C））的药物治疗相结合。12015年，美国食品药品监督管理局（FDA）批准了一种新型的降胆固醇药物PCSK9i。Abifadel等人在2003年所做的开创性发现将PCSK9基因的功能获得性突变与常染色体显性遗传性高胆固醇血症联系在一起。这一发现揭示了PCSK9是胆固醇稳态的关键参与者，胆固醇是一种动态循环蛋白，对血浆LDL-C浓度的影响最大。3PCSK9与低密度脂蛋白受体直接相互作用，并通过靶向溶酶体破坏而促进其降解。停止有效的回收利用。由于PCSK9引起低密度脂蛋白受体的降解，因此抑制其作用可延长低密度脂蛋白受体的寿命，并导致血浆LDL-C水平大幅降低。这项工作的最终高潮是2种PCSK9单克隆抗体抑制剂（alirocumab和evolocumab）的监管批准。最近，随机，安慰剂对照试验FOURIER（对风险升高的受试者进行PCSK9抑制的进一步心血管预后研究）表明，将依维洛沙单抗联合他汀类药物作为背景治疗后，ASCVD结局得到改善。他汀类药物与依伏洛单抗的组合可显着降低主要复合终点（心血管死亡，心肌梗塞，中风和住院……）的绝对和相对风险。FOURIER（对风险升高的受试者进行PCSK9抑制的进一步心血管结果研究）显示，将依维洛沙单抗联合他汀类药物作为背景治疗后，ASCVD的结局得到改善。他汀类药物与依伏洛单抗的组合可显着降低主要复合终点（心血管死亡，心肌梗塞，中风和住院……）的绝对和相对风险。FOURIER（对风险升高的受试者进行PCSK9抑制的进一步心血管结果研究）显示，将依维洛沙单抗联合他汀类药物作为背景治疗后，ASCVD的结局得到改善。他汀类药物与依伏洛单抗的组合可显着降低主要复合终点（心血管死亡，心肌梗塞，中风和住院……）的绝对和相对风险。