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二甲双胍

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二甲双胍
临床资料
读音聆听i/mɛtˈfɔːrmɪn/, met-FOR-min
商品名（英语：Drug nomenclature）Glucophage及其他
其他名称N,N-dimethylbiguanide[1]
AHFS/Drugs.comMonograph
MedlinePlusa696005
核准状况
怀孕分级
给药途径口服给药
药物类别抗糖尿病药
ATC码
法律规范状态
法律规范
药物动力学数据
生物利用度50–60%[10][11]
血浆蛋白结合率Minimal[10]
药物代谢Not by liver[10]
生物半衰期4–8.7小时[10]
排泄途径尿液 (90%)[10]
识别信息
  • N,N-Dimethylimidodicarbonimidic diamide
CAS号657-24-9
1115-70-4
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)
ECHA InfoCard100.010.472 编辑维基数据链接
化学信息
化学式C4H11N5
摩尔质量129.17 g·mol−1
3D模型（JSmol（英语：JSmol））
密度1.3±0.1[12] g/cm3
  • CN(C)C(=N)N=C(N)N

  • as HCl: Cl.CN(C)C(=N)NC(N)=N
  • InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
  • Key:XZWYZXLIPXDOLR-UHFFFAOYSA-N

  • as HCl: InChI=1S/C4H11N5.ClH/c1-9(2)4(7)8-3(5)6;/h1-2H3,(H5,5,6,7,8);1H
  • Key:OETHQSJEHLVLGH-UHFFFAOYSA-N

二甲双胍（INN:metformin），以商品名Glucophage（中文译名有库鲁化、格华止）等于市场上贩售，是治疗第2型糖尿病的主要一线药物，[13][14][15][16]特别适用于超重的患者。[14]它也用于治疗多囊性卵巢症候群，[15]有时会作为仿单标示外使用辅助用药，以降低服用抗精神病药者出现代谢症候群的风险。[17]研究显示此药物能抑制发炎反应，[18][19]且不会导致体重增加（英语：weight gain）。[20]

二甲双胍采口服方式给药。[15]

使用者对二甲双胍通常具有良好的耐受性。[21]而使用后常见的副作用有腹泻、恶心和腹痛。[15]它导致低血糖的风险很小。[15]如果药物剂量过大或有严重肾脏问题的人使用，则需要注意乳酸性酸中毒的风险。[22][23]

二甲双胍是一种双胍类降血糖药物。[15]它的作用机制是减少肝脏的葡萄糖生成、增加身体组织对胰岛素的敏感性，[15]以及增加生长分化因子（英语：Growth differentiation factor）GDF15（英语：GDF15）分泌，进而降低食欲和热量摄取。[24][25][26][27]

二甲双胍最早由爱尔兰化学家埃米尔·维尔纳（Emil Werner）和詹姆斯·贝尔（James Bell）于1922年首次在科学文献中描述。[28]法国医生尚·斯特恩（Jean Sterne）在1950年代开始对其进行人体研究，[15][29]于1957年在法国作为药物推出。[15][30]此药物已列入世界卫生组织基本药物标准清单之中。[31]市场上已有其通用名药物（学名药）供应。[15]它是美国于2022年处方量第二大的药物，开立的处方笺数量超过8,600万张。[32][33]在澳大利亚，二甲双胍于2017年至2023年之间的处方量也是该国排名前十大的药物之一。[34]

医疗用途

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二甲双胍用于降低第2型糖尿病患者的血糖。[15]它也被用作治疗多囊性卵巢症候群所引起不孕症的二线药物。[15][35]

第二型糖尿病

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美国糖尿病协会（英语：American Diabetes Association）和美国内科医师学会（英语：American College of Physicians）都推荐二甲双胍作为治疗第2型糖尿病的一线药物。[36][37][38]它与瑞格列奈同样有效，且比所有其他口服第2型糖尿病药物都更为有效。[39]

多囊性卵巢症候群

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对于患有多囊性卵巢症候群的个体，初步证据显示使用二甲双胍能提高活产（英语：live birth）率，[40]包括那些使用可洛米分后仍未能怀孕的女性。[41]二甲双胍似乎不会改变流产的风险。[40]

糖尿病与怀孕

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有一项全面审查，将怀孕期间使用二甲双胍与单独使用胰岛素的情况进行比较，结果显示二甲双胍示对母亲和婴儿的短期安全性良好，但长期安全性尚不明确。[42]多项观察性研究和随机对照试验发现二甲双胍在妊娠期糖尿病的管理上与胰岛素同样有效，而且安全。[43][44]

体重变化

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使用二甲双胍通常与体重减轻有关。[45]它在抵消抗精神病药奥氮平和氯氮平引起的体重增加方面，似乎是安全且有效。[46][47][48]虽然使用二甲双胍能帮助已经因氯氮平而增加体重的人能稍微减轻一些体重，但最有效，也是最有价值的做法是在患者开始服用氯氮平的时候，就设法避免体重增加，而不是等到体重增加后，才用二甲双胍或其他方法来补救。[49]

与胰岛素并用

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二甲双胍可能会减少第1型糖尿病患者对胰岛素的需求，但同时会增加出现低血糖的风险。[50]

禁忌症

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有以下情况的个体禁用二甲双胍：

副作用

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二甲双胍引发的副作用，最常见的是肠胃道不适，包括腹泻、腹绞痛、恶心、呕吐和放屁频率增加。[53]二甲双胍较大多数其他降血糖药会更常引起肠胃道副作用。[53][54]二甲双胍所引发最严重的潜在副作用是乳酸性酸中毒。这种并发症很少见，且似乎与肝功能或肾功能受损有关。[55][56]二甲双胍禁用于患有严重肾脏疾病的人，但在有肾脏问题的患者中仍可以较低剂量使用。[57]

肠胃道

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肠胃道不适有导致严重身体不适的可能，这种情况最常见于刚开始服用二甲双胍时，或在增加剂量时。[52][58]通常可透过从低剂量（每日1.0至1.7克）开始，并逐步增加剂量来避免，但即便使用低剂量，仍有5%的人可能无法耐受二甲双胍。[52][59]使用缓释或长效制剂或能会改善耐受性。[59]

长期使用二甲双胍与同半胱胺酸水平升高[60]以及维生素B12吸收不良有关。[52][61][62]较高剂量和长期使用会增加维生素B12缺乏症的发生率，[63]一些研究人员建议进行筛查或预防策略以为因应。[64]

过量

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过量服用二甲双胍最常见的症状有呕吐、腹泻、腹痛、心跳过速、嗜睡，以及罕见的低血糖或高血糖。[65][66]二甲双胍过量的治疗通常仅为支持性，目前并无已知的特定解毒剂。严重过量时建议采用体外治疗（指将患者的血液引出体外，透过医疗设备进行处理，以清除血液中的有害物质（例如过量的药物），然后再将净化后的血液输回体内）。[67]由于二甲双胍分子量低且不与血浆蛋白结合，这些技术有助于将二甲双胍从血浆中清除，而阻止乳酸过度产生。[67]

二甲双胍可在血液、血浆或血清中进行定量检测，以监测治疗效果、确认中毒诊断，或协助法医进行死亡调查。接受治疗剂量的患者，血液或血浆中的二甲双胍浓度通常介于1–4毫克/升。急性过量受害者则介于40–120毫克/升。而致死案例则介于80–200毫克/升。色层分析法是常用的检测方法。[68][69]

虽然使用相当大的剂量也通常不会致命，但二甲双胍过量会增加二甲双胍相关的乳酸性酸中毒风险。[70]

交互作用

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H2受体拮抗剂西咪替丁会减少肾脏对二甲双胍的清除，而导致其血浆浓度升高。[71]二甲双胍和西咪替丁都经由肾小管分泌从体内清除，两者，尤其是西咪替丁的阳离子形式，可能会竞争相同的转运机制。[8]一项小型的双盲随机研究发现抗生素头孢氨苄也能透过类似机制增加二甲双胍在体内的浓度。[72]理论上，其他阳离子药物也可能产生相同的效果。[8]

二甲双胍也会与抗胆碱剂产生交互作用，原因在于后者会影响胃肠蠕动。抗胆碱剂会减缓胃肠蠕动，延长药物在胃肠道中的停留时间。这种影响可能导致比没使用抗胆碱剂时会吸收更多的二甲双胍，进而增加二甲双胍在血浆中的浓度，并提高出现副作用的风险。[73]

药理学

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作用机制

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二甲双胍的分子作用机制尚未完全阐明。目前已提出多种潜在的作用机制，包括：抑制线粒体呼吸链（{{le|呼吸链复合体 I|Respiratory complex I))）、活化AMP活化蛋白激酶（英语：AMP-activated protein kinase）（AMPK）、抑制胰高血糖素诱导的环腺苷酸（cAMP）升高并减少蛋白激酶A（PKA）的活化、透过复合体IV介导抑制线粒体甘油-3-磷酸脱氢酶的GPD2变体（从而减少甘油对肝脏糖质新生的贡献），以及对肠道菌群的影响。[27][74][75][76]

药物动力学

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二甲双胍在空腹条件下口服，生物利用度为50–60%，且吸收缓慢。[8][77]服用即释型二甲双胍后，最大血药浓度（Cmax）会在1–3小时内达到。而长效缓释剂型则需4–8小时。[8][77]二甲双胍的血浆蛋白结合率可忽略不计，这也反映在其非常高的表观分布容积（单次给药后为300–1,000升）上。药物浓度通常在1–2天内达到稳定状态。[8]

历史

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山羊豆天然就含有山羊豆碱。

二甲双胍所属的双胍类降血糖药物，源自山羊豆这种植物，其在民间医学中已有数百年历史。[78]虽然山羊豆本身不含双胍类药物，二甲双胍是经化学合成的化合物，旨在降低植物中衍生的胍和山羊豆碱的毒性。[78]

二甲双胍最早于1922年被文献提及，[79]1929年其降糖作用被发现，[80]但当时未受重视。直到1940年代末，对二甲双胍的兴趣才重新兴起。1950年，菲律宾裔医师Eusebio Y. Garcia发现二甲双胍（他称之为Fluamine）能降低血糖，且无毒性。[81][82]

法国糖尿病学家Jean Sterne受到Garcia报告的启发，重新研究二甲双胍的降血糖特性。Sterne是首位将二甲双胍用于治疗人类糖尿病的医生，他将其命名为"Glucophage"（食糖者），并于1957年发表研究成果。[83][84]同年，二甲双胍在法国作为药物上市，[15]并于1958年进入英国药典。

直到1970年代其他双胍类药物被撤下市场后，二甲双胍才再次引起广泛关注。[5]它于1972年在加拿大获准用于医疗用途，[5]但直到1994年才获得美国食品药物管理局（FDA）批准用于治疗第2型糖尿病。[85]必治妥施贵宝获授权生产的Glucophage于1995年3月3日首次在美国上市。现于多个国家都能买到二甲双胍的学名药。[84]

二甲双胍在FDA和欧洲药品管理局均被授予孤儿药资格。[86][87][88][89][90]

社会与文化

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环境影响

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二甲双胍及其主要的转化产物胍基脲（guanylurea）存在于废水处理厂的排放物中，并经常在地表水中被检测到。在德国的埃佩河中，曾测得超过200微克/升的胍基脲浓度，这已是水生环境中检测到的药物转化产物最高浓度之一.[91]

市售制剂

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于英国贩售的二甲双胍学名药 - 500毫克片剂。

英国核准名称（英语：British Approved Name） (BAN)、美国采用名称 (USAN) 和国际非专有药名 （INN）均使用metformin的名称。它以多种品牌名称贩售。在美国，常见的品牌名称有Glucophage、Riomet、Fortamet和Glumetza。[92]

与其他药物并用

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二甲双胍经常会与其他药物一同开立处方，用于治疗第2型糖尿病。市面上有几种固定剂量复方药，有减少服药负担、降低成本并简化给药方式的潜力。[93][94]

三重组合药物

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二甲双胍与达格列净和沙格列汀组合的复方药达格列净/沙格列汀/二甲双胍（英语：Dapagliflozin/saxagliptin/metformin）在美国以Qternmet XR的品牌名称贩售。[95][96]

二甲双胍与吡格列酮和格列本脲组合的复方药在印度以Accuglim-MP、Adglim MP和Alnamet-GP等品牌名称贩售。在菲律宾则以Tri-Senza品牌贩售。[97]

二甲双胍与吡格列酮和硫辛酸的组合药物在土耳其以Pional品牌贩售。[98]

研究

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二甲双胍是一种多效性（英语：Pleiotropy (drugs)）药物，除能降血糖作用外，还具有广泛的脱靶（英语：Off-target activity）活性。其中大部分归因于它对AMP活化蛋白激酶 (AMPK) 的作用，也有其他机制被提出。[99][100]二甲双胍已被研究，用于多种病症，包括：

衰老与延长寿命

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二甲双胍正被研究作为一种能延缓衰老的药物。[113][114][115]它在某些动物（例如：秀丽隐杆线虫和蟋蟀）中可能可增加寿命。[116][117]这种效果可能透过胰岛素和碳水化合物的调节来实现，类似于它对糖尿病的作用。[112][118]二甲双胍是否能帮助延长寿命，即使是对于原本健康的人，目前仍是未知数。于2021年发布的一项文献回顾发现它更有可能改善健康寿命（即健康生活的年数），而非整体寿命。[119]

于2017年发布的一项回顾发现服用二甲双胍的糖尿病患者，全因死亡率较低。[110]他们罹患癌症和心血管疾病的风险也较接受其他疗法的人为低。[110]然而，对于没有糖尿病的人，二甲双胍似乎无法降低罹患癌症和心血管疾病的风险。[120]

参考文献

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