PCSK9抑制剂预防高胆固醇血症患者心血管疾病的药物经济学评价系统综述

目的 系统评价前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂预防高胆固醇血症患者心血管疾病的药物经济学评价研究,为优化临床治疗方案、制定相关政策及开展后续药物经济学评价研究提供参考。方法 检索PubMed、中国知网等中英文数据库,收集建库至2023年10月8日发表的PCSK9抑制剂（依洛尤单抗、阿利西尤单抗）预防高胆固醇血症患者心血管疾病的药物经济学评价文献,使用2022版卫生经济学评价报告标准共识（CHEERS 2022）量表进行文献质量评价,对纳入文献的基本信息、模型结构及相关参数、敏感性分析、结果等进行描述性分析。结果与结论 共纳入29篇文献,总体质量较好。研究视角包括卫生体系、支付方、全社会等,均采用了Markov模型;效果和效用值数据主要来自既往研究,成本主要测算了直接成本,贴现率为每年1.5%～5.0%,意愿支付阈值多设定为1～3倍人均国内生产总值,健康产出指标大部分采用生存年和质量调整生命年;大部分研究的敏感性分析显示,基础评价结果具有稳健性,主要影响因素为药品价格。大部分的中国研究发现,急性冠脉综合征、心肌梗死、动脉粥样硬化性心血管疾病患者使用PCSK9抑制剂预防心血管疾...     

PCSK9抑制剂治疗高胆固醇血症安全性文献分析

目的分析PCSK9抑制剂不良反应发生的规律及特点,为临床合理用药提供参考。方法检索2015年1月至2020年12月Web of Science、PubMed、The Cochrane Library、中国知网、万方数据知识服务平台、中国生物医学文献数据库、维普网数据库内有关PCSK9抑制剂不良反应的文献并进行统计分析。结果PCSK9抑制剂所致不良反应较少,发生1例严重血小板减少事件,预后良好。其他不良反应主要集中在注射部位反应(9%)、流感样症状(13%)、呼吸道感染症状(12%)、流感样肌样症状(10%)、皮疹(8%)等。结论目前PCSK9抑制剂临床应用安全性较高,但因涵盖样本量较小,仍需继续加强用药监测,警惕不良反应发生。     

PCSK9抑制剂依洛尤单抗和阿利西尤单抗致不良反应文献分析

目的:分析PCSK9抑制剂依洛尤单抗(evolocumab)和阿利西尤单抗(alirocumab)致不良反应(ADRs)发生情况及临床特点,为临床安全用药提供参考.方法:检索Web of Science、PubMed、维普数据库、中国知网数据库和万方数据库关于PCSK9抑制剂ADR的文献并进行分析.结果:PCSK9抑制...     

临床药师参与他汀不耐受的家族性高胆固醇血症患者降脂策略探讨

通过回顾1例他汀不耐受的家族性高胆固醇血症患者的临床资料和文献,探讨临床药师参与制订降脂方案和实施药学监护的方法与思路。临床药师从他汀相关肌病的发病机制与应对措施等方面为临床提供药物治疗信息,最终为患者制订普伐他汀40 mg,qn+依折麦布10 mg,qd+阿利西尤单抗75 mg,q2w三联降脂方案,同时对患者实施药学监护、用药指导和随访。患者调整治疗方案后,不良反应轻微可耐受,用药依从性提高,血脂水平达标。     

儿童家族性高胆固醇血症的治疗

家族性高胆固醇血症(FH)为常染色体显性遗传性疾病,主要为低密度脂蛋白受体基因突变引起的血脂代谢异常.本病临床症状明显,随年龄增长病情逐渐加重,早期治疗患儿病情可得到最佳控制并改善预后.目前,儿童FH患者可采取饮食、规律运动、药物治疗、血浆净化等干预措施,必要时可行肝脏移植及基因治疗.     

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。     

PCSK9抑制剂在动脉粥样硬化性心血管疾病中的临床研究进展

动脉粥样硬化性心血管疾病(ASCVD)现已成为危害人类健康的主要疾病之一。降低胆固醇治疗尤其是低密度脂蛋白-胆固醇(LDL-C),是ASCVD防治的基石,目前指南推荐控制LDL-C水平首选他汀类药物。但在临床实践中,经过他汀治疗的ASCVD患者仍存在较高剩留风险,另仍有部分患者不能耐受他汀类药物或在他汀类药物最大耐受剂量的情况下血脂仍不能达标。人前蛋白转化酶枯草溶菌素9(PCSK9)与LDL-C代谢密切相关,近年来大量基础和临床研究均证实PCSK9抑制剂能够显著降低血LDL-C水平,且耐受性和安全性良好。目前国外已批准PCSK9抑制剂用于临床。本文将系统综述有关PCSK9基因与血脂代谢的关系、PCSK9抑制剂的研发过程,总结其在基础和临床研究的最新进展。     

纯合子型家族性高胆固醇血症治疗药物-Mipomersen sodium

Mipomersen sodium是一种apo B-100合成的寡核苷酸抑制剂,是一种具有全新作用机制的降胆固醇药,临床上用于纯合子型家族性高胆固醇血症的辅助治疗。文中对Mipomersen sodium的作用机制、药效学、药代动力学、药物相互作用、临床评价和安全性等进行综述。     

杂合子型家族性高胆固醇血症的药物疗法

给出了结构化仿真模型以及它的两个基本组成部分，即模块和模块层次结构的框架描述，提出了一个用于搜索结构化仿真模型模块求解顺序的算法，在此算法的驱动下计算机可顺序组织仿真模型的求解，以催化裂化动态系统作为仿真实例，说明所提出的仿真模型结构设计技术的可行性。     

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.     

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。     

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.     

PCSK9 inhibitors for treating hypercholesterolemia

ABSTRACT

Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.

Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.

Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.     

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。     

Novel treatment options for the management of heterozygous familial hypercholesterolemia

Introduction: Even though statins represent the mainstay of treatment of heterozygous familial hypercholesterolemia (FH), their low-density lipoprotein cholesterol (LDL-C) lowering efficacy is finite and most patients with FH will not achieve LDL-C targets with statin monotherapy. Addition of ezetimibe with or without bile acid sequestrants will also not lead to treatment goals in many of these patients, particularly in those with established cardiovascular disease. In this selected subgroup of the FH population, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide substantial reductions in LDL-C levels, reduce cardiovascular morbidity and appear to be safe. Mipomersen, an antisense single-strand oligonucleotide that inhibits the production of apoB by binding to the mRNA that encodes the synthesis of apoB, and lomitapide, an inhibitor of microsomal triglyceride transfer protein, also reduce LDL-C levels but are currently indicated only for the management of homozygous FH.

Areas covered: In the present review, the role of PCSK9 inhibitors, mipomersen and lomitapide in the management of FH is briefly discussed. Other LDL-C-lowering agents under evaluation include inclisiran, a small interference RNA molecule that induces long-term inhibition of PSCK9 synthesis, anacetrapib, a cholesterol ester-transfer protein inhibitor, ETC-1002 (bempedoic acid), an inhibitor of adenosine triphosphate citrate lyase, and gemcabene, which reduces hepatic apolipoprotein C-III mRNA. The safety and efficacy of these agents are also reviewed.

Expert Commentary: Even though several novel treatment options for heterozygous FH are under development, it remains to be shown whether these treatments will also reduce cardiovascular morbidity in these high-risk patients.     

Proprotein convertase subtilisin / kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015)

Introduction: The identification by Abifadel et al. in 2003 of the first mutations of PCSK9 was the major breakthrough in the cholesterol field that led to a new therapeutic target. This discovery paved the way to new lipid lowering drugs reducing LDL-cholesterol levels through the inhibition of PCSK9. Two anti-PCSK9 monoclonal antibodies have received FDA and EMA approvals: Alirocumab and Evolocumab.

Areas covered: This article reviews the different strategies that are pursued to modulate the functional activity of PCSK9 for lowering LDL-cholesterol levels. It also provides a brief overview of the patents related to PCSK9 from 2011 until the end of 2015. This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9, focusing on anti-PCSK9 monoclonal antibodies and the related clinical trials.

Expert opinion: Anti-PCSK9 antibodies are a new class of lipid lowering drugs with promising results in reducing LDL-cholesterol. Long-term ongoing studies investigating on a large scale the efficacy and safety of the anti-PCSK9 antibodies and their cardiovascular outcomes are eagerly awaited.     

Discovery of [5,5′-bibenzo[d][1,3]dioxol]-6-substituted amine derivatives as potent proprotein convertase subtilisin/kexin type 9 inhibitors

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hyperlipidemia. In discovery of novel small molecules that interfere PCSK9/LDLR protein–protein interaction (PPI), structural modification was performed based on our previously derived compounds. A series of [5,5′-bibenzo[d][1,3]dioxol]-6-amine analogs were designed and synthesized for the activity evaluation. In the PCSK9/LDLR PPI impairing test, molecules D28 and D29 , exhibited remarkable inhibitory potency with IC₅₀ values of 8.30 and 6.70 μM compared with SBC-115337 (17.89 μM), respectively. Molecular docking predicted the binding pattern of compounds D28 and D29 in the LDLR binding site of PCSK9. Hydrophobic interactions play an important role in the binding of aromatic molecular fragments to the pockets in the PCSK9/LDLR binding interface. Further LDLR expression and LDL uptake studies revealed that both D28 and D29 restored LDLR expression on the surface of hepatic HepG2 cells and improved extracellular LDL uptake in the presence of PCSK9. It is significant that molecules D28 and D29 exhibited potential for the treatment of hyperlipidemia in current in vitro investigations. Generally, lead compounds with novel structures were developed in the present study for further design of lipid-lowering molecules by targeting PCSK9/LDLR PPI.     

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.     

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.