1 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
2 Department of Hypertension, Medical University of Lodz, Poland.
Eur J Prev Cardiol. 2019 Jun;26(9):930-949. doi: 10.1177/2047487319831500. Epub 2019 Feb 18.
Regulation of pro-protein convertase subtilisin/kexin type 9 (PCSK9) by drugs has led to the development of a still small number of agents with powerful activity on low-density lipoprotein cholesterol levels, associated with a significant reduction of cardiovascular events in patients in secondary prevention. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) studies, with the two available PCSK9 antagonists, i.e. evolocumab and alirocumab, both reported a 15% reduction in major adverse cardiovascular events. Regulation of PCSK9 expression is dependent upon a number of factors, partly genetic and partly associated to a complex transcriptional system, mainly controlled by sterol regulatory element binding proteins. PCSK9 is further regulated by concomitant drug treatments, particularly by statins, enhancing PCSK9 secretion but decreasing its stimulatory phosphorylated form (S688). These complex transcriptional mechanisms lead to variable circulating levels making clinical measurements of plasma PCSK9 for cardiovascular risk assessment a debated matter. Determination of total PCSK9 levels may provide a diagnostic tool for explaining an apparent resistance to PCSK9 inhibitors, thus indicating the need for other approaches. Newer agents targeting PCSK9 are in clinical development with a major interest in those with a longer duration of action, e.g. RNA silencing, allowing optimal patient compliance. Interest has been expanded to areas not only limited to low-density lipoprotein cholesterol reduction but also investigating other non-lipid pathways raising cardiovascular risk, in particular inflammation associated to raised high-sensitivity C-reactive protein levels, not significantly affected by the present PCSK9 antagonists.
蛋白水解酶枯草溶菌素 9（PCSK9）的调节药物已开发出少数几种对低密度脂蛋白胆固醇水平具有强大活性的药物，这些药物与二级预防中患者心血管事件的显著减少相关。进一步心血管结局研究用 PCSK9 抑制剂治疗高危人群（FOURIER）和评价依洛尤单抗治疗急性冠脉综合征后的心血管结局（ODYSSEY OUTCOMES）研究，使用两种可用的 PCSK9 拮抗剂，即依洛尤单抗和阿利西尤单抗，均报告主要不良心血管事件减少 15%。PCSK9 的表达调节取决于多种因素，部分是遗传的，部分与复杂的转录系统有关，主要受固醇调节元件结合蛋白控制。PCSK9 还受伴随的药物治疗调节，特别是他汀类药物，增强 PCSK9 的分泌，但减少其刺激磷酸化形式（S688）。这些复杂的转录机制导致循环水平的变化，使得临床测量血浆 PCSK9 用于心血管风险评估成为一个有争议的问题。测定总 PCSK9 水平可能为解释对 PCSK9 抑制剂的明显耐药提供一种诊断工具，从而表明需要其他方法。新型靶向 PCSK9 的药物正在临床开发中，人们对作用时间更长的药物（例如 RNA 沉默）更感兴趣，这可以提高患者的依从性。人们的兴趣不仅扩展到不仅限于降低低密度脂蛋白胆固醇的领域，还扩展到研究其他增加心血管风险的非脂类途径，特别是与高敏 C 反应蛋白水平升高相关的炎症，这一途径不受目前 PCSK9 拮抗剂的显著影响。
