王晓霞教授：糖尿病指南与新型降糖药的价值（上）
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？医粒种子特别邀请到了国家卫健委直属北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，届时敬请关注医粒种子公众号推文。
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。
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：
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(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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