Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, USA.
Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Connecticut, USA.
Pharmacotherapy. 2021 Dec;41(12):1009-1023. doi: 10.1002/phar.2635. Epub 2021 Oct 30.
The advent of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) ushered in a new era of dyslipidemia pharmacotherapy. The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran-a small interfering RNA-based agent targeting PCSK9-reported similar lipid-lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta-analysis (random-effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low-density lipoprotein cholesterol (LDL-C) was observed across all agents (-51% [95% confidence interval {CI}: -61%, -41%]). Despite the impressive reduction in LDL-C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73-0.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74-0.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26-3.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9-targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow-up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum.
针对前蛋白转化酶枯草溶菌素/ kexin 9 型（PCSK9）的单克隆抗体的出现开创了血脂异常治疗的新纪元。美国食品和药物管理局（FDA）批准的前两种针对 PCSK9 的抗体（依洛尤单抗，阿利罗库单抗）可显著且持续降低致动脉粥样硬化性脂质，并降低动脉粥样硬化性心血管疾病（ASCVD）事件的风险。最近，靶向 PCSK9 的小干扰 RNA 药物 inclisiran 的 3 期试验报告了类似的降脂作用和 ASCVD 风险降低的初步证据，尽管在心血管结局方面，获益程度仍存在重大问题。我们对靶向 PCSK9 的药物降低血脂、发生 ASCVD 事件和安全性的现有数据进行了系统评价和荟萃分析（随机效应模型）。所有药物均显著且一致地降低了低密度脂蛋白胆固醇（LDL-C）（-51%[95%置信区间（CI）：-61%，-41%]）。尽管 LDL-C 显著降低，但对死亡率、心血管死亡、心肌梗死（MI）和中风的个体影响仍无统计学意义。然而，在 MI、中风和心血管死亡的复合结局[相对风险（RR）（95%CI）：0.80（0.73-0.87）]以及 MI、中风、不稳定型心绞痛（需要血运重建）和心血管死亡[RR（95%CI）：0.85（0.74-0.97）]方面观察到一致的降低。在安全性结局方面，严重不良事件、新发糖尿病、神经认知障碍或肌痛无显著差异。同时，与安慰剂相比，接受这些药物治疗的患者注射部位反应更为频繁[RR 2.11（95%CI）：1.26-3.54]。这些发现表明靶向 PCSK9 的药物具有良好的血脂变化作用，且严重不良事件风险低。虽然有令人信服的证据表明 PCSK9 靶向药物可降低某些心血管结局的风险，但可能需要进行更大规模、随访时间更长的研究，以充分描述心血管谱中获益的程度。
