王晓霞教授:糖尿病指南与新型降糖药的价值(下)

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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。上期内容已经于1月18日推送,本期为下篇内容。

王晓霞:糖尿病指南与新型降糖药的价值(下)

三、较新降糖药都为舶来品 我国人群的研究证据有几何? 

CDS糖尿病治疗指南2017版,对较新降糖药在我国的应用,也提供了相关指导意见:

我国2型糖尿病患者的临床研究结果显示,DPP-4抑制剂可降低HbA1c 0.4%~0.9%[11-27],单独使用DPP-4抑制剂不增加低血糖发生风险,对体重的作用为中性[13] 。除沙格列汀可能增加心衰住院风险外[29],西格列汀、阿格列汀不增加心血管病变发生风险[28-30]。肾功能不全患者使用西格列汀、沙格列汀、阿格列汀和维格列汀时,应注意按照药品说明书来减少药物剂量。肝、肾功能不全患者使用利格列汀,不需要调整剂量[13]。我国的研究显示,在二甲双胍联用西格列汀的基础上加格列美脲、格列奇特缓释片、瑞格列奈或阿卡波糖后,可进一步降低HbA1c[31]。

SGLT2抑制剂降低HbA1c的幅度大约为0.5%~1.0%;减轻体重1.5~3.5kg,降低收缩压3~5mmHg。心血管高风险2型糖尿病患者应用SGLT2抑制剂恩格列净或卡格列净的临床研究结果显示,该药物可使主要心血管不良事件和肾脏事件复合终点发生风险显著下降,心衰住院率显著下降[32,33]。SGLT2抑制剂单独使用时不增加低血糖发生风险,联合胰岛素或磺脲类药物时,可增加低血糖发生风险。中度肾功能不全患者可以减量使用SGLT2抑制剂。在重度肾功能不全患者中,因降糖效果显著下降,不建议使用。SGLT2抑制剂的常见不良反应为生殖泌尿道感染,罕见的不良反应包括酮症酸中毒(主要发生在1型糖尿病患者中)。可能的不良反应包括急性肾损伤(罕见)、骨折风险(罕见)和足趾截肢(见于卡格列净)[32,2,34-36] 。

GLP-1受体激动剂可有效降低血糖,并有显著降低体重和改善甘油三酯、血压的作用。单独使用GLP-1受体激动剂,不明显增加低血糖发生风险。GLP-1受体激动剂可单独使用,或与其他降糖药联合使用。多项临床研究结果显示,在一种口服降糖药(二甲双胍、磺脲类)治疗失效后,加用GLP-1受体激动剂有效。GLP-1受体激动剂的常见不良反应为胃肠道症状(如恶心、呕吐等),主要见于初始治疗时,不良反应可随治疗时间延长逐渐减轻。

研究报道,利拉鲁肽、利司那肽和艾塞那肽用于伴有心血管病史或心血管危险因素的2型糖尿病患者,具有有益的作用及安全性[37-39]。

四、MACE和死亡率作为试金石 较新降糖药是否仍具优势? 

大家知道,2型糖尿病患者50%以上都死于ASCVD---动脉粥样硬化性心血管疾病。因此,降糖治疗的目标就是要降低主要不良心血管事件(MACE)发生率,最终降低死亡率。因此,与传统药物相比,较新的降糖药物在心血管获益方面是否具有优势?目前已成为大家关注的热点:

2018年9月,发表于《Diabetes Obes Metab》上的一项由中国台湾、英国及丹麦学者共同完成的随机对照试验的Meta分析[40],考察了与常规降糖药物比较,这三类较新降糖药对心血管结局的影响。研究共纳入10项RCT,92400名2型糖尿病患者,在中位2.6年的随访期内提供了9773个MACE信息。

Meta回归分析(Meta-regression analysis)证实,较新降糖药组,糖化血红蛋白降低与MACE风险降低显著相关(β=−0.39~−0.55;P<0.02),糖化血红蛋白每降低1%,MACE风险显著降低30%(95% CI,17%~40%)。相反,常规药物组Meta回归分析未能证实糖化血红蛋白降低和MACE风险之间存在显著的相关性(P>0.74)。这提示:较新降糖药可显著降低MACE风险,而常规药物,由于低血糖不良事件的发生而增加患者死亡率,进而抵消降糖药物所带来的心血管获益。

类似的情况,2018年6月,发表于《Cardiovasc Diabetol》上的一项网络Meta分析,以严重不良心血管事件(MACE)和全因死亡率为结局,纳入170项随机对照试验中166371名参与者 [41],也比较了包括较新降糖药在内的多种降糖药物对心血管(CV)结局的影响。研究结果同样显示:当以磺脲类药物作为参考时,较新降糖药在减少MACE上具有显著性优势。并且,MACE和全因死亡率的排序都与严重低血糖风险正相关(根据个体药物:R2=0.3178,P=0.018;根据类别:R2=0.2574,P=0.038)。

此外,关于单个或某一类较新口服降糖药与常规药物比较的研究也很多。比如,2018年9月,《Diabetes Obes Metab》上发表的一项日本学者的研究[42],考察了初治接受DPP4抑制剂与接收磺脲类对每日血糖波动的影响。结果显示:与磺脲相比,DPP4抑制剂具有每天血糖波动更小的优势。这意味着低血糖和心血管事件发生可能更少。

还有,2018年6月,发表于《J Am Coll Cardiol》上的一项CVD-REAL 2研究[43],旨在考察亚太、中东和北美地区6个国家中,比较SGLT-2抑制剂与其他降糖药物相关的心血管(CV)事件。研究纳入了韩国、日本、新加坡、以色列、澳大利亚和加拿大的数据,在每个国家进行SGLT-2i使用的倾向性评分,按1:1匹配。按国家评估死亡的危险比(HRs)、心衰住院(HHF)、死亡或HHF、MI和卒中,并采用加权meta分析进行汇总。结果显示:SGLT-2i的使用与较低CV事件风险相关。

因此,从现有证据来看,这三类较新降糖药有明显的优势,值得临床医生重视其临床价值。

需要指出的是,降糖药物的选择还必须考虑药物的可及性、长期应用患者的经济承受能力、方便程度、依从性、医保报销等情况。因此,就个体患者而言,重视新药的临床价值并不等于盲目地给患者换用新药。医生还是应当遵循指南,以二甲双胍为基石等原则,按个体化原则选择最适合患者的指南推荐药物。

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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