Article(id=1208144411159020139, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208144409313526368, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.03.0292, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1628611200000, receivedDateStr=2021-08-11, revisedDate=null, revisedDateStr=null, acceptedDate=1633968000000, acceptedDateStr=2021-10-12, onlineDate=1765973673858, onlineDateStr=2025-12-17, pubDate=1648396800000, pubDateStr=2022-03-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765973673858, onlineIssueDateStr=2025-12-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765973673858, creator=13701087609, updateTime=1765973673858, updator=13701087609, issue=Issue{id=1208144409313526368, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='3', pageStart='213', pageEnd='319', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765973673415, creator=13701087609, updateTime=1765974822867, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208149230531756320, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208144409313526368, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208149230531756321, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208144409313526368, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=292, endPage=298, ext={EN=ArticleExt(id=1208144411544896118, articleId=1208144411159020139, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Progress of clinical research and application of PCSK9 inhibitors on the management of dyslipidaemias, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

To strengthen the management of dyslipidaemias in patients with atherosclerotic cardiovascular disease (ASCVD)is regarded as an important measure to delay the disease progression and improve the long-term prognosis. However, there are still a high proportion of domestic patients, whose lipids levels are not up to the standard after receiving conventional lipid lowering therapy, causing an unoptimistic form of lipids management of ASCVD patients in China. As researchers found the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, targeted PCSK9 inhibitors have been put into clinical researches gradually and accumulated series evidence on efficacy and safety. Main literature referred to the clinical research and application progress of PCSK9 inhibitors were reviewed in present paper, to provide a reference for future clinical practice.

, correspAuthors=Yun-Dai Chen, authorNote=null, correspAuthorsNote=
*E-mail:
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加强动脉粥样硬化性心血管疾病(ASCVD)患者的血脂管理,是延缓其疾病进展并改善远期预后的重要举措。然而,目前我国ASCVD患者血脂管理形势不容乐观,仍有较高比例的患者在接受传统降脂药物治疗后血脂管理并不达标。已有研究发现,前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9)在血脂代谢中具有重要作用,而针对此靶点研发的PCSK9抑制剂投入临床后已积累了大量有效性与安全性方面的数据。本文主要针对PCSK9抑制剂的临床研究进行综述,为其在临床实践中的进一步应用提供参考依据。

, correspAuthors=陈韵岱, authorNote=null, correspAuthorsNote=
陈韵岱,E-mail:
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王玺,博士研究生,主要从事冠心病无创影像与临床方面的研究

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王玺,博士研究生,主要从事冠心病无创影像与临床方面的研究

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tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208144411159020139, language=CN, orderNo=3, keyword=PCSK9抑制剂)], refs=[Reference(id=1208144414787093277, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208144411159020139, doi=null, pmid=null, pmcid=null, year=2020, volume=35, issue=9, pageStart=833, pageEnd=854, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=The Writing Committee of the Report on Cardiovascular Health and Diseases in China, journalName=Chin Circ J, refType=null, unstructuredReference=The Writing Committee of the Report on Cardiovascular Health and Diseases in China. 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PCSK9抑制剂在血脂管理中的临床研究与应用进展
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王玺 1, 2 , 杨俊杰 2 , 陈韵岱 2, *
解放军医学杂志 | 综述 2022,47(3): 292-298
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解放军医学杂志 | 综述 2022, 47(3): 292-298
PCSK9抑制剂在血脂管理中的临床研究与应用进展
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王玺1, 2, 杨俊杰2, 陈韵岱2, *
作者信息
  • 1解放军医学院,北京 100853
  • 2解放军总医院心血管病医学部,北京 100048
  • 王玺,博士研究生,主要从事冠心病无创影像与临床方面的研究

通讯作者:

陈韵岱,E-mail:
Progress of clinical research and application of PCSK9 inhibitors on the management of dyslipidaemias
Xi Wang1, 2, Jun-Jie Yang2, Yun-Dai Chen2, *
Affiliations
  • 1Medical School of Chinese PLA, Beijing 100853, China
  • 2Department of Cardiovascular Medicine, Chinese PLA General Hospital, Beijing 100048, China
出版时间: 2022-03-28 doi: 10.11855/j.issn.0577-7402.2022.03.0292
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加强动脉粥样硬化性心血管疾病(ASCVD)患者的血脂管理,是延缓其疾病进展并改善远期预后的重要举措。然而,目前我国ASCVD患者血脂管理形势不容乐观,仍有较高比例的患者在接受传统降脂药物治疗后血脂管理并不达标。已有研究发现,前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9)在血脂代谢中具有重要作用,而针对此靶点研发的PCSK9抑制剂投入临床后已积累了大量有效性与安全性方面的数据。本文主要针对PCSK9抑制剂的临床研究进行综述,为其在临床实践中的进一步应用提供参考依据。

冠心病  /  血脂异常  /  PCSK9抑制剂

To strengthen the management of dyslipidaemias in patients with atherosclerotic cardiovascular disease (ASCVD)is regarded as an important measure to delay the disease progression and improve the long-term prognosis. However, there are still a high proportion of domestic patients, whose lipids levels are not up to the standard after receiving conventional lipid lowering therapy, causing an unoptimistic form of lipids management of ASCVD patients in China. As researchers found the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, targeted PCSK9 inhibitors have been put into clinical researches gradually and accumulated series evidence on efficacy and safety. Main literature referred to the clinical research and application progress of PCSK9 inhibitors were reviewed in present paper, to provide a reference for future clinical practice.

coronary artery disease  /  dyslipidaemias  /  proprotein convertase subtilisin/kexin type 9 inhibitors
王玺, 杨俊杰, 陈韵岱. PCSK9抑制剂在血脂管理中的临床研究与应用进展. 解放军医学杂志, 2022 , 47 (3) : 292 -298 . DOI: 10.11855/j.issn.0577-7402.2022.03.0292
Xi Wang, Jun-Jie Yang, Yun-Dai Chen. Progress of clinical research and application of PCSK9 inhibitors on the management of dyslipidaemias[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (3) : 292 -298 . DOI: 10.11855/j.issn.0577-7402.2022.03.0292
《中国心血管健康与疾病报告2019》明确指出了我国心血管疾病防治工作面临的严峻挑战,同时对心血管疾病危险因素的管理、控制提出了更高要求[1]。随着对动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease,ASCVD)认识的逐渐深入,基于心血管疾病危险因素的风险分层和管理策略不断完善,但传统药物治疗的有效性及其对远期主要不良心血管事件(major adverse cardiovascular events,MACEs)的预防作用并未完全达到预期。以血脂管理为例,虽然反复强调严格控制低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)的临床意义,但接受传统降脂药物治疗后仍有部分ASCVD患者血脂管理未达标或发生MACEs。2003年Abifadel等[2]发现了前蛋白转化酶枯草杆菌蛋白酶/kexin9型(proprotein convertase subtilisin/kexin type 9,PCSK9)在血脂代谢中的作用,后续研究进一步揭示了PCSK9与低密度脂蛋白受体(low density lipoprotein receptor,LDL-R)相互作用的机制[3],这些研究均有力地推动了PCSK9抑制剂的研发。目前,已有单克隆抗体类PCSK9抑制剂经国家食品药品监督管理总局(National Medical Products Administration,NMPA)批准在中国上市。本文对PCSK9抑制剂的主要研发历程、临床疗效、在特殊人群中的应用及其对MACEs的保护作用进行综述,为其在临床实践中的进一步应用提供参考依据。
前期基础研究证实PCSK9对于维持血脂稳态具有重要意义,并支持PCSK9为降低LDL-C的新型药物靶点[2-4]。随着对PSCK9晶体结构认识的深入,PCSK9抑制剂的研发步入了新的阶段[5],相应的单克隆抗体可通过与PCSK9结合而抑制其与LDL-R的结合,阻止PCSK9介导的LDL-R降解,使LDL-R重新循环至肝细胞表面,而结合LDL-C的LDL-R数量增加则有利于降低LDL-C水平。Chan等[6]将PCSK9抑制剂注射入小鼠和非人类灵长类动物(猴)并取得了显著效果。随后,Ⅰa期临床研究对健康受试者以剂量递增的方案经皮下注射或静滴的方式给药1次,Ⅰb期临床研究则对接受他汀治疗的高脂血症患者以不同时间间隔给药,结果初步体现了PCSK9抑制剂显著降低LDL-C的临床效果[7]。药效动力学和药代动力学研究表明,PCSK9抑制剂在低浓度时通过与靶点的可饱和结合清除,在高浓度时通过非可饱和蛋白质降解途径清除,对肝肾功能无明显影响;此外,140 mg/Q2W(140 mg,每2周1次)和420 mg/QM(420 mg,每月1次)两种给药方案降低LDL-C的效果相似,提示给药时间间隔延长1倍需要增加3倍给药剂量[8]
早期的Ⅱ期临床研究以给药12周后LDL-C降幅为首要研究终点,结果显示PCSK9抑制剂可明显降低LDL-C(至少40%),为后续研究的开展及PCSK9抑制剂的临床应用奠定了坚实基础[9]。经最大耐受剂量他汀治疗后LDL-C仍未达标的ASCVD极高危人群,接受PCSK9抑制剂治疗12周后,超过90%的患者达到了既定的降脂目标[10]。此外,对于PCSK9抑制剂联合他汀治疗的高脂血症患者,在给予PCSK9抑制剂12周后LDL-C较基线水平至少下降了40%,且在达到有效性的同时保证了联合用药的安全性和耐受性[11]。GAUSS研究[12]针对他汀不耐受人群,同样发现PCSK9抑制剂既能有效降低纳入患者的LDL-C水平,还可显著提高其对治疗的耐受性。
PCSK9抑制剂应用于亚洲人群同样取得了令人瞩目的研究成果。基于日本人群的YUKAWA研究[13],对ASCVD极高危并接受他汀治疗(无论是否联合依折麦布)的高脂血症患者联合应用12周PCSK9抑制剂,研究组较安慰剂组LDL-C水平的降幅高达65%,且超过96%的受试者LDL-C水平降至1.8 mmol/L以下,仅4例因不良反应而停止相关治疗。
在PCSK9抑制剂相关的临床研究中,一般将不良反应判定为:上呼吸道感染、流感、胃肠炎、鼻咽炎、恶心、肌肉骨骼疼痛,注射部位的反应,认知功能改变,肌酸激酶升高超过5倍或10倍基线值,肝酶升高超过3倍基线值,PCSK9抗体的结合和中和等[14]。无论是上述Ⅱ期临床研究,还是后面将提及的其余临床研究,几乎均未报告与PCSK9抑制剂相关的严重不良反应,且已出现的不良反应在研究组与对照组中的发生情况差异无统计学意义。
OSLER研究[15]结果显示,将PCSK9抑制剂治疗周期由12周延长至52周仍安全有效,该研究共纳入1104例高脂血症患者,凡继续接受PCSK9抑制剂治疗者,用药期间LDL-C水平降幅依旧维持在50%左右,而未继续接受治疗者,其LDL-C水平最终恢复到基线水平。对于其他非首要干预靶点,PCSK9抑制剂组的非高密度脂蛋白胆固醇(non-high density lipoprotein cholesterol,N-HDL-C)、三酰甘油(triglyceride,TG)、脂蛋白(a)[lipoprotein(a),Lp(a)]水平均出现不同程度的下降,且高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)水平也有所上升。OSLER-1研究[16]发布了迄今为止PCSK9抑制剂治疗周期最长的临床研究结果,在长达5年的时间里,PSCK9抑制剂对于高脂血症患者表现出持久的有效性和良好的耐受性,为此类新型降脂药物的长期应用提供了有益证据。
基于日本人群的一项开放标签研究结果显示,纳入患者接受PCSK9抑制剂治疗1年后LDL-C的降幅可达65%以上[17]。进一步延长随访时间至3~5年,Hirayama等[18]发现,纳入患者接受PCSK9抑制剂治疗后LDL-C水平的降幅仍稳定维持在60%左右,且总体安全性与耐受性较1年时无明显改变。上述有关长期有效性和安全性的临床研究证据支持了PSCK9抑制剂可以进行更大样本量的Ⅲ期临床研究。
他汀类药物是降低LDL-C的基石,其他种类的降脂药物必须在他汀类药物的基础上发挥作用或仅在他汀类药物不耐受的少数情况下适用。在Ⅲ期临床研究阶段,MENDEL-2研究[19]发现,PCSK9抑制剂单药治疗12周是有效、安全的,而在联合用药方面,LAPLACE-2研究[20]发现,以不同剂量的阿托伐他汀、瑞舒伐他汀、辛伐他汀作为基础药物经4周稳定降脂治疗后,再经随机分组给予PCSK9抑制剂、依折麦布或安慰剂,在基线LDL-C接近的情况下,12周后联合PCSK9抑制剂组LDL-C明显下降且安全可耐受。对于稳定型冠心病患者而言,无论接受高强度或次高强度他汀治疗,且无论基线LDL-C是否<700 mg/L,PCSK9抑制剂均可继续稳定降低LDL-C水平,并带来显著的MACEs事件获益[11]。此外,一项涉及25 000余例患者的大样本研究再次证实了PCSK9抑制剂的用药安全性,在中位随访2.2年的时间内,PCSK9抑制剂较安慰剂降低LDL-C至极低水平不会带来严重不良反应,也不会导致肝功能异常、肌酸激酶升高、认知功能改变,以及新发糖尿病、出血性卒中、非心源性死亡等风险升高[21]
他汀不耐受定义为:因难以忍受的肌肉疼痛或肌病,不能耐受任何剂量的至少一种他汀类药物或不能耐受低剂量他汀基础上的任何剂量增加,且停药后症状改善或缓解[12]。他汀类药物相关的肌肉不良反应是造成部分患者他汀治疗依从性低甚至中断治疗的重要原因。GAUSS-2研究[22]纳入未接受或仅接受低剂量他汀治疗且LDL-C水平未达标的患者,经PCSK9抑制剂治疗12周后LDL-C水平较基线下降55%左右,肌肉不良反应发生率(12%)也低于依折麦布组(23%)。GAUSS-3研究[23]则在严格的药物交互和药物洗脱阶段后将纳入患者随机分为PCSK9抑制剂组与依折麦布组,经24周治疗后两组出现肌肉症状的比例差异无统计学意义(20.7% vs. 28.8%)。Cho等[24]对382例他汀不耐受患者进行了2年的跟踪调查后证实,在有效降低LDL-C水平的前提下,PCSK9抑制剂的肌肉不良反应发生率不高于依折麦布和安慰剂。
一方面糖尿病患者需要更加严格控制LDL-C水平确保达标,但实际LDL-C达标率仍不容乐观;另一方面既往部分研究发现,接受他汀类药物治疗后有新发糖尿病风险[25],但目前其机制尚未明确。因此,PCSK9抑制剂对于糖尿病患者的血脂管理能否达到预期效果,是否同样会造成新发糖尿病,均需进一步积累临床研究证据。
DESCARTES研究[26]根据患者基线血糖及糖尿病患病情况,将纳入患者分为2型糖尿病、空腹血糖受损、代谢综合征以及无以上情况者,经52周的研究周期,在优化降脂治疗的基础上所有接受PCSK9抑制剂的患者LDL-C水平均较相应的安慰剂组明显降低,且血糖、糖化血红蛋白、胰岛素、C肽水平较基线均无明显改变,PCSK9抑制剂组新发糖尿病与安慰剂组比较差异无统计学意义(5.6% vs.6.6%)。另一项开放标签研究结果也显示,PCSK9抑制剂不会造成血糖升高及新发糖尿病风险[27]。BANTING研究[28]和BERSON研究[29]也证实了PCSK9抑制剂在糖尿病患者中应用的有效性和安全性。BERSON研究亚组中,中国2型糖尿病合并高脂血症或混合型高脂血症患者的分析结果显示,在阿托伐他汀降脂治疗的基础上,联合PCSK9抑制剂对糖尿病患者的血脂管理可带来极大获益,且对患者血糖管理并无干扰[30]。此外,Sabatine等[31]发布的来自FOURIER研究的数据进一步表明,糖尿病患者应用PCSK9抑制剂可有效降低MACEs事件风险。
大脑中的胆固醇由胶质细胞局部合成并以脂蛋白的形式分泌,鉴于胆固醇在突触形成及其功能实现中的重要性,降脂药物对认知功能的潜在影响值得关注,尤其是能够穿越血脑屏障的亲脂性他汀类药物。基于一些小样本和短期的临床研究,2012年美国食品药品监督管理局(Food and Drug Administration,FDA)发布了他汀类药物潜在影响认知功能的警告,但目前仍欠缺大规模临床研究证据。尽管如此,因PCSK9抑制剂可显著降低LDL-C水平,其对认知功能的潜在影响需要引起足够的重视[32]
EBBINGHAUS研究[33]结果显示,受试者在他汀治疗的基础上经中位随访19个月后,并未发现PCSK9抑制剂引起明显的认知功能改变。另一项更大样本量、中位随访2.2年的调查结果同样未发现PCSK9抑制剂联合可耐受最大剂量他汀会带来认知功能的下降,即使LDL-C水平下降到200 mg/L以下[34]
FH患者的基因突变会造成LDL-R功能下调,减弱LDL-C与LDL-R之间的相互作用,减少LDL-R的循环,导致其LDL-C水平很高且传统降脂药物治疗效果欠佳。对于杂合子家族性高胆固醇血症(heterozygous familial hypercholesterolemia,HeFH)患者,LDL-R的残余功能尚可使PCSK9抑制剂发挥作用,而在发病率更低的纯合子家族性高胆固醇血症(homozygous familial hypercholesterolemia,HoFH)患者中,PCSK9抑制剂发挥作用的能力取决于基因突变的种类及患者自身上调相应受体的能力[35]。多项Ⅱ期临床研究也针对FH患者发布了相应的研究结果。
对于成年HeFH患者,PCSK9抑制剂可达到良好的降LDL-C效果。RUTHERFORD研究[36]结果表明,应用大剂量他汀联合PCSK9抑制剂(无论是否联合依折麦布),12周后能有效降低HeFH患者LDL-C水平至少40%,且安全性、耐受性良好,无严重不良反应。后续RUTHERFORD-2研究(Ⅲ期临床研究)[37]则显示,HeFH患者应用PCSK9抑制剂后LDL-C降幅甚至可达60%。Hovingh等[38]的研究则进一步证实了HeFH患者长期(48周)应用PCSK9抑制剂的有效性、安全性和耐受性。此外,针对未成年HeFH患者的HAUSER-RCT研究也在进行中[39]
对于HoFH患者,因其LDL-R功能严重下降,导致LDL-C水平严重升高且对传统降脂药物治疗反应极差。Stein等[40]曾对8例HoFH患者行基因型检测并给予PCSK9抑制剂皮下注射,发现受体功能缺陷者其LDL-C仅下降20%左右,而受体无功能者则未观察到LDL-C水平的明显改变。TESLA PART B研究(Ⅲ期临床研究)[14]纳入多中心来源的50例HoFH患者(未纳入受体无功能的HoFH患者),在为期12周的研究周期内,接受PCSK9抑制剂治疗后不同基因突变型患者的LDL-C降幅波动在10%~30%。此外,TAUSSIG研究[41]结果显示,PCSK9抑制剂治疗与血液成分单采治疗对HoFH患者的LDL-C水平降低作用差异无统计学意义(12周:P=0.38,48周:P=0.09)。
PCSK9抑制剂较传统降脂药物对于Lp(a)具有更明显的治疗效果。Lp(a)是一类特殊的脂蛋白胆固醇,由载脂蛋白(a)[apolipoprotein(a),apo(a)]和类LDL颗粒的载脂蛋白B(apolipoproteinB,apoB)部分共价连接而成。目前的流行病学和基因组学研究证据显示,Lp(a)是促进ASCVD发生发展并导致远期MACEs的独立危险因素[42]。在LDL-C、N-HDL-C等主要血脂干预靶点的基础上,进一步测定Lp(a)有助于完善ASCVD风险重分层[42]。传统降脂药物治疗对于降低Lp(a)收效甚微,甚至可造成Lp(a)水平小幅升高,因此,亟需一种新的治疗方式以改变Lp(a)的治疗现状。
对15项Ⅱ期和Ⅲ期临床研究的荟萃分析结果显示,接受PCSK9抑制剂治疗12周后Lp(a)平均降低20%~38%,且纳入患者接受长期治疗后效果仍显著[43]。对FOURIER研究数据进行深入挖掘后发现,PCSK9抑制剂治疗48周可有效降低Lp(a)达26.9%,在中位随访2.2年的时间内,Lp(a)降低有助于降低远期MACEs发生风险[44]。但考虑到人群中的Lp(a)呈偏态分布,PCSK9抑制剂约30%的有效降幅能否改善Lp(a)极高水平人群的远期预后尚需进一步研究。
大量研究已证实降低LDL-C带来的远期临床获益,LDL-C每降低1 mmol/L,发生MACEs的总体风险可降低22%[45]。但即使联合应用他汀类药物和依折麦布控制血脂达标,7年时MACEs发生率仍超过70%,因此,对于ASCVD极高危患者来说有必要进一步加强降脂治疗以减少远期MACEs的发生风险[46]
应用PCSK9抑制剂有效降低LDL-C水平会带来显著的临床获益,FOURIER研究[47]共纳入27 564例ASCVD患者,且接受他汀治疗后LDL-C≥1.8 mmol/L,然后将受试者以1:1的比例随机分为PCSK9抑制剂组与安慰剂组。该研究主要研究终点为心源性死亡、心肌梗死、卒中、因不稳定型心绞痛住院、再血管化治疗的复合研究终点,次要研究终点为心源性死亡、心肌梗死、卒中的复合研究终点。经中位随访2.2年,结果显示,PCSK9抑制剂较安慰剂可明显降低主要研究终点(9.8% vs. 11.3%,HR=0.85,95%CI 0.79~0.92,P<0.001)和次要研究终点(5.9% vs. 7.4%,HR=0.80,95%CI 0.73~0.88,P<0.001)风险;PSCK9抑制剂较安慰剂的主要研究终点事件累积发生率(1年:5.3% vs.6.0%;2年:9.1% vs. 10.7%;3年:12.6% vs. 14.6%;log-rank P<0.001)和次要研究终点事件累积发生率(1年:3.1% vs. 3.7%;2年:5.5% vs. 6.8%;3年:7.9% vs. 9.9%;log-rank P<0.001)均明显降低。
对于心肌梗死患者,因其存在再发MACEs的高风险,应当更严格地进行血脂管理。Gencer等[48]的研究结果显示,PCSK9抑制剂可减少近期(既往12个月内)心肌梗死患者发生主要及次要研究终点的风险[分别为19%(HR=0.81,95%CI 0.70~0.93)和25%(HR=0.75,95%CI 0.62~0.91)];对于既往(超过12个月)的心肌梗死患者,其风险分别降低约8%(HR=0.92,95%CI 0.84~1.01)和15%(HR=0.85,95%CI 0.76~0.96)。此外,PCSK9抑制剂还可降低斑块破裂相关的心肌梗死风险,但不会降低2型心肌梗死的风险[49]
随着临床研究证据的逐渐积累,临床指南对于ASCVD患者的风险分层和精细化管理也日趋完善,PCSK9抑制剂作为新型强效降脂药物在各大指南中的重要地位逐渐突显。
2018年AHA发布的血脂管理指南对于PCSK9抑制剂的推荐为:(1)年龄40~75岁、基线LDL-C≥2200 mg/L、应用最大耐受剂量他汀及依折麦布后LDL-C仍≥1300 mg/L人群的一级预防(Ⅱb/C);(2)针对ASCVD极高危风险患者的二级预防(Ⅱa),对于非极高危ASCVD患者则不建议应用PCSK9抑制剂;(3)应用最大耐受剂量他汀和依折麦布后LDL-C≥1000 mg/L的HeFH患者(Ⅱb);(4)患糖尿病但无临床ASCVD表现的患者不建议应用PCSK9抑制剂[50]
2019年ESC发布的血脂管理指南作出如下建议:(1)对他汀不耐受的替代治疗(Ⅱa/C);(2)以下情况的补充治疗:一级预防(除FH)人群(Ⅱb),二级预防人群及高危患者最大耐受剂量他汀与依折麦布治疗后LDL-C仍未达标(Ⅰ/A),合并ASCVD或伴有另外一项主要危险因素的极高危FH人群或最大剂量他汀联合依折麦布治疗后LDL-C仍未达标(Ⅰ/C),联合依折麦布(Ⅱb/C),急性冠脉综合征(acute coronary syndrome,ACS)患者经最大耐受剂量他汀联合依折麦布治疗4~6周后LDL-C水平仍未达标者[50]
现阶段,我国ASCVD患者血脂管理形势不容乐观,有数据显示,接受降脂治疗后LDL-C达标率不足1/3[51],即便是接受高强度或最大耐受剂量的他汀治疗,仍有超过60%的ACS患者LDL-C水平未达标[52]。在2016年中国成人血脂异常防治指南的基础上,2019中国胆固醇教育计划(China Cholesterol Education Program,CCEP)专家建议和2020中华医学会心血管病学分会(Chinese Society of Cardiology,CSC)专家共识进一步对ASCVD患者强化风险分层并给出了相应的降脂治疗方案[53-54],建议极高危患者LDL-C<1.4 mmol/L或较基线降幅>50%,如果他汀类药物联合依折麦布治疗4~6周后LDL-C水平仍不能达标,则建议加用PCSK9抑制剂,对于预估不能达标者也可直接启用他汀联合PCSK9抑制剂治疗。
综上所述,PCSK9抑制剂可有效降低LDL-C水平,促进ASCVD患者血脂管理达标,在多类人群的临床应用研究中展示出良好的有效性、安全性和耐受性,并可有效降低远期MACEs事件风险,为患者带来积极的临床获益。因此,PCSK9抑制剂对稳定高危斑块、延缓斑块进展甚至逆转斑块的临床价值值得进一步研究。随着ASCVD患者接受更精准的风险分层和更严格的血脂管理,PCSK9抑制剂在未来的临床应用中有望进一步发挥作用。
  • 国家重点研发计划(2016YFC1300304)
  • 北京市科技新星计划(Z181100006218055)
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2022年第47卷第3期
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doi: 10.11855/j.issn.0577-7402.2022.03.0292
  • 接收时间:2021-08-11
  • 首发时间:2025-12-17
  • 出版时间:2022-03-28
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  • 收稿日期:2021-08-11
  • 录用日期:2021-10-12
基金
National Key Research and Development Program of China(2016YFC1300304)
国家重点研发计划(2016YFC1300304)
Beijing NOVA Program(Z181100006218055)
北京市科技新星计划(Z181100006218055)
作者信息
    1解放军医学院,北京 100853
    2解放军总医院心血管病医学部,北京 100048

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陈韵岱,E-mail:
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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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