前蛋白转化酶枯草溶菌素9抑制剂:调节血脂的新策略

前蛋白转化酶枯草溶菌素9(PCSK9)主要促进肝脏中低密度脂蛋白受体(LDLR)降解来调节胆固醇代谢。PCSK9功能获得型基因突变是导致常染色体显性遗传性高胆固醇血症的原因之一,而PCSK9功能缺失型基因突变则与低水平的低密度脂蛋白胆固醇(LDL-C)和冠心病发生的减少有关。目前,PCSK9已经成为新的调节血脂药物作用靶点,两种单克隆抗体类PCSK9抑制剂已完成Ⅱ、Ⅲ期临床试验。本文就单克隆抗体类PCSK9抑制剂的最新研究进展作一综述。     

PCSK9抑制剂调脂作用的研究进展

前蛋白转化酶枯草杆菌蛋白酶9型(PCSK9)与血脂代谢关系密切,其通过竞争性结合低密度脂蛋白受体(LDLR),导致低密度脂蛋白(LDL)降解减少,引发以低密度脂蛋白胆固醇(LDL-C)水平升高为特点的脂代谢紊乱.PCSK9抑制剂可通过抑制PCSK9与LDLR结合、抑制PCSK9表达发挥调脂作用,降低LDL-C水平.目前...     

前蛋白转化酶枯草溶菌素9抑制剂的研究进展

低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)升高是心血管疾病危险因素之一。前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)是一种人血清蛋白,通过促进低密度脂蛋白受体(low-density lipoprotein receptor,LDLR)降解,导致LDL-C升高,因此PCSK9已经成为新的调节血脂药物作用靶点。在目前研究中的PCSK9抑制剂中,2种单克隆抗体类抑制剂已完成Ⅱ期临床试验,1种小分子干扰RNA抑制剂正在进行Ⅰ期临床试验,2种反义寡核苷酸类抑制剂Ⅰ期临床试验提前终止。本文对上述PCSK9抑制剂的研究情况作一综述。     

人前蛋白转化酶枯草溶菌素9抑制剂在治疗高脂血症中的研究进展

动脉粥样硬化是一种贯穿于每个人体生命过程中的慢性疾病,其最终结局以导致动脉粥样硬化性心血管疾病(ASCVD)最为常见。而促使动脉粥样硬化(AS)发生发展的最主要因素就是高脂血症,他汀类药物是目前临床上应用最广泛、最经典的一线降脂药物,给广大病人带来了获益。但有一部分病人在充分使用他汀类降脂药物时会出现血脂仍不达标或不能耐受的情况。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)抑制剂作为临床上另外一类新型降脂药,具有总体降脂效果好、不良反应相对较少、能改善病人预后等优势,是近几年最被看好的新型降脂药物。但也存在比如价格昂贵、病人依从性差、可能出现相关并发症等劣势。该文将系统地阐述PCSK9抑制剂在治疗高脂血症的研究进展。     

前蛋白转化酶枯草溶菌素9对胆固醇水平的影响

目的 探讨前蛋白转化酶枯草溶菌素9(PCSK9)水平与血脂等代谢相关指标的关系.方法 采用随机抽样方法收集388名体检人员的空腹血样本388份,并对入选者进行问卷调查、体格检查及代谢相关指标的测定,用ELISA方法检测血清样本PCSK9水平.结果 PCSK9水平为(86.19±32.33)ng/ml,呈偏态分布,女性PCSK9水平显著高于男性(P<0.01).PCSK9水平与总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)呈正相关(P<0.05).他汀类药物治疗组PCSK9水平显著高于未服用他汀类药物组(P<0.01).结论 人群中PCSK9水平呈偏态分布,并且与性别、TC、LDL-C、HDL-C有关.他汀类药物可以升高血PCSK9水平.     

胆固醇酯转移蛋白抑制药在调脂治疗中的作用再评价

胆固醇酯转移蛋白抑制药是一种新型的调脂药物,具有升高高密度脂蛋白胆固醇,促进胆固醇转运等作用。托塞匹布是目前研究最多的胆固醇酯转移蛋白抑制药,最近一些有关托塞匹布的研究得出了不利的结果。本文对胆固醇酯转移蛋白抑制药在调脂治疗和冠心病预防中的作用和地位进行讨论。     

一种调血脂的新型单抗药物evolocumab

evolocumab是首个用于调节血脂的前蛋白转化酶枯草溶菌素9(PCSK9)型抑制剂,用于治疗原发性高胆固醇血症和12岁及以上青少年和成年患者的纯合子家族性高胆固醇血症(Ho FH)。evolocumab通过与PCSK9特异性结合,从而减缓低密度脂蛋白受体的降解,显著降低体内低密度脂蛋白胆固醇(LDL-C)的水平。单独用药或联合他汀类药物可以使患者LDL-C水平降低55%~65%,特别适合于对他汀类不耐受以及高剂量他汀类(如阿托伐他汀、瑞舒伐他汀)调脂不达标的患者,为调脂治疗带来了新的选择。本文对其药理作用,在治疗和改善胆固醇高血脂的临床试验和安全性研究等方面的研究进展进行综述。     

中性内肽酶抑制药在心血管疾病治疗中的应用

中性内肽酶抑制药通过抑制中性内肽酶 ,延迟缓激肽分解 ,抑制血管紧张肽Ⅱ和内皮素生成等机制发挥扩血管 ,改善血管内皮功能、促进排钠利尿等作用 ,在高血压、心力衰竭等疾病的治疗中发挥重要作用。     

新型降脂药人前蛋白转化酶枯草溶菌素9抑制剂与动脉粥样硬化性心血管疾病、静脉血栓栓塞疾病关系的研究进展

随着生活方式的改变,心脑血管疾病逐渐成为全人类死亡的“头号杀手”,高于恶性肿瘤、糖尿病等。血脂的升高尤其是低密度脂蛋白胆固醇(LDL-C)的升高与动脉粥样硬化性心血管疾病(ASCVD)的发生、发展息息相关。现有的专家共识、指南提出他汀类药物是降低LDL-C的一线用药,但仍可能会发生复发性缺血事件。人前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂作为一类新型降脂药,有显著降低血LDL-C水平,同时又可降低脂蛋白(a)的水平,又与ASCVD与静脉血栓栓塞疾病(VTE)的发病可能相关。本文将系统地阐述新型降脂药PCSK9抑制剂与ASCVD、VTE的关系研究进展。     

Narc-1/pcsk9在脂质代谢与动脉粥样硬化发生中的作用

血脂代谢紊乱是导致动脉粥样硬化(AS)发生的主要危险因素。人类前蛋白转化酶枯草溶菌素9(PCSK9)是近年来新发现的一种与调节脂质代谢密切相关的基因,编码前蛋白转化酶NARC-1。Narc-1/pcsk9可通过调节细胞表面的低密度脂蛋白受体(LDLR)水平,参与脂质代谢,从而在动脉粥样硬化性疾病的发生、发展中发挥重要作用。因此,阐明Narc-1/pcsk9在脂质代谢以及动脉粥样硬化发生中的作用及机制,对高胆固醇血症和动脉粥样硬化药物的研发具有重要意义。     

前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂——Evolocumab

前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)是一种由肝脏合成的丝氨酸激酶,可促使体内低密度脂蛋白胆固醇(LDL-C)累积,抑制PCSK9活性则可使LDL-C水平显著下降。Evolocumab(商品名Repatha)是由美国安进公司研发的全球第一个PCSK9抑制剂,2015年7月在欧盟上市,被批准用于治疗原发性和家族性高胆固醇血症。该药的特别之处在于能大幅降低他汀类药物耐受患者体内的LDL-C,因此可有效解决广泛使用他汀类药物后出现的大面积耐药问题。笔者就Evolocumab的基本性质、作用机制、药效学、药动学、临床应用、研发历程等情况作一概述,以期能为医院临床用药及药物开发提供参考。     

Impact of diet and exercise on proprotein convertase subtilisin/kexin 9: A mini-review

Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) plays an important role in the regulation of blood cholesterol levels, and inhibition of PCSK9 with monoclonal antibodies reduces LDL cholesterol by more than 50% over and above what can be achieved with statins or ezetimibe alone. Diet and exercise influence PCSK9 levels; however data on this issue are scarce. Regarding diet, a high oleic canola/docosahexaenoic acid oil blend, marine n-3 polyunsaturated fatty acids, vegetable n-6 polyunsaturated fatty acids, a Mediterranean style diet and acute fasting, but not necessarily weight reduction are associated with low PCSK9 concentrations, whereas a high fructose diet is associated with high PCSK9 concentrations. Animal data regarding the effect of diet on PCSK9 must be interpreted with caution, because even between rodent species, significant differences become apparent. Regarding exercise, a decrease in PCSK9 has been reported in one investigation along with an intervention promoting active use of stairs rather than elevators. Reports from sparse animal studies regarding the effect of exercise on PCSK9 have yielded varying results.     

Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents

Importance of the field: Proprotein convertase subtilisin kexin 9 (PCSK9) is a new actor discovered in 2003 that is implicated in autosomal dominant hypercholesterolemia, cholesterol homeostasis and coronary heart disease. It has been shown to degrade the low-density lipoprotein (LDL) receptor independently of its catalytic activity. Several pharmacological strategies to reduce PCSK9 are being thoroughly investigated.

Areas covered in this review: This article reviews all different strategies that are presently pursued to modulate the functional activity of PCSK9 which is a prime target for controlling LDL-cholesterol. It also provides a briefing of all the patents up to July 2010 from various organizations including pharmaceutical companies and academic institutions that have been submitted and/or approved.

What the reader will gain: This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation and in the development of cholesterol lowering drugs. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9 including antisense technology and specific antibodies.

Take home message: Clinical trials have been launched using RNA interference approaches to reduce PCSK9 expression or specific antibodies targeting and inhibiting PCSK9 interaction with the LDL receptor. They constitute very promising approaches to reducing cholesterol levels and coronary heart disease.     

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

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。     

Marine n-3 polyunsaturated fatty acids lower plasma proprotein convertase subtilisin kexin type 9 levels in pre- and postmenopausal women: A randomised study

ObjectiveTo investigate whether a supplement of 2.2 g of marine n-3 polyunsaturated fatty acids (PUFA) influences plasma proprotein convertase subtilisin kexin type 9 (PCSK9) levels in pre- and postmenopausal women.MethodsNinety-two healthy women were randomly assigned to consume 2.2 g marine n-3 PUFA or a control oil (thistle oil) daily for 12 weeks. Adipose tissue, a long-term marker of dietary intake of seafood was collected at baseline and blood samples were drawn at baseline and after 12 weeks of supplement intake.ResultsPlasma PCSK9 levels were significantly reduced by 11.4% for premenopausal women and 9.8% for postmenopausal women after the supplement of 2.2 g of marine n-3 PUFA compared with control oil. The mean change of plasma PCSK9 levels between participants receiving marine n-3 PUFA and control oil was 16.1% for premenopausal women and 13.1% for postmenopausal women. There was, however, no correlation between baseline levels of plasma PCSK9 and the fatty acid content of marine n-3 PUFA in adipose tissue.ConclusionThis study showed that 2.2 g marine n-3 PUFA reduce plasma PCSK9 levels in both pre- and postmenopausal women.     

Efficacy and safety of different proprotein convertase subtilisin/kexin type 9 inhibitors in patients with hypercholesterolemia at high cardiovascular risk: a systematic review and meta-analysis

OBJECTIVE To evaluate the efficacy and safety of different PCSK9 inhibitor therapy in hypercholesterolemia patients at high cardiovascular risk.METHODS Pubmed, Embase, Cochrane Library and Clinical Trials.gov were searched from their inception up to January 2019. Inclusion criteria were randomized clinical trials, hypercholesterolemia patients at high cardiovascular risk and received PCSK9 inhibitor. Study-arm-level weighted mean differences(WMDs) and 95% CIs were pooled for continuous data, meanwhile relative risks(RRs) and 95%CIs were pooled for discontinuous data, both using random-effects model. Subgroup analysis based on drug types, doses, race and control types were conducted.The primary outcomes were mean or percent change in low density lipoprotein cholesterol(LDL-C) and percentages of participants who have experienced treatmentemergent adverse events(TEAEs). The secondary outcomes were percent change in other lipid profiles, incidence of major cardiovascular events and incidence of adverse events of interest. RESULTS 27 trials recruiting37,630 individuals were included in the meta-analysis. Of these, 27 062(71.9%) were men and the mean age was61.6; 4 trials included only Asians and the population of the remaining trials were mainly Caucasian(>75%).Alirocumab and evolocumab presented significant reduction of LDL-C(alirocumab: WMD: 1.48; 95% CI:-1.74～1.22; P<0.01; evolocumab: WMD:-2.14; 95%CI:-2.43～-1.85; P<0.01) and no racial difference was found. Results of indirect comparison with placebo as reference control showed that evolocumab was superior to alirocumab for the levels of absolute change of LDL-C(WMD: 0.60; 95%CI: 0.24～0.97; P=0.01) and percent change of several other lipid profiles(P<0.05). Evolocumab was also associated with lower risk of major cardiovascular events(RR: 0.86; 95% CI: 0.80 to 0.92; P<0.01). PCSK9 inhibitor presented overall good safety except the significantly increased risk of injection site reactions(RR: 1.82; 95%CI: 1.28～2.60; P=0.01). Bococizumab presented a notable increase of TEAEs(RR: 1.15; 95%CI:1.08-1.23; P<0.01)and higher risk of injection site reactions(RR: 6.57, 95%CI: 4.28-10.08; P<0.01). CONCLUSION Both alirocumab and evolocumab were effective and safe for hypercholesterolemia patients at high cardiovascular risk of all races.Evolocumab performed relatively better for the lipid-management improvement.     

The role of proprotein convertase subtilisin/kexin type-9 concentration and paraoxonase 1 activities in the blood of women with polycystic ovary syndrome

This study aimed to evaluate the concentration of proprotein convertase subtilisin/kexin type-9 (PCSK9) and the activities of paraoxonase 1 in women with and without polycystic ovary syndrome (PCOS). We found significant higher PCSK9, whereas lower high-density lipoprotein concentration in the serum of women with PCOS when compared to the group without PCOS. Also paraoxonase 1 activities were significantly different between women with PCOS than without PCOS. In addition, the women with PCOS and insulin resistance had higher concentrations of PCSK9 than women with PCOS and insulin sensitivity. Higher PCSK9 concentration in the group with PCOS could be also associated with hormones concentrations.Changes in paraoxonase 1 activities and lipid profile parameters as well as higher concentration of PCSK9 in the group of women with PCOS could be associated with metabolism disorders, but due to the small clinical sample size, the study should be continued.