PCSK9抑制剂治疗家族性高胆固醇血症有效性与安全性的系统评价

Efficacy and safety of proprotein convertase subtilisin/kexin9 inhibitors on familial hypercholesterolemia: a systematic review

目的:系统评价PCSK9抑制剂治疗家族性高胆固醇血症(familial hypercholesterolemia, FH)的有效性与安全性。方法:计算机检索PubMed、Embase、Cochrane Library、中国知网、维普、万方数据库以及临床试验注册平台Clinical Trials.gov,筛选并纳入PCSK9抑制剂治疗FH的随机对照试验(randomized controlled trials, RCTs),检索时限为建库至2020年10月,由2名研究者根据纳入及排除标准独立筛选文献、评价研究质量和提取资料。采用RevMan 5.3软件对符合标准的RCT进行荟萃分析。结果:最终纳入10篇文献,11项RCT,共计2 453例患者,随访时间为12~78周。有效性分析结果显示:与安慰剂相比,PCSK9抑制剂可降低FH患者低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)47.03%(95%CI:41.29~52.77,P<0.05),并显著改善其他7项血脂指标;且12周时杂合子型家族性高胆固醇血症(heterozygous familial hypercholesterolemia, HeFH)患者LDL-C降幅大于纯合子型家族性高胆固醇血症(homozygous familial hypercholesterolemia, HoFH)患者[(46.66%,95%CI:40.67~52.65)vs.(32.80%,95%CI:23.03~42.56),P<0.05]。安全性分析结果显示,在严重治疗相关不良反应(SAEs)方面,PCSK9抑制剂组与安慰剂组之间差异无统计学意义(P>0.05)。最常见的不良反应为鼻咽炎、注射部位反应、流感、神经系统反应和疲劳;其中PCSK9抑制剂相关神经系统反应(RR=1.65,95%CI:1.05~2.57)、疲劳(RR=2.81,95%CI:1.17~6.74)发生率更高,且差异具有统计学意义(P<0.05)。结论:研究结果表明,与安慰剂相比,PCSK9抑制剂可显著改善各项血脂指标,而严重不良反应发生率差异无统计学意义。

OBJECTIVE To systemically evaluate the efficacy and safety of proprotein convertase subtilisin/kexin9(PCSK9)inhibitors on familial hypercholesterolemia(FH).METHODS The databases of PubMed, Embase, Cochrane Library, CNKI,VIP,WangFang and ClinicalTrial.gov were searched for the randomized controlled trials(RCTs)of PCSK9 inhibitors for FH from inception until October 2020.Two independent reviewers identified the literatures according to the inclusion and exclusion criteria, evaluated the quality of assessment methods of each study and extracted the relevant information.Then Meta-analysis was performed with RevMan 5.3 software. RESULTS A total of 10 articles(11 RCTs)comprising 2 453 subjects were enrolled with a follow-up period of 12-78 weeks.As compared with placebo, PCSK9 inhibitors significantly reduced low density lipoprotein cholesterol(LDL-C)by 47.03%(95%CI:41.29-52.77,P<0.05)and improved markedly the other 7 lipid parameters;LDL-C decreased more for heterozygous familial hypercholesterolemia(HeFH)than for homozygous familial hypercholesterolemia(HoFH)at Week 12[(46.66%,95%CI:40.67-52.65)vs.(32.80%,95%CI:23.03-42.56),P<0.05].For safety analysis, no difference existed between PCSK9 inhibitors and placebo in serious adverse events(SAEs)(P>0.05).The most common adverse events were nasopharyngitis, injection-site reaction, influenza, neurologic events and fatigue;only for neurologic events(RR=1.65,95%CI:1.05-2.57),fatigue(RR=2.81,95%CI:1.17-6.74).There was significant inter-group difference(P<0.05). CONCLUSION PCSK9 inhibitors show significant improvements in lipid parameters.However, there is no significant difference in SAEs while comparing with placebo.