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血脂速递丨优化血脂管理 预防心血管疾病:关注风险评估和治疗选择

作者:国际循环网   日期:2019/8/30 14:14:50

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动脉粥样硬化性心血管疾病(ASCVD)是当前全球发病和死亡的首要原因[1-4]。作为降低ASCVD事件发生风险关键之一,血脂管理的重要性不言而喻。

  动脉粥样硬化性心血管疾病(ASCVD)是当前全球发病和死亡的首要原因[1-4]。作为降低ASCVD事件发生风险关键之一,血脂管理的重要性不言而喻。如何通过优化血脂管理来改善心血管疾病的一级和二级预防成为心血管治疗领域的关注焦点。2019年8月发表于Current Cardiology Reports上的一篇文章[5]回顾和总结了ASCVD一级预防的相关进展,并重点阐述了新型降脂药物PCSK9抑制剂可显著降低低密度脂蛋白胆固醇(LDL-C)水平达50%~70%,使已知ASCVD高危患者主要心血管事件额外减少15%的卓越疗效。
 
  进行风险评估和生活方式调整可降低ASCVD风险
 
  ASCVD风险评估对于血脂异常的管理和了解每例患者的心血管风险至关重要,是一级预防的基础(图1)。临床上已经建立了众多风险评估模型,包括Framingham模型、系统性冠状动脉风险估计(SCORE)和汇总队列方程(PCE)[6-8]等,其目的在于为临床医生提供有意义和可操作的参考指标,以鼓励患者进行生活方式调节和/或接受药物干预。
 
  调节生活方式,包括饮食和体育锻炼,是降低心血管疾病风险的主要干预措施。建议血脂异常患者接受植物性饮食,以全谷类、水果、蔬菜和豆类为主,以降低胆固醇,改善血糖异常,降低炎症,甚至是降低脂蛋白(a)[9-13]。
 
图1. 一级预防中确定ASCVD风险的关键因素
 
  低密度脂蛋白胆固醇是血脂管理中重要干预指标
 
  大量研究已证实,LDL-C在心肌梗死、缺血性卒中和心血管死亡的发生发展中具有重要作用[14,15,16],低密度脂蛋白(LDL)沉积在血管壁上是形成动脉粥样硬化的根本原因[17]。美国和欧洲的心血管指南均推荐将LDL-C作为一种可改善的危险因素,建议医生与患者给予高度重视[4,18]。
 
  HMG辅酶A还原酶抑制剂——他汀类药物作为当前针对LDL-C治疗的主要药物,被誉为是降脂治疗的基石。他汀主要通过上调LDL受体发挥疗效。多项研究证明,他汀类药物治疗在心血管疾病的一级和二级预防中显著减少主要心血管事件的发生风险[19-22]。一项针对随机对照研究的荟萃分析显示,他汀类药物每降低LDL-C 1 mmol/L(38.7 mg/dl),ASCVD事件的风险降低20%以上,这一疗效也进一步夯实了LDL-C“越低越好”的治疗理念[23,24]。既往二十年中,他汀类药物治疗被引入心血管一级和二级预防工作,使心血管医学领域发生了革命性变化。
 
  另一种降脂药物——胆固醇吸收抑制剂依折麦布则表现出可降低LDL-C约20%的临床作用。依折麦布常用于心血管高危患者的二级预防,也可选择性用于某些高危一级预防患者以及对他汀类药物不耐受的患者[4,25]。
 
  尽管他汀类药物和依折麦布可带来一定的LDL-C改善。然而目前降脂领域最受关注的药物无疑是新型的降脂利器——前蛋白转化酶枯草杆菌蛋白酶/kexin 9(PCSK9)抑制剂。PCSK9抑制剂的问世为管理心血管高危患者的LDL-C水平和残余心血管风险提供了有效选择。PCSK9是一种由肝脏合成的分泌型丝氨酸蛋白酶,能与肝细胞表面的低密度脂蛋白受体(LDL-R)结合,使LDL-R降解,导致循环中LDL-C增加。PCSKP抑制剂是一种人单克隆免疫球蛋白G2,可抑制肝脏LDLR降解,增加肝脏的LDL-C清除率,降低LDL-C水平[26]。研究显示,PCSK9抑制剂可将LDL-C水平显著降低达50%~70%,并可进一步降低已接受他汀类药物治疗的ASCVD高危患者的主要心血管事件15%[25,27,28]。其中,关于中国首个上市的PCSK9抑制剂依洛尤单抗的里程碑式研究FOURIER研究发现:相较于安慰剂,依洛尤单抗显著降低LDL-C至0.8 mmol/L(30 mg/dl),降幅达59%(P<0.001),降幅绝对值为1.5 mmol/L(56 mg/dl) (95%CI:55~57)。并且,在长达120周的持续观察时间内,依洛尤单抗使LDL-C始终保持在较低水平,治疗的有效性持久存在。在降低主要终点和关键次要终点方面,与安慰剂相比,依洛尤单抗(140 mg每隔一周或420 mg每月一次)显著降低主要复合终点(心肌梗死、卒中、心血管死亡、冠脉血运重建及因不稳定心绞痛住院)风险达15%;降低次要终点(心肌梗死、卒中或心血管死亡)风险达20%。
 
  根据最新ACC/AHA指南,PCSK9抑制剂目前被推荐用于以下几类患者:(a)接受最大耐受量他汀类药物治疗但LDL-C仍高于1.8 mmol/L(70 mg/dl)的极高危二级预防患者;(b)尽最大耐受量治疗但未达到目标的重度原发性高胆固醇血症(LDL-C >4.9 mmol/L或190 mg/dl)或杂合子家族性高胆固醇血症患者[4]。此外,在临床实践中,PCSK9抑制剂还用于具有多种风险因素的“一级预防”患者,这些患者具有显著的他汀类药物不耐受(即使是低剂量他汀类药物也无法耐受),以及存在冠状动脉粥样硬化的证据。
 
  目前仍有一些新型降脂药物处于试验阶段,如ATP柠檬酸裂解酶抑制剂bempedoic acid。我们期待新的药物能为未来的血脂管理再添助力。
 
  关注多重靶点全面改善血脂异常
 
  既往20年中,主要通过LDL-C的治疗来改善血脂异常和减轻总体心血管风险。但其他的血脂蛋白,如高密度脂蛋白胆固醇(HDL-C)、甘油三酯和脂蛋白(a)在保证心血管健康中也发挥着重要作用。随着针对这些指标的研究不断开展,未来或许有更多的脂蛋白干预药物研发上市,从而进一步降低ASCVD患者的残余心血管风险。
 
  高密度脂蛋白胆固醇
 
  HDL-C被认为是心血管事件的独立和强预测因子,在降低心血管风险中起关键作用[29]。研究发现,HDL-C每增加1 mg/dl,不良心血管结局的发生率大约降低2%~4%,表明HDL-C是一种动脉粥样硬化的保护分子[30]。
 
  尽管有大量证据表明HDL-C和心血管疾病之间存在关联,但HDL-C在ASCVD中的致病作用一直受到挑战。通过直接升高HDL-C水平以提供心血管保护作用的观点已在很大程度上被否定。越来越多的证据表明,HDL在促进细胞胆固醇流出方面的功能差异,即“胆固醇流出能力”,可能是比HDL-C更好的心血管风险指标 [31,32]。但目前尚未开展大规模的针对HDL功能的3期临床试验证实上述观点[33]。因此,虽然HDL-C仍然是ASCVD发生的一个强有力的独立危险因素,但HDL-C的作用可能是作为总体心血管风险的标志,而非作为预防ASCVD事件的直接治疗靶点。
 
  甘油三酯
 
  甘油三酯水平处于200~499 mg/dl的患者缺血性心脏病的发生率增加,即使这些患者的LDL-C控制良好[34]。轻、中度高甘油三酯血症(空腹或非空腹 TG 水平在 150~499 mg/dl之间)者的治疗方案包括调整生活方式、治疗继发危险因素和合理用药[4,18]。生活方式方面,应鼓励患者减轻体重,进行有氧运动,限制过量酒精摄入[35,36,37]。
 
  尽管有大量证据表明甘油三酯水平升高与ASCVD相关,但在缺乏某些高危特征或其他循证指征的情况下,通常不推荐轻度至中度高甘油三酯血症患者接受药物治疗[4,18]。他汀类药物是用于ASCVD风险升高的轻中度高甘油三酯血症患者的一线药物。
  脂蛋白(a)
 
  血清脂蛋白(a)[Lp(a)]水平升高与冠心病、钙化性主动脉瓣狭窄和脑卒中风险增加有关[38-43]。最新的ACC/AHA和ESC/EAS指南已推荐对Lp (a)升高的患者加强危险因素干预以及LDL-C管理。新的证据表明,PCSK9抑制剂可显著降低Lp (a)水平,并可能为基线Lp (a)水平升高的患者提供更多的心血管获益。FOURIER的一项事后分析研究了PCSK9抑制剂依洛尤单抗的心脏保护作用,证明与Lp (a)水平低于中位数的患者相比,依洛尤单抗可使Lp (a)升高患者的主要心血管事件风险降低更为显著,降幅达16%。而当按Lp (a)水平分层时,Lp (a)高于中位数的患者主要终点降低23%;Lp (a)水平低于中位数的患者降低7%[44]。这些发现提示:Lp (a)是一种可改变的风险因素,可进行针对性的靶向治疗;PCSK9抑制剂可对不同水平的Lp (a)产生获益。
 
  结 论
 
  尽管在过去三十年中血脂管理取得了巨大的进步,但如何在一级预防中进一步识别和降低心血管疾病的风险,以及降低患心血管疾病却未得到最佳管理患者的未来事件发生率等一系列问题仍待解决(图2)。但值得欣喜的事,我们看到了新型降脂药物PCSK9抑制剂在降低LDL-C,改善ASCVD方面的显著疗效。随着首个PCSK9抑制剂依洛尤单抗在中国上市,我们坚信,中国国的血脂管理和心血管风险控制必将得到极大改善。
 
图2. 评估和治疗 ASCVD 风险增加的个体需要主要关注 LDL-C,并考虑其他剩余风险/可改变的风险因素
 
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  专家简介
 
 
  田莉莉,女,浙江大学医学院附属邵逸夫医院心内科,毕业于武汉大学医学院,医学博士,主治医师。主要从事:心律失常,冠心病,心力衰竭,高血压等心血管疾病的诊疗。
 

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