目的采用系统评价方法确定前蛋白转化酶枯草溶菌素9型抑制剂(PCSK9i)治疗冠状动脉粥样硬化斑块的有效性和安全性。方法计算机检索PubMed、Web of Science、Cochrane Library、EmBase、CNKI数据库、万方数据库、维普中文科技期刊数据库...目的采用系统评价方法确定前蛋白转化酶枯草溶菌素9型抑制剂(PCSK9i)治疗冠状动脉粥样硬化斑块的有效性和安全性。方法计算机检索PubMed、Web of Science、Cochrane Library、EmBase、CNKI数据库、万方数据库、维普中文科技期刊数据库和中国生物医学文献数据库,时间限定为从建库起至2023年3月。由2名独立评价者按照纳入与排除标准筛选文献、提取数据并评价纳入研究的质量。采用RevMan 5.4和Stata 16.0软件进行Meta分析。结果共纳入6项随机对照试验,包括2003例冠状动脉粥样硬化性心脏病(冠心病)患者。与他汀类药物治疗组相比,联合PCSK9i后显著降低了斑块体积百分比(PAV)[均数差(MD)=-1.02,95%CI:-1.34~-0.69,P<0.001]及最大脂质弧度(MD=-11.25,95%CI:-22.39~-0.11,P=0.050),同时增加了最小纤维帽厚度(FCTmin)(MD=20.33 mm^(3),95%CI:10.73~29.93,P<0.001)及平均纤维帽厚度(FCTmean)(MD=27.74,95%CI:4.56~50.91,P<0.050)。PCSK9i联合他汀类药物治疗组与单用他汀类药物治疗组相比,两组间神经认知功能受损、新发糖尿病和肌痛差异无统计学意义(P>0.050)。亚组分析显示,不同治疗时间、PCSK9i类型、冠心病亚型对PAV结果无显著影响(P>0.050)。灵敏度分析未见显著影响PAV结果的研究(P>0.050)。漏斗图和Egger检验示无明显发表偏倚。结论PCSK9i联合他汀类药物可明显逆转冠心病患者的斑块进展,并增加斑块稳定性,期待进一步确定PCSK9i对斑块的作用是否能够改善患者预后。展开更多
目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取202...目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取2023年1月-2024年12月在天津市胸科医院心内科就诊且应用英克司兰或PCSK9单抗治疗的ACS患者87例,依据其用药种类不同,将其分为英克司兰组(n=34)和PCSK9单抗组(n=34)。收集分析真实世界中ACS患者治疗前及治疗后d 30,d 90,d 180时的低密度脂蛋白(low density lipoprotein,LDL)降幅、达标率及血脂谱,以评估治疗获益。通过标准差(standard deviation,SD)、平均连续变异度(average successive variability,ASV)、变异系数(coefficient of variation,CV)和校正独立于均值的变异性(variation independent of mean,VIM)评估两组的血脂变异性差异。结果:治疗后30 d时,英克司兰组和PCSK9单抗组患者LDL-C降幅(P=0.126)和达标率(P=0.300)无显著性差异;治疗后90 d及180 d时,英克司兰组LDL-C降幅(P=0.048;P=0.038)及达标率(P=0.006;P=0.010)均显著优于PCSK9单抗组。此外,与PCSK9单抗组相比,英克司兰组的血脂变异性更小(SD:0.16 vs 0.37,P=0.01;CV:19.15 vs 33.24,P=0.02;ASV:0.19 vs 0.48,P=0.01;VIM:18.57 vs 33.98,P=0.05)。结论:对ACS患者予以英克司兰治疗可同时实现短期和长期持续的LDL-C降低效果,提高达标率,且安全性良好。展开更多
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...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.展开更多
文摘目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取2023年1月-2024年12月在天津市胸科医院心内科就诊且应用英克司兰或PCSK9单抗治疗的ACS患者87例,依据其用药种类不同,将其分为英克司兰组(n=34)和PCSK9单抗组(n=34)。收集分析真实世界中ACS患者治疗前及治疗后d 30,d 90,d 180时的低密度脂蛋白(low density lipoprotein,LDL)降幅、达标率及血脂谱,以评估治疗获益。通过标准差(standard deviation,SD)、平均连续变异度(average successive variability,ASV)、变异系数(coefficient of variation,CV)和校正独立于均值的变异性(variation independent of mean,VIM)评估两组的血脂变异性差异。结果:治疗后30 d时,英克司兰组和PCSK9单抗组患者LDL-C降幅(P=0.126)和达标率(P=0.300)无显著性差异;治疗后90 d及180 d时,英克司兰组LDL-C降幅(P=0.048;P=0.038)及达标率(P=0.006;P=0.010)均显著优于PCSK9单抗组。此外,与PCSK9单抗组相比,英克司兰组的血脂变异性更小(SD:0.16 vs 0.37,P=0.01;CV:19.15 vs 33.24,P=0.02;ASV:0.19 vs 0.48,P=0.01;VIM:18.57 vs 33.98,P=0.05)。结论:对ACS患者予以英克司兰治疗可同时实现短期和长期持续的LDL-C降低效果,提高达标率,且安全性良好。
文摘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.
