Dyslipidaemia is characterised by elevated lipid and lipoprotein levels in the blood, particularly LDL-胆固醇 (also known as ‘bad 胆固醇’). 高水平的LDL-C可急剧增加不良心血管(CV)结果(如冠状动脉疾病)的风险, 中风和心力衰竭.1-3 It is estimated that dyslipidaemia causes 2.全球600万人死亡2,4 and the global burden of disease has been on the rise5
The growing burden of dyslipidemia
血脂异常, or a dysregulation in the levels of circulating lipids in plasma, 是心血管疾病的可改变危险因素，与包括中风和心肌梗死(MI)在内的不良患者预后密切相关。. Of the many manifestations of dyslipidemia, hyper胆固醇aemia is the most common form, 血浆低密度脂蛋白胆固醇(LDL-C)水平从1990年的第15大死亡危险因素上升, 2007年至第11位, 2019年将升至第8位.
通过降低LDL-C治疗来管理血脂异常已经证明可以改善心血管疾病的全球结局, 在初级预防方面, which is to prevent or delay the onset of cardiovascular disease, 并对已知心血管疾病的患者进行二级预防，以降低严重心血管事件的风险.
The mainstay of 胆固醇 lowering: Inhibiting 胆固醇 合成 with statins
改善心血管预后的首要目标之一是提高低密度脂蛋白胆固醇(LDL-C)。,6,7 due to its established role in increased CV risk.1,5 目前的LDL-C水平升高的护理标准(SoC)包括一些降脂剂, 包括他汀类药物, 它们被广泛使用, 有效的, and generally well tolerated.8
Despite widespread use of lipid-lowering therapies, up to 70% of patients do not reach their LDL-C targets under the current SoC.7,9,10 这是由于依从性差和单药治疗往往不够有效等问题. Even among patients 谁 meet LDL-C goals with the current SoC, 40% still experience life threatening CV events, indicating residual risk remains even when low LDL-C levels are achieved. Therefore, the current SoC may not be enough or suitable for every patient.7
目前使用降脂疗法的升级方法是复杂的，对患者和医生来说，在现实世界中遵守治疗计划是很难实现的. 能够优化治疗方案，不需要反复改变剂量，通过多种作用模式的联合策略来降低LDL胆固醇水平，可能有助于改善更多患者的预后.
Addressing complementary mechanisms: The potential of statins and PSCK9 inhibition
在胆固醇代谢中，有两种被充分理解和验证的途径被确定为降低LDL-C水平的目标:细胞内 胆固醇 合成 and LDL-receptor (LDL-R) degradation.8,11 Statins reduce intracellular LDL-C levels by inhibiting a key enzyme involved in 胆固醇 合成.8 While statins address one of the two modes of action involved in LDL-C regulation, 它们的功效各不相同,10 这表明他汀类药物可能不足以将一些患者的LDL-C水平降低到目标水平.7
In addition to statin-targeted intracellular LDL-C 合成, the process of LDL-R recycling and degradation by the protein, PCSK9(蛋白转化酶枯草杆菌素/ keexin 9型)是另一种经过充分验证的机制，可以靶向降低LDL-C水平8,11,12
PCSK9 causes the LDLC/LDLR complex to be sent to the lysosome for degradation.11 通过抑制PCSK9, 细胞表面LDL-R的增加，促进了血液中LDL-C的自然清除，从而促进了溶酶体的降解.11,12
Statins work to reduce total LDL-C levels by inhibiting intracellular LDL-C 合成, while inhibition of PCSK9 can reduce LDL-C levels by increasing LDL-C clearance.8,11,12 Statins also indirectly increase expression of LDL-R and PCSK9, further increasing the amount of LDL-R on cell surfaces and potential LDL-C clearance.8,13 他汀类药物和PCSK9抑制这两种潜在互补的降LDL-C作用提供了解决多种途径以达到较低LDL-C目标的可能性.7
大, 已知单克隆抗体等可注射生物制剂可有效抑制PCSK9, 但口服小分子PCSK9抑制剂的开发已被证明更为复杂.14 这是因为PCSK9与LDL-R相互作用的位点相对较大且平坦, making small molecule design especially difficult.15
未来的发展方向
而目前的证据表明，心血管发病率和死亡率的积极转变与低密度脂蛋白降低治疗, 有必要创新和优化血脂异常的治疗方案，以应对越来越多的患者，包括那些患有糖尿病等合并症的患者, 高血压和肥胖, which could put them at greater risk of developing CV disease.
