二甲双胍

**二甲双胍**
系统（IUPAC）命名名称
	N,N-Dimethylimidodicarbonimidic diamide
临床数据
读音	/mɛtˈfɔːrm[不支援的输入]n/, met-FAWR-min
商品名	Glucophage, other
Drugs.com	Monograph
MedlinePlus	a696005
医疗法规	US FDA: metformin;
妊娠分级	AU: C ; US: B (非人类研究中表明无风险) ; ;
给药途径	口服
合法状态
合法状态	AU: 限医生处方 (S4) ; CA: 处方药（℞-only） ; UK: 处方药（℞-only） (POM) ; US: 处方药（℞-only） ;
药代动力学数据
生物利用度	50–60%
蛋白结合度	很小
代谢	不经过肝脏
生物半衰期	4-8.7小时
排泄	尿液（90%）
识别信息
CAS注册号	657-24-9
ATC代码	A10BA02
PubChem	CID 4091
IUPHAR/BPS	4779
DrugBank	DB00331
ChemSpider	3949
UNII	9100L32L2N ; hydrochloride: 786Z46389E
KEGG	D04966
ChEBI	CHEBI:6801
ChEMBL	CHEMBL1431
化学信息
化学式	C4H11N5
摩尔质量	129.16364 g/mol
	SMILES CN(C)C(=N)NC(=N)N; ;
	InChI InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8); Key:XZWYZXLIPXDOLR-UHFFFAOYSA-N ;

二甲双胍（guā）（英语：Metformin）^{[注 1]}，常见商品名格华止、库鲁化（Glucophage），为治疗2型糖尿病的一线药物^[3]^[4]，特别是针对超重的患者^[5]。本品也可用于治疗多囊卵巢综合症^[3]，少数研究显示也能用于预防糖尿病患者包含如心血管疾病及癌症的并发症^[6]^[7]。本品属于口服药物^[3]，且用药不会造成体重增加^[7]。

二甲双胍在人体通常没有显著副作用^[8]。常见副作用包含腹泻、恶心，以及腹痛^[3]，造成低血糖的机会不大^[3]。但值得关注的是，不当用药可能会导致乳酸中毒，严重者甚至会死亡^[9]。肝病、肾功能衰竭者不宜服用本品^[3]，妊娠期间用药目前没有已知影响，但妊娠糖尿病一般建议以胰岛素进行治疗^[3]^[10]。本品属于双胍类药物^[3]，借由降低肝脏糖质新生及提升胰岛素敏感度来达到治疗的效果^[3]。

二甲双胍最早于1922年发现^[11]，但直到1950年代，法国内科医师让·斯特恩（Jean Sterne）开启了二甲双胍人类应用的临床研究^[11]。1957年，本品开始在法国用于药用，并于1995年开始于美国使用^[3]^[12]。本品列名于世界卫生组织基本药物标准清单之中，为基础公卫体系必备药物之一^[13]。目前相信口服给药是最有效的给药途径^[11]，本品属于通用名药物^[3]。2014年本品于已开发国家的批发价为0.21至5.55美元之间^[14]。在美国，一个月疗程的药物花费约于 5 至 25 美元之间^[3]。

药理

二甲双胍的分子药理机制目前尚不完全清楚。已知其至少作用于肝脏，减少糖异生（即葡萄糖的生产）与减轻胰岛素抵抗^[15]。有研究表明二甲双胍可激活单磷酸腺苷活化的蛋白激酶（AMP-activated protein kinase，AMPK），是二甲双胍抑制肝脏糖异生、在胰岛素信号传导通路中提高胰岛素的敏感性不可缺少的机制之一^[16]。AMPK作为蛋白激酶不仅在胰岛素信号传导通路中，在全身能量平衡以及葡萄糖和脂肪的代谢中也起着重要作用^[17]。动物实验和临床研究均表明二甲双胍可诱导糖尿病的粪便微生物菌群构成发生重大变化，不仅可能有助于胰高血糖素样肽-1（GLP-1）的分泌及作用，还证实可改善胰岛素的敏感性，也是其抗2型糖尿病作用的重要机制之一^[18]^[19]。

优势

不会增加体重
与其他药品相比不易造成低血糖
减少三酸甘油酯
对低密度脂蛋白有很好的效果
对血压无影响
价格低廉

缺点

患中到重度肾脏疾病或心脏病者忌用，因为可能由于酗酒导致乳酸性酸中毒。
肠胃道症状，包括恶心、腹泻、腹痛
维生素B12缺乏
金属味觉

抗衰老研究

一些资料显示，服用二甲双胍的糖尿病患者，其存活率甚至超过其他条件类似但未患糖尿病的人群^[20]，而对二甲双胍在人类身上是否有抗衰老效果的临床实验预计于2016年冬在美国开始进行。^[21]

注解

↑ “胍”，拼音：guā，注音：ㄍㄨㄚ，音同“瓜”

参考文献

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 Dunn CJ, Peters DH. Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs. 1995-05, 49 (5): 721–49. PMID 7601013. doi:10.2165/00003495-199549050-00007.
↑ Hundal RS, Inzucchi SE. Metformin: new understandings, new uses. Drugs. 2003, 63 (18): 1879–94. PMID 12930161. doi:10.2165/00003495-200363180-00001.
↑ ^3.00 ^3.01 ^3.02 ^3.03 ^3.04 ^3.05 ^3.06 ^3.07 ^3.08 ^3.09 ^3.10 ^3.11 Metformin Hydrochloride. The American Society of Health-System Pharmacists. [Jan 2016].
↑ Maruthur, NM; Tseng, E; Hutfless, S; Wilson, LM; Suarez-Cuervo, C; Berger, Z; Chu, Y; Iyoha, E; Segal, JB; Bolen, S. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis.. Annals of Internal Medicine. 2016-04-19. PMID 27088241. doi:10.7326/M15-2650.
↑ Clinical Obesity. 2nd. Oxford: John Wiley & Sons. 2008: 262. ISBN 9781405143660.
↑ Malek, M; Aghili, R; Emami, Z; Khamseh, ME. Risk of Cancer in Diabetes: The Effect of Metformin. (PDF). ISRN Endocrinology. 2013, 2013: 636927 [2016-09-07]. PMC 3800579 . PMID 24224094. doi:10.1155/2013/636927.
↑ ^7.0 ^7.1 Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects.. Prescrire international. 2014-11, 23 (154): 269–72. PMID 25954799.
↑ Triggle, CR; Ding, H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium.. Acta physiologica (Oxford, England). 2015-12-17. PMID 26680745. doi:10.1111/apha.12644.
↑ Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011-06, 34 (6): 1431–7. PMC 3114336 . PMID 21617112. doi:10.2337/dc10-2361.
↑ Lautatzis, ME; Goulis, DG; Vrontakis, M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review.. Metabolism: clinical and experimental. 2013-11, 62 (11): 1522–34. PMID 23886298. doi:10.1016/j.metabol.2013.06.006.
↑ ^11.0 ^11.1 ^11.2 Fischer, Janos. Analogue-based Drug Discovery II. John Wiley & Sons. 2010: 47–49. ISBN 9783527632121.
↑ McKee, Mitchell Bebel Stargrove, Jonathan Treasure, Dwight L. Herb, nutrient, and drug interactions : clinical implications and therapeutic strategies. St. Louis, Mo.: Mosby/Elsevier. 2008: 217. ISBN 9780323029643.
↑ WHO Model List of EssentialMedicines (PDF). World Health Organization. 2013-10 [2014-04-22].
↑ Metformin. [2016-01-11]. ^{[永久失效链接]}
↑ How does this medication work?. OnlineClinic. [2015-01-30].
↑ Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of Clinical Investigation. 2001-10, 108 (8): 1167–74. PMC 209533 . PMID 11602624. doi:10.1172/JCI13505 （英语）.
↑ Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circulation Research. 2007-02, 100 (3): 328–41. PMID 17307971. doi:10.1161/01.RES.0000256090.42690.05 （英语）.
↑ Burcelin R. The antidiabetic gutsy role of metformin uncovered?. Gut. 2014-05, 63 (5): 706–7. PMID 23840042. doi:10.1136/gutjnl-2013-305370 （英语）.
↑ Wu, Hao; Esteve, Eduardo; Tremaroli, Valentina; Khan, Muhammad Tanweer; Caesar, Robert; Mannerås-Holm, Louise; 等. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nature Medicine. 2017-07, 23 (7): 850–858. ISSN 1546-170X. doi:10.1038/nm.4345 （英语）.
↑ Bannister, C. A.; Holden, S. E.; Jenkins-Jones, S.; Morgan, C. Ll; Halcox, J. P.; Schernthaner, G.; Mukherjee, J.; Currie, C. J. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obesity & Metabolism. 2014-11, 16 (11): 1165–1173. ISSN 1463-1326. PMID 25041462. doi:10.1111/dom.12354.
↑ 世界首例抗衰老药将临床试验或让人活到120岁. 中新网. 2015-12-02 [2015-12-02].

延伸阅读

Markowicz-Piasecka M, Huttunen KM, Mateusiak L, et al. Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics. Curr. Pharm. Des. 2017, 23 (17): 2532–2550. PMID 27908266. doi:10.2174/1381612822666161201152941.
McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016-03, 59 (3): 426–35. PMC 4742508 . PMID 26780750. doi:10.1007/s00125-015-3844-9.
Moin T, Schmittdiel JA, Flory JH, et al. Review of Metformin Use for Type 2 Diabetes Prevention. Am J Prev Med. 2018-10, 55 (4): 565–574. PMC 6613947 . PMID 30126667. doi:10.1016/j.amepre.2018.04.038.
Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017-09, 60 (9): 1577–1585. PMC 5552828 . PMID 28776086. doi:10.1007/s00125-017-4342-z.
Sanchez-Rangel E, Inzucchi SE. Metformin: clinical use in type 2 diabetes. Diabetologia. 2017-09, 60 (9): 1586–1593. PMID 28770321. doi:10.1007/s00125-017-4336-x.
Zhou J, Massey S, Story D, et al. Metformin: An Old Drug with New Applications. Int J Mol Sci. 2018-09, 19 (10). PMC 6213209 . PMID 30241400. doi:10.3390/ijms19102863.
Zhou T, Xu X, Du M, et al. A preclinical overview of metformin for the treatment of type 2 diabetes. Biomed. Pharmacother. 2018-10, 106: 1227–1235. PMID 30119191. doi:10.1016/j.biopha.2018.07.085.

外部链接

Metformin. Drug Information Portal. U.S. National Library of Medicine. [2020-02-16].

[3] “胍”，拼音：guā，注音：ㄍㄨㄚ，音同“瓜”

[D95-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 Dunn CJ, Peters DH. Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs. 1995-05, 49 (5): 721–49. PMID 7601013. doi:10.2165/00003495-199549050-00007.

[D03-2] Hundal RS, Inzucchi SE. Metformin: new understandings, new uses. Drugs. 2003, 63 (18): 1879–94. PMID 12930161. doi:10.2165/00003495-200363180-00001.

[AHFS2016-4] 3.00 ^3.01 ^3.02 ^3.03 ^3.04 ^3.05 ^3.06 ^3.07 ^3.08 ^3.09 ^3.10 ^3.11 Metformin Hydrochloride. The American Society of Health-System Pharmacists. [Jan 2016].

[Ann2016-5] Maruthur, NM; Tseng, E; Hutfless, S; Wilson, LM; Suarez-Cuervo, C; Berger, Z; Chu, Y; Iyoha, E; Segal, JB; Bolen, S. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis.. Annals of Internal Medicine. 2016-04-19. PMID 27088241. doi:10.7326/M15-2650.

[6] Clinical Obesity. 2nd. Oxford: John Wiley & Sons. 2008: 262. ISBN 9781405143660.

[7] Malek, M; Aghili, R; Emami, Z; Khamseh, ME. Risk of Cancer in Diabetes: The Effect of Metformin. (PDF). ISRN Endocrinology. 2013, 2013: 636927 [2016-09-07]. PMC 3800579 . PMID 24224094. doi:10.1155/2013/636927.

[Pres2014-8] 7.0 ^7.1 Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects.. Prescrire international. 2014-11, 23 (154): 269–72. PMID 25954799.

[9] Triggle, CR; Ding, H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium.. Acta physiologica (Oxford, England). 2015-12-17. PMID 26680745. doi:10.1111/apha.12644.

[pmid21617112-10] Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011-06, 34 (6): 1431–7. PMC 3114336 . PMID 21617112. doi:10.2337/dc10-2361.

[11] Lautatzis, ME; Goulis, DG; Vrontakis, M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review.. Metabolism: clinical and experimental. 2013-11, 62 (11): 1522–34. PMID 23886298. doi:10.1016/j.metabol.2013.06.006.

[Fis2010-12] 11.0 ^11.1 ^11.2 Fischer, Janos. Analogue-based Drug Discovery II. John Wiley & Sons. 2010: 47–49. ISBN 9783527632121.

[13] McKee, Mitchell Bebel Stargrove, Jonathan Treasure, Dwight L. Herb, nutrient, and drug interactions : clinical implications and therapeutic strategies. St. Louis, Mo.: Mosby/Elsevier. 2008: 217. ISBN 9780323029643.

[14] WHO Model List of EssentialMedicines (PDF). World Health Organization. 2013-10 [2014-04-22].

[15] Metformin. [2016-01-11]. ^{[永久失效链接]}

[16] How does this medication work?. OnlineClinic. [2015-01-30].

[Zhou-17] Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of Clinical Investigation. 2001-10, 108 (8): 1167–74. PMC 209533 . PMID 11602624. doi:10.1172/JCI13505 （英语）.

[18] Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circulation Research. 2007-02, 100 (3): 328–41. PMID 17307971. doi:10.1161/01.RES.0000256090.42690.05 （英语）.

[Burcelin-19] Burcelin R. The antidiabetic gutsy role of metformin uncovered?. Gut. 2014-05, 63 (5): 706–7. PMID 23840042. doi:10.1136/gutjnl-2013-305370 （英语）.

[20] Wu, Hao; Esteve, Eduardo; Tremaroli, Valentina; Khan, Muhammad Tanweer; Caesar, Robert; Mannerås-Holm, Louise; 等. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nature Medicine. 2017-07, 23 (7): 850–858. ISSN 1546-170X. doi:10.1038/nm.4345 （英语）.

[21] Bannister, C. A.; Holden, S. E.; Jenkins-Jones, S.; Morgan, C. Ll; Halcox, J. P.; Schernthaner, G.; Mukherjee, J.; Currie, C. J. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obesity & Metabolism. 2014-11, 16 (11): 1165–1173. ISSN 1463-1326. PMID 25041462. doi:10.1111/dom.12354.

[22] 世界首例抗衰老药将临床试验或让人活到120岁. 中新网. 2015-12-02 [2015-12-02].

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