Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Connecticut, USA.
J Clin Pharmacol. 2022 Sep;62(9):1079-1085. doi: 10.1002/jcph.2045. Epub 2022 Apr 2.
Inclisiran increases the number of low-density lipoprotein surface receptors expressed on hepatocytes using small interfering RNA directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA. This novel mechanism can reduce low-density lipoprotein by ≈50%, like reductions achieved with high-intensity statins or PCSK9-inhibiting monoclonal antibodies. Inclisiran is indicated in the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, unable to achieve target LDL concentrations with diet and maximally tolerated statin therapy. It is more expensive than PCSK9-inhibiting monoclonal antibodies and still lacks clinical evidence for the expected reduction in atherosclerotic cardiovascular disease events when added to statin therapy. Although some patients experience injection-site reactions of mild or moderate severity, current evidence suggests a strong safety profile with total and serious adverse events approximating that of placebo. The dosing protocol of inclisiran offers its biggest clinical advantage over PCSK9-inhibiting monoclonal antibodies, being administered only every 6 months after initial baseline and 3-month doses rather than every second or fourth week. Unlike PCSK9-inhibiting monoclonal antibodies, inclisiran has not as yet been noted to induce neutralizing antidrug antibodies that can impact drug efficacy. Thus, inclisirin is a novel small interfering RNA molecule that provides further options in the management of hypercholesterolemia refractory to statins alone. However, cost and evidence considerations suggest it should not supplant adjunctive therapy with the PCSK9-inhibiting monoclonal antibodies, despite having an efficacy, safety, tolerability, and drug interaction profile superior to other antihypercholesterolemic options such as lomitapide, niacin, bile acid sequestrants, and bempedoic acid.
依洛西仑通过靶向针对前蛋白转化酶枯草溶菌素/糜蛋白酶 9（PCSK9）mRNA 的小干扰 RNA，增加肝细胞上表达的低密度脂蛋白（LDL）表面受体数量。这种新机制可使 LDL 降低约 50%，与高强度他汀类药物或 PCSK9 抑制性单克隆抗体的降低幅度相当。依洛西仑用于治疗杂合子家族性高胆固醇血症或有临床动脉粥样硬化性心血管疾病但不能通过饮食和最大耐受他汀类药物治疗达到 LDL 目标浓度的成人。它比 PCSK9 抑制性单克隆抗体更昂贵，并且在添加到他汀类药物治疗中时，其预期降低动脉粥样硬化性心血管疾病事件的临床证据仍然缺乏。虽然一些患者出现轻度或中度严重程度的注射部位反应，但目前的证据表明，其总体和严重不良事件的安全性状况良好，与安慰剂相当。依洛西仑的给药方案是其相对于 PCSK9 抑制性单克隆抗体的最大临床优势，在初始基线和 3 个月剂量后每 6 个月给药一次，而不是每两周或每四周给药一次。与 PCSK9 抑制性单克隆抗体不同，依洛西仑尚未被注意到诱导可能影响药物疗效的中和性抗药物抗体。因此，依洛西仑是一种新型的小干扰 RNA 分子，为他汀类药物单独治疗无效的高胆固醇血症的治疗提供了更多选择。然而，考虑到成本和证据，尽管其疗效、安全性、耐受性和药物相互作用谱优于洛美他派、烟酸、胆汁酸螯合剂和贝匹莫德酸等其他抗高胆固醇血症药物，但它不应替代 PCSK9 抑制性单克隆抗体的辅助治疗。
