GLP多方面协同调控血糖

1、1会计学GLP多方面协同调控血糖多方面协同调控血糖目前治疗2型糖尿病的药物Moller DE. Nature. 2001;414:821-827.; Pickup JC, Williams G, eds. Textbook of Diabetes 2. Malden, MA: Blackwell;2003:45.5.药物分类药物分类分子标靶分子标靶作用位点作用位点不良反应不良反应磺脲类磺脲类磺脲类受体/K+ ATP 通道胰腺 细胞低血糖体重增加格列耐类格列耐类双胍类双胍类不明肝脏、肌肉胃肠道反应乳酸性酸中毒 葡萄糖苷酶抑制剂葡萄糖苷酶抑制剂- 葡萄糖苷酶肠道胃肠道反应噻唑烷二酮噻唑烷二酮 (T

2、ZDs)PPAR (激动剂)肝脏肌肉脂肪体重增加水肿贫血胰岛素胰岛素胰岛素受体低血糖体重增加u 极低的低血糖风险u 不增加或降低体重u 改善 细胞功能，延缓疾病进程治疗2型糖尿病的新希望肠促胰素及其类似物静脉血浆葡萄糖 (mg/dL)时间 (min)C肽 (nmol/L)2001000016012018001601201800.00.51.01.52.0时间 (min)0202肠促胰素效应口服葡萄糖 静脉注射葡萄糖*Mean SE; N=6; *p.05; 01-02=glucose infusion time.Nauck MA, et al. J Clin Endocrinol Metab.

3、 1986;63:492-498. 肠促胰岛素效应口服葡萄糖和静脉注射葡萄糖的效应比较约占餐后胰岛素分泌总量的60左右Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-497; Drucker DJ. Diabetes Care. 2003;26:2929-2940. Drucker DJ. Diabetes Care. 2003;26:2929-2940; Thorens B. Diabetes Metab. 1995;21:311-318; Baggio LL, Drucker DJ. Gastroenterology. 2007;

4、132:2131-2157; Nyberg J, et al. J Neurosci. 2005;25:1816-1825.020406080胰岛素 (mU/L)0306090 120 150 180时间 (min)*0204060800306090 120 150 180时间 (min)*2型糖尿病患者正常人静脉注射葡萄糖口服葡萄糖*与口服后的相应值相比p.05Nauck MA, et al. Diabetologia. 1986;29:46-52. 5002型糖尿病患者 GIP (pg/mL)时间 (min)050010001500200025006012018002时间 (min)010

5、0015002000250060120180正常人010201口服葡萄糖静脉注射葡萄糖Mean SE; N=22; 01-02=葡萄糖输注时间。Nauck MA, et al. Diabetologia. 1986;29:46-52. GIP (pg/mL)*20151050060120180240时间 (min)进餐GLP-1 (pmol/L)正常糖耐量糖耐量受损2型糖尿病Mean SE; N=54; * T2DM和NGT组的差别p.05。Toft-Nielsen M, et al. J Clin Endocrinol Metab. 2001;86:3717-3723. 2GLP-1GIP胰

6、岛素 (pmol/L)2型糖尿病患者030 60 90 120150180210025050075010001250150017502000时间 (min)030 60 90 120150180210025050075010001250150017502000时间 (min)正常人低剂量 GIP 或 GLP-1 (7-36酰胺)高剂量 GIP 或 GLP-1 (7-36酰胺)GLP-1 (7-36酰胺)GIP高糖钳夹Mean SE; N=18.Nauck MA, et al. J Clin Invest. 1993;91:301-307. GLP-1GIP主要合成部位主要合成部位L 细胞细胞(

7、回肠和结肠)K 细胞细胞 (十二指肠和空肠)2型糖尿病患者中分泌减少型糖尿病患者中分泌减少是否抑制餐后胰高糖素分泌抑制餐后胰高糖素分泌是否减少食物摄入减少食物摄入是 否延缓胃排空延缓胃排空是 否促进促进 细胞增殖细胞增殖是是促进胰岛素生物合成促进胰岛素生物合成是是Drucker DJ. Diabetes Care. 2003;26:2929-2940.n的临床意义Drucker DJ. Diabetes Care. 2003;26:2929-2940. 促进饱胀感降低食欲 细胞:增强葡萄糖依赖的胰岛素分泌肝脏: 胰高糖素水平下降减少肝糖输出细胞:抑制餐后胰高糖素分泌胃: 帮助调节胃排空Adap

8、ted from Flint A, et al. J Clin Invest. 1998;101:515-520; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.提高细胞反应减轻细胞工作量进食促进GLP-1分泌26平均血浆葡萄糖浓度 (mmol/L)时间 (hour)252015

9、10500123456788小时血糖谱Mean SE; N=20; 仅显示了用GLP-1治疗的患者的数据； *p=.003. Zander M, et al. Lancet. 2002;359:824-830. HbA1c平均 HbA1c (%)0246810129.2%7.9%*第 0 周第 6 周第0周第6周-10134625300250200150100500012826104Mean SEM; N=10; *安慰剂与GLP-1组相比p.0001; 注意胰岛素数据所用的单位刻度不同。Nauck MA, et al. Diabetes Care. 1998;21:1925-1931. -1

10、0123456* * *血糖 ( mmol/L)胰岛素 (pmol/L)IV GLP-1 或安慰剂IV GLP-1或安慰剂GLP-1安慰剂时间 (小时)时间 (小时)胰高糖素 (pmol/L)300 200 100 0 胰岛素 (pmol/L)时间 (min)-30 060120180240*葡萄糖 (mg/dL)270180900-30 060120180240 * * * * * *时间 (min)-30 06012018024020100时间 (min)*安慰剂GLP-1安慰剂GLP-1安慰剂GLP-1安慰剂GLP-1N=10; Mean SEM; *p.05.Nauck MA, et

11、al. Diabetologia. 1993;36:741-744. GLP-1受体胰岛素颗粒胰腺细胞ATP/ADP葡萄糖转运蛋白K/ATP通道电压依赖性Ca2+ 通道葡萄糖Ca2+胰岛素释放Gromada J, et al. Pflugers Arch Eur J Physiol. 1998;435:583-594; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.葡萄糖转运蛋白K/ATP通道电压依赖性Ca2+通道GLP-1受体cAMPATPCa2+胰岛素颗粒胰腺细胞胰岛素释放葡萄糖Gromada J, et al. Pflugers Arc

12、h Eur J Physiol. 1998;435:583-594; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.GLP-1受体胰岛素颗粒胰腺细胞ATP/ADP葡萄糖转运蛋白K/ATP通道电压依赖性Ca2+ 通道cAMPATPCa2+葡萄糖Ca2+胰岛素释放Gromada J, et al. Pflugers Arch Eur J Physiol. 1998;435:583-594; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.*1501005010007505002500*磺脲类GLP

13、-1Mean SEM; 数据用与5 mmol/L葡萄糖的对照组平均值相比刺激作用的%表示； *药物与对照相比p.05; GLP-1与磺脲类药物相比p.05 。Hargrove DM, et al. Metabolism. 1996;45:404-409.安慰剂刺激%刺激%胰岛的胰岛素分泌反应5 mmol/L 葡萄糖胰岛的胰岛素分泌反应15 mmol/L葡萄糖0胰岛素pmol/L1800750时间 (min)时间 (min)1500120090060030006004503001500-1501530456075-1501530456075葡萄糖静脉推注葡萄糖静脉推注没有糖尿病的受试者糖尿病患者

14、*盐水对照GLP-1-短时间用药GLP-1-长期间用药Mean SE; N=18;长时间输注p.05;短时间输注p=.33; *注意胰岛素数据的单位刻度不同。Quddusi S, et al. Diabetes Care. 2003;26:791-798. Reprinted with permission from The American Diabetes Association.GLP-1组生理盐水组C-肽 (pmol/L)0100200300400500600700GLP-1组中，胰岛素敏感性升高77% (p=.002)p=.0062型糖尿病患者第0周第6周Mean SE; N=19;

15、 变化值的组间差别 p=.02.Zander M, et al. Lancet. 2002;359:824-830.用GLP-1治疗的糖尿病大鼠7天龄大鼠的胰岛素免疫组化Tourrel C, et al. Diabetes. 2002;51:1443-1452.对照GLP-1第1天第3天第5天岛失去3维结构(与对照相比p.01)Farilla L, et al. Endocrinology. 2003;144:5149-5158. 对照 细胞内 bcl-2 水平 和第一天测定的值相比的与对照组相比，培养的人胰岛细胞中加入 GLP-1后，抗凋亡分子bcl-2的表达明显上调(*与对照组相比p.01

16、)Farilla L, et al. Endocrinology. 2003;144:5149-5158.53时间 (天)GLP-10501001502001*GLP-1细胞内 Caspase-3 水平和第一天测定的值相比的培养的人胰岛细胞中加入GLP-1后，促进凋亡的 细胞凋亡蛋白酶-3的表达明显下调(*与对照组相比p.001)Farilla L, et al. Endocrinology. 2003;144:5149-5158.35时间 (天)GLP-1050010001*对照 葡萄糖依赖的胰岛素分泌第1天第3天第5天p0.05p0.01p0.05NSNSNS时间 (min)0102060

17、010206001020600102060012345010206001234501020600123450123450123450123456 mM葡萄糖15 mM葡萄糖胰岛素U/mL/g蛋白质胰岛素U/mL/g蛋白质对照GLP-1Mean SD.Farilla L, et al. Endocrinology. 2003;144:5149-5158. Copyright 2003, The Endocrine Society . 时间 (min)进食流质皮下注射 GLP-1胃容量 (mL)* *0100200300400500-300601201802403090150210安慰剂GLP-1

18、Mean SEM; N=7; *p.0001.Nauck MA, et al. Diabetologia. 1996;39:1546-1553. 平均视觉模拟评分（mm）对时间（小时）作图的的平均曲线下面积时间 (周)0100200300400500016*饱胀感饱胀感饱感摄食期望饥饿感Mean SE; N=10; 仅显示了用GLP-1治疗的患者的数据。*第0周与第6周相比 p.05 ； 第0周与第1周相比p.05。Zander M, et al. Lancet. 2002;359:824-830.Mean SEM. 患者有纽约心脏协会 III级或IV级充血性心衰。对照组N=9 (5例患者有糖

19、尿病); GLP-1组 N=12 (8例有糖尿病). LVEF = 左室射血分数。Sokos GG, et al. J Card Fail. 2006;12:694-699. 米LVEF (%)6分钟步行距离的平均变化050100150200250300基线第5周051015202530基线第5周左室射血分数的平均变化(%) p.001p.001GLP-1对照Mean SEM; 对照组 N=10; GLP-1组 N=11 (急性心肌梗死患者(AMI)和LVEF 40%的患者直接血管成形术成功后。LVEF = 左室射血分数。IV用GLP-1后 = 72小时静脉输注GLP-1后。 包括糖尿病和非糖

20、尿病患者Nikolaidis LA, et al. Circulation. 2004;109:962-965.A.S.E 局部室壁运动评分LVEF (%)局部室壁运动评分的平均变化0123基线IV用GLP-1后01020304050基线IV用GLP-1后左室射血分数的平均变化(%)p.01p.01GLP-1对照Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157. Reprinted with permission from Elsevier 2007.脂肪组织脑 肝脏胰腺肌肉胃葡萄糖摄取和储存胰岛素敏感性胰岛素分泌胰高糖素分

21、泌胰岛素生物合成细胞增殖细胞凋亡胃排空食欲神经保护心脏保护心脏功能葡萄糖生成心脏GLP-1肠道 T2D 缺陷缺陷1,3持续灌注持续灌注 GLP-11,2 胰岛素生成胰岛素生成 1相胰岛素分泌相胰岛素分泌 胰高糖素分泌胰高糖素分泌 葡萄糖输出葡萄糖输出胃排空胃排空 摄食摄食1. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190; 2. Nielsen LL, et al. Regul Pept. 2004;117:77-88; 3. Drucker DJ and Nauck MA. Lancet. 2006;368:1696-1705.持

22、续输注GLP-1可改善2型糖尿病的病理缺陷一次性皮下注射后时间 (hour)Log Mean (SE)血浆GLP-1 (pM)-1012345110100100010000100000二肽基肽酶-4 (DPP-4) 降解 GLP-150 nmol5 nmol0.5 nmolH A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R NH2GLP-1人Mean SEM;N=4-7 (大鼠); p.05.Adapted from Parkes D, et al. Drug Dev Res. 2001;53:260-267; Eng J,

23、et al. J Biol Chem. 1992;267:7402-7405.6快速灭活 (DPP-4),清除半衰期短 (1-2 min)GLP-1 必须持续给药 (静脉注射)用于治疗2型糖尿病这样的慢性疾病非常不便Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940.Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940GLP-1受体激动剂与DPPIV抑制剂作用机制的不同艾塞那肽 (Exendin-4)l人工合成的赫拉毒蜥唾液中的一种蛋白质l与人GLP-1约有50的同源性体外试验中与人 细胞表面

24、GLP-1受体结合,对GLP-1受体的激活作用至少和GLP-1相近能抵抗DPP-4降解灭活作用Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88. Reprinted from Regulatory Peptides, 117, Nielsen LL, et al, Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycaemic control of type 2 diabetes,

25、77-88, 2004, with permission from Elsevier for English use only.DPP-4灭活位点H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S NH2H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R NH2艾塞那肽人GLP-1安慰剂艾塞那肽 0.05 g/kg艾塞那肽 0.10 g/kgMean (SE); N = 12; p.0001 for glucose; p.0

26、01 for insulin.Adapted from Kolterman OG, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3082-3089. Copyright 2003, The Endocrine Society.血清胰岛素浓度 (pmol/L)时间(小时)血浆葡萄糖浓度(mmol/L)皮下注射

27、血清胰岛素空腹血糖时间 (小时)02468571012689110246805090150200皮下注射安慰剂时间 (min)时间 (min)餐后血糖 (mmol/L)艾塞那肽进餐第一天基线Mean (SE); N = 109; p.004.Fineman MS, et al. Diabetes Care. 2003;26:2370-2377. Reprinted with permission from The American Diabetes Association.681012141618-30030 60 90 120 150 180 210 240进餐681012141618-30

28、 030 60 90 120150180210240安慰剂对照组安慰剂治疗组艾塞那肽N = 20; Mean (SE).Adapted from Kolterman OG, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3082-3089. Copyright 2003, The Endocrine Soci

29、ety.血胰高糖素 (ng/L)时间 (min)进餐艾塞那肽/安慰剂血糖 (mmol/L)时间 (min)安慰剂艾塞那肽 0.10 g/kg进餐0120180605010015020002006012018024030010515艾塞那肽/安慰剂安慰剂艾塞那肽晚餐午餐早餐夜间28825221618036144721084P12P8A4A12A8P4P6P血糖 (mg/dL)Patients with T2D receiving MET TZD; LS mean SE; N = 30; TZD indicates thiazolidinedione Adapted from Schwartz S

30、L, et al. Clin Ther. 2008;30:858-867.026527810413015645678910N = 217; Mean SE; Reductions from baseline to Wk 12 were sustained to Wk 156 (P0.0001); A1C, glycosylated hemoglobin A1C; CI, confidence interval.Adapted from Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.基线 A1C: 8.2% 0.1%安慰剂对照研究开放

31、标签非对照延长期研究156周-1.0% (95% CI: -1.1% to -0.8%)Treatment (week)A1C (%)Mean (SE); N=25.Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997. Copyright 2005, The Endocrine Society.正常人, 安慰剂2型糖尿病, 安慰剂2型糖尿病, 艾塞那肽Exenatide versus HealthyExenatide versus Placebop=.0002p=.0002p=.0029Time (min)Insulin Sec

32、retion (pmolkg-1min-1) Exenatide increased AUC0-10 min and AUC10-120 min of insulin and C-peptide by 180% to 310% 生理盐水Exendin-4生理盐水Exendin-40123胰岛面积(Arbitrary Units X 104)Mean (SE).Stoffers D, et al. Diabetes. 2000;49:741-748. Copyright 2000 American Diabetes Association. From Diabetes, Vol 49, 2000

33、; 741-748. Reprinted with permission from The American Diabetes Association.对照 STZ(细胞量 = 2.2 mg/个胰腺)GLP-1 STZ(细胞量 = 3.1 mg/个胰腺)Exendin-4 STZ(细胞量 = 3.6 mg/个胰腺)p.001 GLP-1 or exenatide compared with control.Tourrel C, et al. Diabetes. 2001;50:1562-1570. Copyright 2001 American Diabetes Association. Re

34、printed with permission from The American Diabetes Association.Mean (SE).Xu G, et al. Diabetes. 1999;48:2270-2276. Copyright 1999 Reprinted with permission from American Diabetes Association.Sham + SalineSham + Exendin-4Pancreatectomy + SalinePancreatectomy + Exendin-4-Cell Mass (mg)p .050246p .01Ex

35、endin-4处理后 细胞新生引起的 细胞量增加安慰剂5 g 艾塞那肽 BID10 g 艾塞那肽 BIDT50: 半排空时间 (min)固体食物液体食物Least Squares Geometric Means shown.*p.01 vs placebo.Linnebjerg H, et al. Diabetes. 2006;55(Suppl 1):A28 Abstract 116-OR.*0265278104130156-6-4-20体重变化 (kg)N = 217; Mean SE; Change from baseline to 3 y, P0.0001Adapted from Klo

36、noff DC, et al. Curr Med Res Opin. 2008;24:275-286.基线体重: 99.3 1.2 kg156周-5.3 kg (95% CI: -6.0 to -4.5 kg)治疗 (周)安慰剂对照研究开放标签非对照延长期研究* Open-label uncontrolled extensions of 30-wk placebo-controlled trials1. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997; 2. Kolterman OG, et al. J Clin Endoc

37、rinol Metab. 2003;88:3082-3089; 3. Linnebjerg H, et al. Regul Pept. 2008 Jul 16. Epub ahead of print; 4. Data on file, Amylin Pharmaceuticals, Inc.; 5. Schwartz SL, et al. Clin Ther. 2008;30:858-867; 6. Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.1. Drucker DJ. Diabetes Care. 2007;30:1335-

38、1343; 2. Herman GA, et al. J Clin Endocrinol Metab. 2006; 91:4612-4619; 3. DPP-4: http:/ Updated June 9, 2008. Accessed June 25, 2008 4. Deacon DF, et al. J Endocrinology. 2002;172:355-362. 5. Vildagliptin approval: http:/www.drugdevelopment- Accessed June 25, 2008; 6. FDA News: /bb

39、s/topics/NEWS/2006/NEW01492.html. Published October 17, 2006. Accessed August 7, 2008.OGTTGLP-1生理范围2活性GLP-1 (pM)1Randomized, double-blind, placebo-controlled, 3-period, single-dose crossover study; Patients with T2D, n = 54-55; Geometric mean SE; *P0.001 vs placebo; OGTT indicates oral glucose toler

40、ance test1. Herman GA, et al. J Clin Endocrinol Metab. 2006;91:4612-4619; 2. Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.DPP-4抑制剂（西他列汀）可阻止GLP-1降解但不刺激其分泌西他列汀25 mg西他列汀200 mg安慰剂 西他列汀25 及200 mg 分别增加加权平均活性GLP-1增加部分的曲线下面积约 1.3 及 1.9 倍研究药物时间 (小时)* 2001234560510157 西他列汀增加胰岛素 AUC0-120

41、min 113% 至 122% *Randomized, double-blind, placebo-controlled, 3-period, single-dose crossover studyPatients with T2D, n = 54-55; Geometric mean SE; *P0.001 vs placebo, geometric LS mean ratioAdapted from Herman GA, et al. J Clin Endocrinol Metab. 2006;91:4612-4619.时间 (小时)研究药物血浆胰岛素 (IU/mL)OGTT西他列汀 2

42、5 mg西他列汀 200 mg安慰剂血浆胰高糖素 (pg/mL)OGTTRandomized, double-blind, placebo-controlled, 3-period, single-dose crossover studyPatients with T2D, n = 54-55; Geometric mean SE; *P0.05 vs placebo, geometric LS mean ratioAdapted from Herman GA, et al. J Clin Endocrinol Metab. 2006; 91:4612-4619. 西他列汀降低 血浆胰高糖素A

43、UC0-120 min 7% 至 14%*西他列汀 25 mg西他列汀 200 mg安慰剂研究药物时间 (小时)Randomized, double-blind, placebo-controlled, crossover study; Patients with T2D, N = 14; Mean SE; 10-d treatment periods separated by a 2-wk washout period; Solid meal labeled with 99mTc-sulfur colloid and 1-13CglucoseAdapted from Vella A, et

44、al. Diabetes. 2007;56:1475-1480.安慰剂维格列汀 50 mg BID时间 (分)Counts Retained (%)0255075100060120180240进餐餐后2小时血糖24周基线 Randomized, double-blind, placebo-controlled, 24-wk study in patients with T2D; standard meal tolerance test (SMTT); 2-h PPG: placebo, n = 205; sitagliptin 100 mg, n = 202; Mean SE; *P0.001

45、; QD, once daily Adapted from Aschner P, et al. Diabetes Care. 2006;29:2632-2637.安慰剂校正的和基线相比的差值 : -46.7 mg/dL*060120144180216252288Plasma Glucose (mg/dL)时间 (分)Randomized, double-blind, placebo-controlled, 24-wk study in patients with T2DITT population: placebo, n = 88; vildagliptin, n = 89; Adjusted

46、 mean SE; *P = 0.001 Adapted from Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007;76:132-138. in Plasma Glucose From Baseline (mg/dL)安慰剂维格列汀 100 mg QD *-19.8-30-20-10010-19.8+1.8基线空腹血糖: 191 mg/dL时间 (周)平均 A1C (%)7.47.0-404824121620安慰剂维格列汀 100 mg QDRandomized, double-blind, placebo-control

47、led, 24-wk study in patients with T2D; ITT populationPlacebo, n = 88; vildagliptin, n = 89; Mean SEAdapted from Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007;76:132-138. 维格列汀100mg QD 时，基线至24周HbA1c改变：-0.8% 0.1% (P0.001 vs 安慰剂)时间 (周)平均体重 (kg)维格列汀 100 mg QD + MET吡格列酮 30 mg QD + METRandomized, doub

48、le-blind, placebo-controlled, 24-wk study in patients with T2DVildagliptin 100 mg + MET, n = 264; pioglitazone 30 mg + MET, n = 246; Mean SEAdapted from Bolli G, et al. Diabetes Obes Metab. 2008;10:82-90.9896949088-404824121620921. Herman GA, et al. J Clin Endocrinol Metab. 2006; 91:4612-4619; 2. Ve

49、lla A, et al. Diabetes. 2007;56:1475-1480; 3. Aschner P, et al. Diabetes Care. 2006;29:2632-2637; 4. Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007;76:132-138; 5. Zerilli T and Pyon EY. Clin Ther. 2007;29(12):2614-2634; 6. Bolli G, et al. Diabetes Obes Metab. 2008;10:82-90.EASD = European Associ

50、ation for the Study of DiabetesNathan DM, et al. Diabetes Care 2009;32:193-203.诊断:生活方式+ 二甲双胍 生活方式 + 二甲双胍+ 基础胰岛素 生活方式 + 二甲双胍+ 磺脲类 生活方式 + 二甲双胍+ 强化胰岛素第一步第二步第三步生活方式 + 二甲双胍+ 吡格列酮 (无低血糖 /有水肿(心衰)/ 骨丢失)第一级: 有很多寻证医学支持的核心治疗第二级: 寻证医学证据较少的核心治疗 生活方式 + 二甲双胍+ GLP-1 受体激动剂 b(无低血糖/可降低体重 /恶心/呕吐 ) 生活方式 + 二甲双胍+ 吡格列酮 + 磺

51、脲类 a 生活方式 + 二甲双胍+ 基础胰岛素CHF = congestive heart failureNathan DM, et al. Diabetes Care 2009;32:193-203.Nathan DM, et al. Diabetes Care 2009;32:193-203.*在某些特殊情况下，应考虑使用第二级治疗方案中的治疗药物，如在某些需尽量避免低血糖发生的患者，或迫切需要降低体重的患者，则艾塞那肽是一个理想的选择降糖效应降糖外效应o降低HbA1co低血糖风险o胰岛素分泌能力o安全性选择特殊的糖尿病干预措施o体重改变o心血管风险因子o安全性o耐受性o使用方便o费用Se

52、e information about hypoglycemia, nausea, or pancreatitis and the Important Safety Information included in this presentation, and the accompanying full Prescribing Information.Nathan DM, et al. Diabetes Care 2009; 32:193-203.*当艾塞那肽与磺脲类合用时，会增高低血糖风险ADA/EASD 治疗标准治疗标准艾塞那肽艾塞那肽 HbA1c 控制控制持续控制HbA1c体重改变体重改变能够降低体重低血糖风险低血糖风险低血糖风险低*胰岛素分泌能力胰岛素分泌能力葡萄糖依赖的胰岛素分泌心血管风险因子心血管风险因子需要更多对心血管长期保护作用的研究安全性安全性/耐受性耐受性主要的不良反应为恶心、呕吐、腹泻、抖动、头晕、头痛、消化不良等，恶心主要见于使用早期，多数随时间延长而逐渐消失使用方便使用方便本品为预充笔，每天两次餐前1小时内注射，无需