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二甲双胍的作用机制及临床疗效,这篇文章讲透了!丨专家共识解读第二篇

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  多管齐下降低血糖,临床疗效卓尔不凡。

  2型糖尿病(T2DM)发病率逐年攀升,其引起心血管并发症所造成的危害与负担日益严峻。而作为全球糖尿病防控的核心药物,二甲双胍的临床应用也随之愈发普遍。因此,对心血管专科医生而言,了解并掌握二甲双胍的作用机制及临床疗效,可以更好地管理合并心血管并发症的糖尿病患者。

  上一期,我们已经了解了《二甲双胍临床应用专家共识(2018版)》中“二甲双胍的临床地位与使用时机”(二甲双胍的临床地位与使用时机,一文教你get!丨专家共识解读第一篇),今天就一起来学习“二甲双胍的作用机制及临床疗效”吧!

  1多种武器齐上阵,360°降糖不留死角

  二甲双胍作用途径丰富,以多路并进的方式全方位、协同降低血糖,逐个击破高血糖防线。

  其主要降糖机制为:

  作用于肝脏,抑制糖异生,减少肝糖输出[1];

  作用于外周组织(肌肉、脂肪),改善肌肉糖原合成,降低游离脂肪酸,提高胰岛素敏感性,增加对葡萄糖的摄取和利用[2, 3];

  作用于肠道,抑制肠壁细胞摄取葡萄糖,提高胰高血糖素样肽- 1(GLP-1)水平[4, 5];

  激活腺苷酸活化蛋白激酶(AMPK),改善肌肉、脂肪、肝脏的能量代谢[6-8]。

  2单打独斗还是众人抬柴?花式应用,卓群依旧

  不论是单药治疗还是与其他口服降糖药、胰岛素联合治疗,二甲双胍确切的降糖疗效都已通过各类大型药物研究的考验,获得共识推荐(表1)。下面对二甲双胍单用/联用以及部分特殊用法的具体疗效逐一介绍。

  表1:二甲双胍的临床疗效

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  二甲双胍单药应用即效果卓群,29周可降低空腹血糖(FPG)3.2 mmol/L、餐?笱牵≒PG)4.0 mmol/L、糖化血红蛋白(HbA1c)1.8%(Ⅰ级) [9]。研究显示基线HbA1c接近9%的新诊断患者,使用二甲双胍单药2000 mg可使近70%的患者达标。

  3老将联手,无往不利

  除出类拔萃的单药降糖疗效,二甲双胍可改善胰岛素抵抗,减少肝糖输出,增强肝脏和肌肉组织的胰岛素敏感性,因此二甲双胍可以与其他经典口服降糖药物和胰岛素联合,可因作用机制互补或协同,产生1+1>2的效应。

  中国的MERIT研究显示,与胰岛素单药治疗相比,二甲双胍联合胰岛素可进一步降低HbA1c,减少胰岛素用量、体重增加和低血糖风险;二者联合与心血管疾病和肿瘤风险下降相关[10-15](Ⅰ级)。

  4新老搭档,一拍即合

  二甲双胍不仅能与降糖老将联手,与近年涌现的降糖新秀也配合默契:加用钠-葡萄糖协同转运蛋白2 (SGLT-2)抑制剂可在二甲双胍疗效的基础上进一步改善血糖控制,显著减轻体重及改善血压[16-18]。

  除单用或与其他降糖药物联用于T2DM治疗外,共识还针对二甲双胍的3种特殊应用场景予以阐释,即:接替短期胰岛素强化治疗、在1型糖尿病(T1DM)中的应用以及减重作用。

  新诊断、初始HbA1c高的T2DM患者经短期胰岛素治疗后,接受以二甲双胍为基础的口服降糖药治疗与继续应用胰岛素治疗的降糖疗效相当[19、20],以二甲双胍为基础的口服降糖药治疗能更好地改善β细胞功能和HbA1c水平(Ⅱ级),简单易行、依从性好,较好地控制体重,成本-效益比更佳。

  T1DM患者在胰岛素治疗基础上加用二甲双胍,能降低T1DM患者的胰岛素用量、体重及血脂水平,且不增加低血糖及酮症酸中毒的发生风险(Ⅰ级)[21],尤其适用于胰岛素剂量较大、体重增加明显的患者(发生糖尿病酮症酸中毒、高血糖高渗综合征、乳酸酸中毒患者禁用二甲双胍)[22]。

  二甲双胍具有减轻体重的作用。基线BMI越高、腰围越大的患者,使用二甲双胍治疗后体重下降越多[23, 24]。磺脲类、格列酮类和胰岛素等药物的使用可增加患者体重,联合二甲双胍可减轻上述药物对体重增加的影响[18, 25](Ⅰ级)。

  综上,二甲双胍丰富多样的降糖机制为其发挥疗效提供了有力保障。无论是单用还是与其他口服降糖药/胰岛素的灵活联用,都可以个体化满足不同患者对降糖、改善胰岛功能、减重、降低低血糖风险等需求,切实提高糖尿病患者临床获益。

  参考文献

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  [8]Coughlan KA, Valentine RJ, Ruderman NB, et al. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes, metabolic syndrome and obesity : targets and therapy. 2014: 241-53.

  [9]DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. The New England journal of medicine. 1995; 9: 541-9.

  [10]Hemmingsen B, Christensen LL, Wetterslev J, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. Bmj. 2012: e1771

  [11]Strowig SM, Aviles-Santa ML, Raskin P. Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes care. 2002; 10: 1691-8.

  [12]Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Archives of internal medicine. 2009; 6: 616-25.

  [13]Guo L, Chen L, Chang B, et al. A randomized, open-label, multicentre, parallel-controlled study comparing the efficacy and safety of biphasic insulin aspart30 plus metformin with biphasic insulin aspart30 monotherapy for type 2 diabetes patients inadequately controlled with oral antidiabetic drugs: The merit study. Diabetes, obesity & metabolism. 2018; 12: 2740-2747.

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  [17]Yang W, Han P, Min KW, et al. Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial. Journal of diabetes. 2016; 6: 796-808.

  [18]Yang T, Lu M, Ma L, et al. Efficacy and tolerability of canagliflozin as add-on to metformin in the treatment of type 2 diabetes mellitus: a meta-analysis. European journal of clinical pharmacology. 2015; 11: 1325-32.

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