王晓霞教授:糖尿病指南与新型降糖药的价值(上)

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本期导读:糖尿病是危害人体健康的常见病之一,给社会和个人带来沉重负担。为了应对这一挑战,各国纷纷制定临床指南来指导实践,各种新的降糖药也层出不穷。面对众说纷纭的临床指南和眼花缭乱的较新降糖药,医生们在临床实践中该如何抉择呢?医纬达特别邀请到了国家卫健委直属北京医院内分泌科王晓霞主任,专门和大家谈一谈糖尿病防治指南与新型降糖药应用的问题。本期为上篇内容,下篇将于1月25日推送,届时敬请关注医纬达公众号推文

王晓霞:糖尿病指南与新型降糖药的价值(上)

一、糖尿病指南数量繁多且众说纷纭,应该怎么用? 

的确,包括中华医学会糖尿病学分会(CDS)在内,全球各大学术组织比如ADA、EASD、AACE等,都在持续更新糖尿病管理指南。这些指南虽然很多细节有所不同,但总的原则和方向一致。

中国的CDS指南于2003年首次发表,2007、2010、2013和2017年进行了四次修订。2017年最新修订的CDS指南更加突出了中国证据和中国实践,可以说是来自于中国自己的实践,同时借鉴了国际糖尿病指南的成功经验,是适合中国国情的指南。所以,在中国的临床上,中国的糖尿病指南应该首先得到遵循,这才是最基本的、符合中国国情的临床实践。

2017版中国指南的主要内容包括:中国2型糖尿病流行病学、糖尿病的诊断与分型、2型糖尿病的三级预防、糖尿病的教育和管理、血糖监测、2型糖尿病综合控制目标、糖尿病的营养、运动治疗;还有糖尿病的代谢手术治疗等等,是一部非常全面的指南。临床医生可以根据临床工作的需要,仔细地对照、实施。

与2013版指南比较,2017版指南中临床医生比较关心的几个变更,在此简单地梳理如下:
1、糖尿病综合控制目标中,血压的控制目标值从140/80变更为130/80;
2、2型糖尿病高血糖药物治疗中,取消一线、二线、三线和四线药物的提法,更改为单药治疗、二
联治疗、三联治疗和胰岛素多次注射;
3、新版指南确定了单药治疗的基本药物,也提出了二联治疗,包括口服类降糖药以及注射类降糖药;
4、预混胰岛素多次注射与基础胰岛素+餐时胰岛素多次注射方案,可以互换;
5、新版指南的高血糖治疗,药物与药物之间的组合更具灵活性,治疗也更具个体化。

遵循指南我们还应该掌握以下原则:
1. 目前的糖尿病管理模式也是全世界各个指南都强调的,突出“以患者为中心”、“个体化治疗”,建议通过生活方式调整、药物联合来治疗糖尿病。
2. 对于新诊断、无并发症发生的年轻患者,建议将 HbA1c 控制 7% 以内;而对于已有合并症的老年患者,应把避免低血糖发生作为治疗重心,糖化血红蛋白的控制目标可以适当放宽。
3. 在降糖的同时,还要兼顾胆固醇、血压、心血管疾病风险等进行综合管理。
4. 二甲双胍是目前糖尿病治疗的基石,是首选的一线药物,较新降糖药物的价值也越来越得到更多的认可,可以积极地和二甲双胍联合使用。

二、盘点降糖药新面孔 认清其真面目
   常规降糖药物,比如:二甲双胍、α- 糖苷酶抑制剂、磺脲类、噻唑烷二酮、格列奈类、胰岛素等,大家已经比较熟悉。近年来陆续上市的较新降糖药,包括口服的DPP-4 抑制剂、SGLT-2 抑制剂,以及注射用GLP-1 受体激动剂。这些较新降糖药通过不同的机制来改善血糖的控制:

DPP-4 抑制剂:
胃肠道是机体重要的内分泌器官,肠道内分泌细胞在代谢调节中的作用日益受到重视。1964年Elrick等人发现,在血糖变化水平相同的情况下,与静脉注射葡萄糖相比,口服葡萄糖可引起更多的胰岛素分泌,这种现象被称为“肠促胰素效应”。后来发现,人体内主要有两种肠促胰素:葡萄糖依赖性胰岛素释放肽(Gastric Inhibitory Polypeptide,GIP)和胰高血糖素样多肽1(glucagon-like peptide-1,GLP-1)[44]。

但是,生理性的GLP-1半衰期很短,在体内会很快被二肽基肽酶4 (Dipeptidyl peptidase-4,DPP-4)水解, DPP-4则是细胞表面的一种丝氨酸蛋白酶。DPP-4抑制剂的作用机制,正是抑制DPP-4的活性,有效地减少GLP-1的失活,在生理范围内增加有活性的GLP-1水平,以葡萄糖浓度依赖的方式促进胰岛β细胞分泌胰岛素,并降低胰高糖素水平,发挥降低血糖的作用。

目前上市的DPP-4抑制剂,从化学结构上可分为4类,共5种药品,分别是:2009年在中国上市的β-苯乙胺类药物,西格列汀;2011年在中国上市的氰基吡咯烷类药物,沙格列汀和维格列汀;2013年在中国上市的甲基黄嘌呤类药物,利格列汀,以及嘧啶二酮类衍生物类,阿格列汀;目前,有些药物在国内许多地区已进入了医保目录,逐渐得到了比较广泛的应用。

GLP-1 受体激动剂:
GLP-1受体激动剂是药物研发的思路上的另外一个思路,即研发GLP-1受体的激动剂,也就是说通过模拟GLP-1的作用来达到降血糖的目的。其作用机制主要是化合物可以模拟GLP-1的作用,结合在GLP-1的受体上,激活GLP-1的受体,促进胰岛素的分泌和抑制胰高血糖素的分泌,从而达到降血糖的作用。
目前国内上市的GLP-1受体激动剂为艾塞那肽、利拉鲁肽、利司那肽和贝那鲁肽[6-10],均需皮下注射。

SGLT-2 抑制剂
SGLT-2(sodium-dependent glucose transporters 2)抑制剂的中文名为:钠-葡萄糖协同转运蛋白2抑制剂。

此类药物通过肾脏通路调节血糖的药物。通过抑制肾脏肾小管中负责从尿液中重吸收葡萄糖的钠-葡萄糖协同转运蛋白2(SGLT2),降低肾糖阈,促进尿葡萄糖排泄,从而达到降低血液循环中葡萄糖水平的作用[1-2]。目前在我国被批准临床使用的SGLT2抑制剂有达格列净、恩格列净和卡格列净。

王晓霞,北京医院内分泌科副主任,副主任医师,医学博士、中华医学会糖尿病分会再生医学学组委员、中华医学会内分泌分会甲状腺学组委员、北京医师协会内分泌医师分会常委兼总干事、中国医师协会内分泌学分会青年委员、医促会甲状腺疾病分会委员、医促会中老年医疗保健分会委员、北京中西医结合学会临床营养治疗分会委员、担任《中国糖尿病杂志》《中华老年医学杂志》通讯编委、开设有甲状腺专病门诊和甲状腺眼病联合门诊

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作者

王晓霞教授 北京医院内分泌科副主任

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