Yadav K, Sharma M, Ferdinand K C
Tulane Heart and Vascular Institute, Tulane University School of Medicine, 1430 Tulane Avenue, #8548, New Orleans, LA, 70112, USA.
Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA.
Nutr Metab Cardiovasc Dis. 2016 Oct;26(10):853-62. doi: 10.1016/j.numecd.2016.05.006. Epub 2016 May 30.
Our comprehensive review highlights the drug development and pharmacogenomics leading to the recent approval of PCSK9 inhibitors. We also review the anticipated future advances into the uses of PCSK9 inhibition.
Despite the present advances in pharmacotherapy, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Low density lipoprotein-cholesterol (LDL-C) lowering is the primary target for ASCVD risk reduction, showing demonstrable benefits in mortality. However, 70% of events occur even in the presence of statins. This residual risk may be approached with additional LDL-C reduction. Statin intolerance is a common clinical concern affecting adherence and the benefit with statins. There is also significant variation of individual lipid-lowering. Following rapid development, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have progressed from genetic observations, to mechanistic studies, to closer realization of the goal of CVD risk reduction. This review discusses the science behind PCSK9 inhibition, evidence of trials involving efficacy and safety, and reflections of its present and future role in clinical care, especially in high-risk patients with ASCVD, persons with suboptimal responses to statins and familial hyperlipidemia. Monoclonal antibodies have demonstrated LDL-C lowering of up to 57% as monotherapy and up to 73% when added to statins. Statins have limited efficacy in reduction of LDL-C due to an increased number of LDL-receptors. Elevated lipoprotein (a) levels may also be significantly lowered by PCSK9i. The journey from discovery to PSCK9 target validation took less than five years, and development and approval of therapeutic modalities for PCSK9 inhibitors happened over the next seven. This review highlights the drug development and pharmacogenomics leading to the recent approval of two agents, alirocumab and evolocumab, with a third bococizumab, and other novel approaches to the pathway pending.
We searched MEDLINE database via Pubmed for reviews, research publications and relevant trials available on PCSK9 inhibition.
Despite decades of medical advances, ASCVD remains one of the major causes of morbidity and mortality worldwide. Statin use has multiplied since the validation of LDL hypothesis, however, it is undeniable a more effective and well-tolerated agent is needed in significant number or patients. With the arrival of the era of unprecedented CV protection with PCSK9 inhibition, this exciting new therapy holds a pivotal promise as the future of lipid management. The data available already indicate safety, tolerability and superb efficacy of these agents, which are already changing contemporary cholesterol management. The rapid translation of innovative basic science research into drug development may lead to CV outcomes reduction and confirm that this pathway will become prominently utilized.
我们的全面综述重点介绍了促成前蛋白转化酶枯草溶菌素9（PCSK9）抑制剂近期获批的药物研发和药物基因组学情况。我们还回顾了PCSK9抑制作用未来预期的进展。
尽管目前药物治疗取得了进展，但动脉粥样硬化性心血管疾病（ASCVD）仍然是全球死亡的主要原因。降低低密度脂蛋白胆固醇（LDL-C）是降低ASCVD风险的主要目标，已证明对降低死亡率有益。然而，即使使用他汀类药物，仍有70%的事件发生。这种残余风险可通过进一步降低LDL-C来解决。他汀类药物不耐受是一个常见的临床问题，会影响依从性以及他汀类药物的疗效。个体降脂效果也存在显著差异。随着快速发展，PCSK9抑制剂已从基因观察发展到机制研究，更接近实现降低心血管疾病风险的目标。本综述讨论了PCSK9抑制作用背后的科学原理、涉及疗效和安全性的试验证据，以及其在临床护理中当前和未来作用的思考，特别是在高危ASCVD患者、对他汀类药物反应欠佳者和家族性高脂血症患者中。单克隆抗体作为单一疗法可使LDL-C降低高达57%，与他汀类药物联合使用时可降低高达73%。由于LDL受体数量增加，他汀类药物降低LDL-C的效果有限。PCSK9抑制剂还可显著降低脂蛋白（a）水平。从发现到PCSK9靶点验证不到五年时间，接下来的七年里PCSK9抑制剂的治疗方式得以研发和获批。本综述重点介绍了促成alirocumab和evolocumab这两种药物近期获批的药物研发和药物基因组学情况，还有第三种药物bococizumab以及该途径的其他新方法尚在等待审批。
我们通过PubMed在MEDLINE数据库中搜索了有关PCSK9抑制作用的综述、研究出版物和相关试验。
尽管医学进步了几十年，但ASCVD仍然是全球发病和死亡的主要原因之一。自LDL假说得到验证以来，他汀类药物的使用成倍增加，然而，不可否认的是，大量患者需要一种更有效且耐受性良好的药物。随着PCSK9抑制作用带来前所未有的心血管保护时代的到来，这种令人兴奋的新疗法作为脂质管理的未来具有关键的前景。现有数据已表明这些药物的安全性、耐受性和卓越疗效，它们已经在改变当代胆固醇管理。创新基础科学研究迅速转化为药物研发可能会降低心血管疾病结局，并证实该途径将得到广泛应用。
