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。     

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。     

PCSK9抑制剂的研究进展

前蛋白转化酶枯草溶菌素9(PCSK9)通过促进低密度脂蛋白受体LDLR降解来调节血浆低密度脂蛋白胆固醇(LDL-C)代谢。抑制PCSK9可以显著降低血浆LDL-C水平,因此PCSK9作为新的降脂靶点受到越来越多的关注。本文对新降脂靶点PCSK9及其抑制剂最新研发现状及临床研究进展进行综述。     

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。     

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.     

心血管疾病的重要靶点PCSK9及其抑制剂的研究进展

高水平的低密度脂蛋白胆固醇(LDL-C)与心血管疾病风险相关。枯草溶菌素前蛋白转换酶9(PCSK9)由肝脏产生,在多个组织和细胞中表达。与肝细胞表面LDLR结合后形成PCSK9/LDLR复合物,导致LDLR被溶酶体降解。抑制PCSK9可减少LDLR降解,提高LDL-C在循环中的清除率,从而降低血液中胆固醇水平。此外,PCSK9还参与动脉粥样硬化、心衰和心肌梗死进程,并存在于各种类型的感染(细菌或病毒)和脓毒症中,与多种炎症标志物相关。鉴于其多种生理作用,抑制细胞外和细胞内PCSK9具有临床意义。目前临床应用的PCSK9抑制剂主要是单克隆抗体,但随着新类型抑制剂的研究,会有更多高效、经济的药物供临床医生选择,如反义寡核苷酸、RNA干扰药物、疫苗、小分子抑制剂等。     

调脂新药Evolocumab的临床评价

Evolocumab是一种抑制前蛋白转化酶枯草溶菌素9（PCSK9）的全人源单克隆抗体,由美国安进公司开发,目前正在进行多项3期临床研究,用于高脂血症的治疗。临床研究显示其降低低密度脂蛋白胆固醇（LDL-C）幅度达40%～80%,安全且耐受性好,为降脂治疗带来了新的药物选择。     

前蛋白转化酶枯草溶菌素9单克隆抗体全球研究趋势及热点分析

目的 分析前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)单克隆抗体的全球研究现状、热点及前沿,为我国相关科研工作的开展及临床合理用药提供参考。方法 检索2011年1月—2022年2月Web of Science数据库中收录的PCSK9单克隆抗体相关研究文献,通过可视化文献分析软件(CiteSpace)对纳入研究的文献进行分析。结果 共纳入文献723篇,年发文量呈总体上升趋势,发文量排名前3位的国家分别为美国、法国和英国,发文量最多的机构是赛诺菲公司,文献篇均被引最高的机构是布莱根妇女医院;研究的热点内容主要有PCSK9单克隆抗体对高胆固醇血症、不耐受他汀类药物的患者、心血管高风险患者、联合他汀类药物降脂治疗的有效性和安全性;近两年研究的前沿为PCSK9单克隆抗体在急性冠脉综合征患者中的应用以及降低脂蛋白(a)水平后的临床获益。结论 PCSK9单克隆抗体降血脂的有效性和安全性已经过大量研究证实,但仍缺乏对其经济性及在特殊人群中的应用研究,未来研究应重点关注。     

以他汀类药物为基础的降脂药物联合应用研究进展

降脂治疗是预防动脉粥样硬化性心血管疾病的基石,其主要目标是降低低密度脂蛋白胆固醇和非高密度脂蛋白胆固醇。目前他汀类药物仍是降脂治疗的首选。然而,在临床实践中,许多患者单用他汀类药物治疗其血脂水平仍不能达标。而降脂药物联合应用不仅增加疗效,且可能减少不良反应。本文对以他汀类药物为基础的降脂药物联合应用的临床研究进展进行了综述。     

PCSK9抑制剂在冠心病患者中的短期治疗效果及预后分析

目的 观察冠心病患者在常规治疗基础上联合使用前蛋白转化酶枯草溶菌素(PCSK9)抑制剂的短期疗效与预后效果。方法 选取2018年3月—2021年2月厦门大学附属心血管医院收治的冠心病患者90例,采用随机数字表法分为观察组和对照组,每组45例。对照组患者给予他汀类药物联合依折麦布治疗,观察组患者在对照组治疗基础上加用PCSK9抑制剂治疗,2组均连续给药3个月。比较2组患者治疗前后血脂水平与心血管不良事件发生率。结果 治疗3个月后,2组患者总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、三酰甘油(TG)及脂蛋白a[Lp(a)]水平均明显低于治疗前,且观察组患者TC、LDL-C、TG水平均低于对照组,差异均有统计学意义(P<0.05),但治疗3个月后2组患者Lp(a)水平比较差异无统计学意义(P>0.05);治疗前后2组患者高密度脂蛋白胆固醇(HDL-C)水平比较差异无统计学意义(P>0.05)。观察组患者心血管不良事件总发生率为6.67%,略低于对照组的13.33%,但差异无统计学意义(χ²=1.111,P=0.292)。结论 他汀类药物联合依折...     

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.     

Meta-analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD

The advent of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) ushered in a new era of dyslipidemia pharmacotherapy. The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran—a small interfering RNA-based agent targeting PCSK9—reported similar lipid-lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta-analysis (random-effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low-density lipoprotein cholesterol (LDL-C) was observed across all agents (−51% [95% confidence interval {CI}: −61%, −41%]). Despite the impressive reduction in LDL-C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73–0.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74–0.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26–3.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9-targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow-up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum.     

What is the impact of the 2017 cochrane systematic review and meta-analysis that evaluated the use of PCSK9 inhibitors for lowering cardiovascular disease and mortality?

Introduction: In 2017, Schmidt et al. conducted a Cochrane systematic review and meta-analysis to evaluate the effect of using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to reduce low-density-lipoprotein- cholesterol (LDL-C) and cardiovascular disease (CVD). The Cochrane review was a systematic review and meta-analysis of 20 randomized, double-blinded trials that compared the use of PCSK9 inhibitors with statins/ezetimibe, ezetimibe, or placebo for a treatment duration of at least 24 weeks. The use of PCSK9 inhibitors lowered the risk for CVD (OR 0.86 (0.80 to 0.92)) but not mortality (OR 1.02 (0.91 to 1.14)) when compared to placebo.

Areas covered: The following article evaluates the recently published Cochrane review and clarifies the efficacy of PCSK9 inhibitors for improving cardiovascular morbidity and mortality.

Expert opinion: The Cochrane review discussed suggests that PCSK9 inhibitors are effective in lowering LDL-C and the risk of CVD but not the risk of mortality. The higher price of PCSK9 inhibitors is a further deterrent for using them as a substitute for statins – cholesterol lowering medications with history showing they lower mortality. Statins should remain the gold-standard cholesterol-lowering drug class until PCSK9 inhibitors become more affordable and demonstrate consistent efficacy for reducing CVD and mortality.     

Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia

When secreted into the circulation, proprotein convertase subtilisin kexin type 9 (PCSK9) blocks the low-density lipoprotein receptors (LDL-R) and, as a consequence, low-density lipoprotein cholesterol (LDL-C) levels increase. Therefore, PCSK9 has emerged as a potential therapeutic target for lowering LDL-C levels and preventing atherosclerosis. The US Food and Drug Administration (FDA) has approved two monoclonal antibodies (mAbs) against PCSK9, but the expensive manufacturing process limits their use. Subsequently, there have been tremendous efforts to develop cost-effective small molecules specific to PCSK9 over the past few years. These small molecules are promising therapeutics that act by preventing the synthesis of PCSK9, its secretion from cells, or the PCSK9–LDRL interaction. In this review, we summarize recent developments in the discovery of small-molecule PCSK9 inhibitors, focusing on their design, therapeutic effects, specific targets, and mechanisms of action.     

A safety evaluation of evolocumab

Introduction: Evolocumab is an injectable, fully human monoclonal antibody and a member of the newest class of low density lipoprotein cholesterol (LDL-C) lowering agents called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The PCSK9 inhibitors are the most significant advance in lipid therapy since the introduction of the first statin 30 years ago.

Areas covered: The PCSK9 monoclonal antibodies have demonstrated a consistently high LDL-C lowering efficacy with and without statins and/or other lipid lowering therapies (LLT). LDL-C levels achieved with these agents are lower than has ever been possible before. This review will focus on the overall safety of evolocumab including cognitive impairment, very low LDL-C levels, new onset diabetes and glucose abnormalities, effect on vitamin E and steroid hormones, liver and muscle abnormalities, and immunogenicity and injection site reactions. The phase II and III clinical trials had relatively low patient-years of exposure, but the open label extension studies and the recently published outcomes trial, FOURIER, will be the focus of this paper. The safety profile of evolocumab to date is remarkable and extremely encouraging as will be demonstrated.

Expert opinion: The PCSK9 inhibitors will be responsible for a new era in lipid therapy that will expand our knowledge of lipid levels and cardiovascular disease (CVD) prevention with an efficacy and safety profile not previously available in clinical practice.     

动脉粥样硬化性心血管疾病的药物治疗研究进展

动脉粥样硬化性心血管疾病（atherosclerotic cardiovascular disease,ASCVD）患病率的快速增长是国内心血管疾病的重要特征。尽管已知多个因素包括家族遗传、生活方式和饮食习惯等与ASCVD的病理过程相关,但其发病机制尚不明确。目前临床对ASCVD的传统干预手段是以低密度脂蛋白胆固醇（low-density lipoprotein cholesterol,LDL-C）为靶标的降脂药物治疗。近年来,前蛋白转化酶枯草溶菌素9（proprotein convertase subtilisin/kexin type 9,PCSK9）单抗等药物的出现使降脂治疗焕发新的“生机”。一些抗炎药物在临床试验中显著降低ASCVD患者心血管事件发生的风险,亦展现出了极大的开发潜力。此外,越来越多的研究从表观遗传的角度来阐明ASCVD的发病机制,发掘出了许多治疗靶点。综述这些药物以及相关靶点的研究进展,为未来的ASCVD临床药物治疗探索方向。     

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。