多管齊下降低血糖，臨床療效卓爾不凡。
2型糖尿病（T2DM）發(fā)病率逐年攀升，其引起心血管并發(fā)癥所造成的危害與負擔(dān)日益嚴峻。而作為全球糖尿病防控的核心藥物，二甲雙胍的臨床應(yīng)用也隨之愈發(fā)普遍。因此，對心血管專科醫(yī)生而言，了解并掌握二甲雙胍的作用機制及臨床療效，可以更好地管理合并心血管并發(fā)癥的糖尿病患者。
上一期，我們已經(jīng)了解了《二甲雙胍臨床應(yīng)用專家共識（2018版）》中“二甲雙胍的臨床地位與使用時機”（二甲雙胍的臨床地位與使用時機，一文教你get!丨專家共識解讀第一篇），今天就一起來學(xué)習(xí)“二甲雙胍的作用機制及臨床療效”吧！
1多種武器齊上陣，360°降糖不留死角
二甲雙胍作用途徑豐富，以多路并進的方式全方位、協(xié)同降低血糖，逐個擊破高血糖防線。
其主要降糖機制為：
作用于肝臟，抑制糖異生，減少肝糖輸出 [1]；
作用于外周組織（肌肉、脂肪），改善肌肉糖原合成，降低游離脂肪酸，提高胰島素敏感性，增加對葡萄糖的攝取和利用 [2, 3]；
作用于腸道，抑制腸壁細胞攝取葡萄糖，提高胰高血糖素樣肽- 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、肝臟的能量代謝[6-8]。
2單打獨斗還是眾人抬柴？花式應(yīng)用，卓群依舊
不論是單藥治療還是與其他口服降糖藥、胰島素聯(lián)合治療，二甲雙胍確切的降糖療效都已通過各類大型藥物研究的考驗，獲得共識推薦（表1）。下面對二甲雙胍單用/聯(lián)用以及部分特殊用法的具體療效逐一介紹。
表1：二甲雙胍的臨床療效
二甲雙胍單藥應(yīng)用即效果卓群，29周可降低空腹血糖（FPG）3.2 mmol/L、餐后血糖（PPG）4.0 mmol/L、糖化血紅蛋白（HbA1c）1.8%（Ⅰ級） [9]。研究顯示基線HbA1c接近9%的新診斷患者，使用二甲雙胍單藥2000 mg可使近70%的患者達標(biāo)。
3老將聯(lián)手，無往不利
除出類拔萃的單藥降糖療效，二甲雙胍可改善胰島素抵抗，減少肝糖輸出，增強肝臟和肌肉組織的胰島素敏感性，因此二甲雙胍可以與其他經(jīng)典口服降糖藥物和胰島素聯(lián)合，可因作用機制互補或協(xié)同，產(chǎn)生1+1＞2的效應(yīng)。
中國的MERIT研究顯示，與胰島素單藥治療相比，二甲雙胍聯(lián)合胰島素可進一步降低HbA1c，減少胰島素用量、體重增加和低血糖風(fēng)險；二者聯(lián)合與心血管疾病和腫瘤風(fēng)險下降相關(guān)[10-15]（Ⅰ級）。
4新老搭檔，一拍即合
二甲雙胍不僅能與降糖老將聯(lián)手，與近年涌現(xiàn)的降糖新秀也配合默契：加用鈉-葡萄糖協(xié)同轉(zhuǎn)運蛋白2 （SGLT-2）抑制劑可在二甲雙胍療效的基礎(chǔ)上進一步改善血糖控制，顯著減輕體重及改善血壓 [16-18]。
除單用或與其他降糖藥物聯(lián)用于T2DM治療外，共識還針對二甲雙胍的3種特殊應(yīng)用場景予以闡釋，即：接替短期胰島素強化治療、在1型糖尿?。═1DM）中的應(yīng)用以及減重作用。
新診斷、初始HbA1c高的T2DM患者經(jīng)短期胰島素治療后，接受以二甲雙胍為基礎(chǔ)的口服降糖藥治療與繼續(xù)應(yīng)用胰島素治療的降糖療效相當(dāng)[19、20]，以二甲雙胍為基礎(chǔ)的口服降糖藥治療能更好地改善β細胞功能和HbA1c水平（Ⅱ級），簡單易行、依從性好，較好地控制體重，成本-效益比更佳。
T1DM患者在胰島素治療基礎(chǔ)上加用二甲雙胍，能降低T1DM患者的胰島素用量、體重及血脂水平，且不增加低血糖及酮癥酸中毒的發(fā)生風(fēng)險（Ⅰ級）[21]，尤其適用于胰島素劑量較大、體重增加明顯的患者（發(fā)生糖尿病酮癥酸中毒、高血糖高滲綜合征、乳酸酸中毒患者禁用二甲雙胍）[22]。
二甲雙胍具有減輕體重的作用?；€BMI越高、腰圍越大的患者，使用二甲雙胍治療后體重下降越多 [23, 24]?；请孱?、格列酮類和胰島素等藥物的使用可增加患者體重，聯(lián)合二甲雙胍可減輕上述藥物對體重增加的影響[18, 25]（Ⅰ級）。
綜上，二甲雙胍豐富多樣的降糖機制為其發(fā)揮療效提供了有力保障。無論是單用還是與其他口服降糖藥/胰島素的靈活聯(lián)用，都可以個體化滿足不同患者對降糖、改善胰島功能、減重、降低低血糖風(fēng)險等需求，切實提高糖尿病患者臨床獲益。
參考文獻
[1]Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. The Journal of clinical investigation. 2010; 7: 2355-69.
[2]Sarabia V, Lam L, Burdett E, et al. Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin. The Journal of clinical investigation. 1992; 4: 1386-95.
[3]Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of clinical investigation. 2001; 8: 1167-74.
[4]Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015; 7581: 262-266.
[5]Hur KY, Lee MS. Gut Microbiota and Metabolic Disorders. Diabetes & metabolism journal. 2015; 3: 198-203.
[6]Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clinical science. 2012; 6: 253-70.
[7]Foretz M, Guigas B, Bertrand L, et al. Metformin: from mechanisms of action to therapies. Cell metabolism. 2014; 6: 953-66.
[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 aspart 30 plus metformin with biphasic insulin aspart 30 monotherapy for type 2 diabetes patients inadequately controlled with oral antidiabetic drugs: The merit study. Diabetes, obesity & metabolism. 2018; 12: 2740-2747.
[14]Liao L, Yang M, Qiu LL, et al. Appropriate insulin initiation dosage for insulin-naive type 2 diabetes outpatients receiving insulin monotherapy or in combination with metformin and/or pioglitazone. Chinese medical journal. 2010; 24: 3684-8.
[15]Giugliano D, Quatraro A, Consoli G, et al. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. European journal of clinical pharmacology. 1993; 2: 107-12.
[16]Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013; 12: 2582-92.
[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.
[19]Cheng Q, Yang S, Zhao C, et al. Efficacy of metformin-based oral antidiabetic drugs is not inferior to insulin glargine in newly diagnosed type 2 diabetic patients with severe hyperglycemia after short-term intensive insulin therapy. Journal of diabetes. 2015; 2: 182-91.
[20]Retnakaran R, Choi H, Ye C, et al. Two-year trial of intermittent insulin therapy vs metformin for the preservation of beta-cell function after initial short-term intensive insulin induction in early type 2 diabetes. Diabetes, obesity & metabolism. 2018; 6: 1399-1407.
[21]Liu C, Wu D, Zheng X, et al. Efficacy and safety of metformin for patients with type 1 diabetes mellitus: a meta-analysis. Diabetes technology & therapeutics. 2015; 2: 142-8.
[22]Lund SS, Tarnow L, Astrup AS, et al. Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes. Diabetes, obesity & metabolism. 2009; 10: 966-77.
[23]Ji L, Li H, Guo X, et al. Impact of baseline BMI on glycemic control and weight change with metformin monotherapy in Chinese type 2 diabetes patients: phase IV open-label trial. PloS one. 2013; 2: e57222.
[24]Zhou L, Cai X, Yang W, et al. The magnitude of weight loss induced by metformin is independently associated with BMI at baseline in newly diagnosed type 2 diabetes: Post-hoc analysis from data of a phase IV open-labeled trial. Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2017; 4: 671-677.
[25]Charbonnel B, Schernthaner G, Brunetti P, et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia. 2005; 6: 1093-104.
聯(lián)系客服
