GLP-1糖尿病治疗的新希望ppt课件

1、GLP-1糖尿病患者的新希望糖尿病患者的新希望糖尿病为进展性疾病，特征表现为：细胞功能下降血糖控制恶化微血管并发症大血管并发症风险添加在控制血糖的治疗中，医生、患者将面临着：低血糖风险添加体重添加复杂的治疗方案自我监测的需求添加 6.2% upper limit of normal rangeMedian HbA1c (%)Conventional*GlibenclamideMetforminInsulinUKPDS6789Years from randomisation24681007.58.56.5Recommended treatment target 15 mmol/L; ADA cl

2、inical practice recommendations. UKPDS 34, n=1704UKPDS 34. Lancet 1998:352:85465; Kahn et al (ADOPT). NEJM 2006;355(23):242743Glibenclamide (n=277)Years from randomisationInsulin (n=409)Metformin (n=342) Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if

3、FPG 15 mmol/LUKPDS: up to 8 kg in 12 yearsADOPT: up to 4.8 kg in 5 yearsWeight (kg) Rosiglitazone, 0.7 (0.6 to 0.8) Metformin, -0.3 (-0.4 to -0.2)* Glibenclamide, -0.2 (-0.3 to 0.0)*Change in weight (kg)015036912876432Years0123459692880100UKPDS 34. Lancet 1998:352:85465. n=at baseline; Kahn et al (A

4、DOPT). NEJM 2006;355(23):242743p0.05 glibenclamide vs. rosiglitazonePatients with hypoglycaemia* (%)1039051015202530354045Rosiglitazone Metformin Glibenclamide12Hypoglycaemia, events/patient/year*051020GlargineNPH*All symptomatic hypoglycaemic events15Riddle et al. Diabetes Care 2003;26:3080; Kahn e

5、t al (ADOPT). NEJM 2006;355:2427432型糖尿病的进展过程:HbA1c, FPG 和 PPG 恶化治疗加强伴随着体重添加及低血糖Beta细胞功能下降Incretin的治疗会改动这些情况吗？大脑 胰岛素分泌 (葡萄糖依赖)胰高血糖素分泌胰岛素合成细胞量胰腺 肝脏 肝糖输出 能量摄取胃肠道减少动力 Slide No 8与人类GLP-1的氨基酸有97% 同源与人类GLP-1的氨基酸有53%同源Study duration: Liraglutide 26 weeks; exenatide 30 weeks.1LEAD1,2,3,4,5 meta-analysis of a

6、ntibody formation; Data on file; 2DeFronzo et al. Diabetes Care 2005;28:1092 人类 GLP-1LiraglutideExenatide患者运用后抗体添加的比例 Liraglutide1 020406080100Exenatide + metformin243%8.6% liraglutide 抗体对疗效没有影响Butler et al. Diabetes 2003Meier et al. Diabetologia 2005Ritzel RA et al. Diabetes Care 2006; 29:717M.A. P

7、feifer et al. Am J Med 1981; 70:579-58885 %Holst JJ ,et al.physiological reviews 87：1409-1439，2007Doyle ME,Egan JM. Pharmacol ther 2007 添加细胞内的钙浓度能够加强胰岛素基因转录 GLP-1添加胰岛素mRNA 程度 经过调理胰岛素转录 经过稳定胰岛素mRNA 添加PDX-1 mRNA及蛋白 程度 与受体结合后激活腺苷酸环化酶构成cAMP 对细胞KATP通道的作用封锁通道，提高细胞膜势，添加对葡萄糖的敏感性 释放细胞内储存的Ca 2+ 添加可释放的胰岛素分泌囊泡数

8、量Farilla et al. Endocrinology 2003, Bulotta et al. J Mol Endocrinol 2002, Holz et al. Nature 1993; Drucker et al. Proc Natl Acad Sci USA 1987X肥大凋亡新生增殖 红色箭头代表GLP-1的作用b-cell mass (mg/pancreas)ZDF rats16-week study 1. Sturis et al. Br J Pharmacol 2003;140:123132.2. Rolin et al. Am J Physiol Endocrinol

9、Metab 2002; 283:E745E75205101520Vehicle(n=7)Liraglutidep 0.05p = 0.0019150 g/kg bid(n=8)02468Vehicle(n=10)Liraglutide200 g/kg bid(n=10)10db/db mice22-week study Farilla et al. Endocrinology 2003; 144:5149-58 Fehse F et al. J Clin Endocrinol Metab 2005;90(11):5991-5997Healthy subjects, PlaceboType 2

10、diabetes, PlaceboType 2 diabetes, ExenatideExenatide vs HealthyExenatide vs PlaceboP=0.0002P=0.0002P=0.0029Time (min)Insulin secretion (pmol/kg/min)Mean (SE); N = 25.Insulin (pmol/L)(n = 7)(n = 7)Hyperglycaemic clamp (20 mmol/L) plus arginineArginineVisbll et al. Diabetic Medicine 2021;25;152-6.Vils

11、bll T et al. Diabetes Care 2007;30(6):1608-1610改善HOMA betap0.0001p0.0001(n=40)Change in HOMA beta-cell function (%) versus baseline-4004080120160(n=42)(n=41)改善胰岛素原/胰岛素Median change in pro-insulin: insulin ratio versus baselinep0.02(n=11)-0.3-0.2-0.100.1(n=21)(n=21)p0.01Zander et al. Lancet 2002; 359

12、:824-830mg Glucose per kg lean body weightper pmol/l InsulinWeek 0Week 6 改善1相及最大胰岛素分泌 恢复细胞的敏感性Slide No 21Mean2SEGarber et al. Diabetes 2021;57(Suppl. 1):LB3 (LEAD 3)Slide No 22Liraglutide 1.8 mgLiraglutide 1.2 mg% reaching ADA targetSU combinationLEAD 1 Metformin combinationLEAD 2 Met + TZD combinat

13、ionLEAD 4 Met + SU combination LEAD 5 MonotherapyLEAD 3*p0.0001 *p0.001 vs. comparator; Patients reaching HbA1c ADA targets for overall population (LEAD 4,5) add-on to diet and exercise failure or up to half of maximum dose of 1 OAD (LEAD 3); or add-on to monotherapy (LEAD 2,1). GlimepirideRosiglita

14、zoneGlargineData originally presented as Marre et al. Diabetes 2021;57(Suppl. 1):A4 (LEAD 1); Nauck et al. Diabetes 2021;57(Suppl. 1):A150 (LEAD 2); Garber et al. Diabetes 2021;57(Suppl. 1):LB3 (LEAD 3); Russell-Jones et al. Diabetes 2021;57(Suppl. 1):A159 (LEAD 5); 26-week studies (LEAD 3=52 weeks)

15、.70605040302010-051%43%54%52%58%57%66%53%62%58%31%56%56%36%44%28%*Placebo体重变化 (kg)p=0.013 absolute valuesp=0.16 change in weight3.02.52.01.51.00.50.0GLP-1 Saline 8h血糖 (GLP-1 组)体重继续皮下输注GLP-1或盐水6周血糖 (mmol/L) 0510152025012345678注射后小时 0周 1周 GLP-1 6周 GLP-1900180270血糖 (mg/dL)360450 Zander et al. Lancet 20

16、02;359:82430T2DM (n = 20)察看6周Slide No 24体脂变化DEXA scan -4-3-2-10123Change in body fat, kg (%) 86% of weight loss was fat tissue (liraglutide 1.8 mg)Liraglutide 1.2 mg + metGlimepiride + met-1.6*(-1.1%*)-2.4*(-1.2%*)+1.1 kg(+0.4%)Liraglutide 1.8 mg + met腹部 vs. 皮下脂肪CT scan-25-20-1550510-10腹部皮下Change in

17、 percentage fat (%)-17.1 -16.4 -4.8 -7.8* -8.5* +3.4 Data are meanSEM; *p0.05 vs. glim+met; n=160.LEAD 2 substudy, originally presented as Jendle et al. Diabetes 2021;57(Suppl. 1):A32.Nauck et al. Diabetes 2003;52(Suppl 1):A128. Data are mean SEM11名2型糖尿病患者Liraglutide或抚慰剂注射后给予阶梯式低糖钳夹实验钳夹血糖程度钳夹血糖程度 mmol/l (mg/dl)Liraglutide (7.5 g/kg体重) (n=11)Placebo (n=11)240胰