血脂异常可以引起多种疾病,临床上大多采用他汀类药物来降低低密度脂蛋白胆固醇(Low density lipoprotein-cholesterol,LDL-C)浓度,但部分患者应用后仍不能使LDL-C浓度降到正常水平.Inclisiran是前蛋白转化酶枯草溶菌素9(Proprotein con...血脂异常可以引起多种疾病,临床上大多采用他汀类药物来降低低密度脂蛋白胆固醇(Low density lipoprotein-cholesterol,LDL-C)浓度,但部分患者应用后仍不能使LDL-C浓度降到正常水平.Inclisiran是前蛋白转化酶枯草溶菌素9(Proprotein convertase subtilisin/kexin type 9,PCSK9)的特异性小干扰RNA(Small interfering RNA,siRNA),可阻止PCSK9信使RNA的翻译,从而降低蛋白质浓度和LDL-C浓度,可治疗动脉粥样硬化和高胆固醇血症等心血管疾病,在临床上还可与他汀类药物联合使用来增强疗效.ORION临床开发计划有部分试验还在进行,主要对其安全性及对心血管结局的改善能力进行评估.本文主要对Inclisiran的临床药理学、临床试验、不良事件和联合用药等进行综述,希望为Inclisiran临床应用提供支持.展开更多
目的Inclisiran是一种抑制前蛋白转化酶枯草溶菌素9(PCSK9)合成的小干扰RNA,具有显著降低低密度脂蛋白胆固醇(LDL-C)水平的潜力,这项研究评估了Inclisiran在高胆固醇血症和心血管预后中的效果及安全性。方法检索中国生物医学文献、中国...目的Inclisiran是一种抑制前蛋白转化酶枯草溶菌素9(PCSK9)合成的小干扰RNA,具有显著降低低密度脂蛋白胆固醇(LDL-C)水平的潜力,这项研究评估了Inclisiran在高胆固醇血症和心血管预后中的效果及安全性。方法检索中国生物医学文献、中国知网、万方、维普、PubMed、EMbase、the Cochrane Library、Web of Science数据库,时间均从建库至2021月3月,对公开发表的Inclisiran治疗高胆固醇血症的随机对照试验进行荟萃分析和试验序贯分析(TSA),评价Inclisiran的调脂效果和不良事件风险。结果共纳入了3个RCT,总样本量3660例。与安慰剂相比,Inclisiran能显著降低LDL-C变化率(MD=-50.55,95%CI:-52.73~-48.38,P<0.0001),LDL-C变化量(MD=-57.17,95%CI:-62.91~-51.43,P<0.0001)和主要心血管不良事件(MACE,RR=0.78,95%CI:0.65~0.93,P=0.006),而总不良事件相当(RR=1.01,95%CI:0.97~1.04,P=0.62)。TSA示当前信息量观察到的MACE结局具有结论性,但总不良事件结局有待更多研究论证。Harbord回归示MACE和总不良事件均不存在发表偏倚。GRADE评价示LDL-C变化率、MACE、总不良事件的证据质量为高,LDL-C变化量的证据质量为低。结论Inclisiran具有降低LDL-C水平和心血管风险的潜力,总不良事件可能和安慰剂相当,具有进一步研究探索的价值。展开更多
Acute myocardial infarction is a deadly disease, and in the Indian context, it occurs at a younger age, even below the age of 40 years, and sometimes even below 30 years. These young MI patients have high mortality ra...Acute myocardial infarction is a deadly disease, and in the Indian context, it occurs at a younger age, even below the age of 40 years, and sometimes even below 30 years. These young MI patients have high mortality rates, and many of them are not able to reach the hospital. The pathophysiology of AMI is very well understood. AMI is a multifactorial disease and has several risk factors, like dyslipidemia, diabetes, hypertension, smoking, diet, etc. However, low-density lipoprotein cholesterol (LDL-C) has a very strong causal relationship with atherosclerosis. Reducing LDL-C to <70 results in the arrest of the progression of atherosclerosis, and slashing its level to below 50 produces the regression of atherosclerosis. The cumulative exposure of LDL-C to the arterial wall is a very strong determinant of atherosclerosis and the development of AMI. The coronary heart disease (CHD) threshold target of LDL-C for the development of AMI is roughly 7000 mg/year. If LDL-C is 100 mg/dL from an early age, the CHD threshold target for the development of AMI will reach 70 years of age. However, if LDL-C target is <70 mg/dL from an early age, the patients will reach the CHD threshold of LDL-C at the age of 100 years. Based on the current science, this is an emerging concept to postpone AMI by several years, even up to 100 years. The goal of LDL-C <70 mg/dL can be achieved by available oral or injectable drugs. Gene editing with CRISPR technology is emerging as a very exciting modality for lowering LDL-C to a very low level for the rest of life.展开更多
文摘血脂异常可以引起多种疾病,临床上大多采用他汀类药物来降低低密度脂蛋白胆固醇(Low density lipoprotein-cholesterol,LDL-C)浓度,但部分患者应用后仍不能使LDL-C浓度降到正常水平.Inclisiran是前蛋白转化酶枯草溶菌素9(Proprotein convertase subtilisin/kexin type 9,PCSK9)的特异性小干扰RNA(Small interfering RNA,siRNA),可阻止PCSK9信使RNA的翻译,从而降低蛋白质浓度和LDL-C浓度,可治疗动脉粥样硬化和高胆固醇血症等心血管疾病,在临床上还可与他汀类药物联合使用来增强疗效.ORION临床开发计划有部分试验还在进行,主要对其安全性及对心血管结局的改善能力进行评估.本文主要对Inclisiran的临床药理学、临床试验、不良事件和联合用药等进行综述,希望为Inclisiran临床应用提供支持.
文摘目的Inclisiran是一种抑制前蛋白转化酶枯草溶菌素9(PCSK9)合成的小干扰RNA,具有显著降低低密度脂蛋白胆固醇(LDL-C)水平的潜力,这项研究评估了Inclisiran在高胆固醇血症和心血管预后中的效果及安全性。方法检索中国生物医学文献、中国知网、万方、维普、PubMed、EMbase、the Cochrane Library、Web of Science数据库,时间均从建库至2021月3月,对公开发表的Inclisiran治疗高胆固醇血症的随机对照试验进行荟萃分析和试验序贯分析(TSA),评价Inclisiran的调脂效果和不良事件风险。结果共纳入了3个RCT,总样本量3660例。与安慰剂相比,Inclisiran能显著降低LDL-C变化率(MD=-50.55,95%CI:-52.73~-48.38,P<0.0001),LDL-C变化量(MD=-57.17,95%CI:-62.91~-51.43,P<0.0001)和主要心血管不良事件(MACE,RR=0.78,95%CI:0.65~0.93,P=0.006),而总不良事件相当(RR=1.01,95%CI:0.97~1.04,P=0.62)。TSA示当前信息量观察到的MACE结局具有结论性,但总不良事件结局有待更多研究论证。Harbord回归示MACE和总不良事件均不存在发表偏倚。GRADE评价示LDL-C变化率、MACE、总不良事件的证据质量为高,LDL-C变化量的证据质量为低。结论Inclisiran具有降低LDL-C水平和心血管风险的潜力,总不良事件可能和安慰剂相当,具有进一步研究探索的价值。
文摘Acute myocardial infarction is a deadly disease, and in the Indian context, it occurs at a younger age, even below the age of 40 years, and sometimes even below 30 years. These young MI patients have high mortality rates, and many of them are not able to reach the hospital. The pathophysiology of AMI is very well understood. AMI is a multifactorial disease and has several risk factors, like dyslipidemia, diabetes, hypertension, smoking, diet, etc. However, low-density lipoprotein cholesterol (LDL-C) has a very strong causal relationship with atherosclerosis. Reducing LDL-C to <70 results in the arrest of the progression of atherosclerosis, and slashing its level to below 50 produces the regression of atherosclerosis. The cumulative exposure of LDL-C to the arterial wall is a very strong determinant of atherosclerosis and the development of AMI. The coronary heart disease (CHD) threshold target of LDL-C for the development of AMI is roughly 7000 mg/year. If LDL-C is 100 mg/dL from an early age, the CHD threshold target for the development of AMI will reach 70 years of age. However, if LDL-C target is <70 mg/dL from an early age, the patients will reach the CHD threshold of LDL-C at the age of 100 years. Based on the current science, this is an emerging concept to postpone AMI by several years, even up to 100 years. The goal of LDL-C <70 mg/dL can be achieved by available oral or injectable drugs. Gene editing with CRISPR technology is emerging as a very exciting modality for lowering LDL-C to a very low level for the rest of life.
