PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.
目的探究达格列净联合常规治疗对2型糖尿病伴心力衰竭患者的心血管保护作用及对血清炎症因子和可溶性生长刺激表达基因2(sST2)水平的影响。方法前瞻性选取2020年9月至2022年8月江苏省昆山市第一人民医院收治的86例2型糖尿病伴心力衰竭患者为研究对象,按随机数字表法分为对照组和观察组,各43例。对照组予以常规治疗降糖及抗心力衰竭治疗,观察组在对照组基础上增加达格列净治疗。比较两组治疗前、治疗6个月后的血糖[糖化血红蛋白(HbA1c)、空腹血糖、餐后2 h血糖(2 h PG)]、血脂[总胆固醇、甘油三酯、低密度脂蛋白胆固醇(LDL-C)]、心功能[左心室射血分数(LVEF)、血浆N端脑钠肽前体(NT-proBNP)、6 min步行试验(6MWT)]、血清指标[白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、sST2]水平及心血管事件及不良反应发生率。结果治疗6个月后,观察组的HbA1c、空腹血糖、2 h PG、总胆固醇、甘油三酯、LDL-C水平分别为(6.65±0.73)%、(6.25±1.54)mmol/L、(7.88±1.35)mmol/L、(3.87±0.85)mmol/L、(1.52±0.46)mmol/L、(2.41±0.63)mmol/L,均明显低于对照组[(7.07±0.85)%、(7.16±1.49)mmol/L、(8.82±1.48)mmol/L、(4.24±0.82)mmol/L、(1.73±0.51)mmol/L、(2.69±0.61)mmol/L],差异均有统计学意义(P<0.05)。治疗6个月后,观察组的LVEF、6MWT水平分别为(52.28±3.43)%、(424.87±72.58)m,均明显高于对照组[(50.79±3.25)%、(367.52±74.43)m],血浆NT-proBNP水平为(1778.65±224.37)pg/mL,低于对照组[(2943.41±256.22)pg/mL],差异均有统计学意义(P<0.05)。治疗6个月后,观察组的血清IL-1β、TNF-α、sST2水平分别为(6.60±1.14)pg/mL、(22.15±4.30)ng/L、(0.42±0.13)g/L,均明显低于对照组[(7.19±1.39)pg/mL、(29.68±5.24)ng/L、(0.50±0.16)g/L],差异均有统计学意义(P<0.05)。观察组心血管事件总发生率为9.30%,低于对照组(25.58%),差异有统计学意义(P<0.05)。两组均无严重不良反应发生。结论在使用常规�