Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR; and.
Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland, OR.
J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.
Hypercholesterolemia is a leading cause of cardiovascular morbidity and mortality. Accordingly, efforts to lower apolipoprotein B-containing lipoproteins in plasma are the centerpiece of strategies for cardiovascular prevention and treatment in primary and secondary management. Despite the importance of this endeavor, many patients do not achieve appropriate low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) goals, even among those who have experienced atherosclerotic cardiovascular disease. The development of new LDL-C-lowering medications with alternative mechanisms of action will facilitate improved goal achievement in high-risk patients. Inclisiran is a novel small interfering RNA-based drug that is experimental in the United States and approved for clinical use in the European Union. It lowers LDL-C and other apolipoprotein B-containing lipoproteins by reducing production of proprotein convertase subtilisin/kexin Type 9 (PCSK9), a protein that normally contributes to LDL-receptor degradation, thereby increasing LDL-receptor density and recycling in hepatocytes. Although the lipid-lowering efficacy of inclisiran is comparable with results achieved with PCSK9-blocking monoclonal antibodies (alirocumab and evolocumab), there are several important differences between the 2 drug classes. First, inclisiran reduces levels of PCSK9 both intracellularly and extracellularly by blocking translation of and degrading PCSK9 messenger RNA. Second, the long biological half-life of inclisiran produces sustained LDL-C lowering with twice yearly dosing. Third, although PCSK9-blocking monoclonal antibodies drugs are proven to reduce atherosclerotic cardiovascular disease events, clinical outcomes trials with inclisiran are still in progress. In this article, we review the clinical development of inclisiran, its mechanism of action, lipid-lowering efficacy, safety and tolerability, and potential clinical role of this promising new agent.
高胆固醇血症是心血管发病率和死亡率的主要原因。因此，降低血浆载脂蛋白 B 脂蛋白是一级和二级管理中心血管预防和治疗策略的核心。尽管这项工作很重要，但许多患者，即使是那些已经患有动脉粥样硬化性心血管疾病的患者，也无法达到适当的低密度脂蛋白胆固醇（LDL-C）和非高密度脂蛋白胆固醇（非-HDL-C）目标。具有替代作用机制的新型 LDL-C 降低药物的开发将有助于高危患者更好地实现目标。Inclisiran 是一种新型的基于小干扰 RNA 的药物，在美国处于实验阶段，在欧盟获准用于临床使用。它通过降低前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）的产生来降低 LDL-C 和其他载脂蛋白 B 脂蛋白，PCSK9 是一种通常有助于 LDL 受体降解的蛋白质，从而增加肝细胞中 LDL 受体的密度和再循环。尽管 inclisiran 的降脂疗效与 PCSK9 阻断单克隆抗体（alirocumab 和 evolocumab）的结果相当，但这两种药物类别之间存在几个重要差异。首先，inclsiran 通过阻断 PCSK9 信使 RNA 的翻译和降解来同时在细胞内和细胞外降低 PCSK9 水平。其次，inclsiran 的长生物学半衰期可通过每年两次给药来持续降低 LDL-C。第三，尽管 PCSK9 阻断单克隆抗体药物已被证明可降低动脉粥样硬化性心血管疾病事件，但 inclisiran 的临床结局试验仍在进行中。在本文中，我们回顾了 inclisiran 的临床开发、作用机制、降脂疗效、安全性和耐受性以及这种有前途的新型药物的潜在临床作用。
