GLP1糖尿病治疗的新希望

1、 1. 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 大血管并发症风险增加 2. 在控制血糖的治疗中，医生、患者将面临着： 低血糖风险增加 体重增加 复杂的治疗方案 自我监测的需求增加 6.2% upper limit of normal range median hba1c (%) conventional* glibenclamide metformin insulin ukpds 6 7 8 9 years from randomisation 2468100 7.5 8.5 6.5 recommended treatment target 15 mmol/

2、l; ada clinical practice recommendations. ukpds 34, n=1704 ukpds 34. lancet 1998:352:85465; kahn et al (adopt). nejm 2006;355(23):242743 glibenclamide (n=277) years from randomisation insulin (n=409) metformin (n=342) conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or

3、 metformin if fpg 15 mmol/l ukpds: up to 8 kg in 12 yearsadopt: up to 4.8 kg in 5 years weight (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) 0 1 5 036912 8 7 6 4 3 2 years 012345 96 92 88 0 100 ukpds 34. lancet 1998:352:

4、85465. n=at baseline; kahn et al (adopt). nejm 2006;355(23):242743 p0.05 glibenclamide vs. rosiglitazone patients with hypoglycaemia* (%) 10 39 0 5 10 15 20 25 30 35 40 45 rosiglitazone metformin glibenclamide 12 hypoglycaemia, events/patient/year* 0 5 10 20 glarginenph *all symptomatic hypoglycaemi

5、c events 15 riddle et al. diabetes care 2003;26:3080; kahn et al (adopt). nejm 2006;355:242743 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 ant

6、ibody formation; data on file; 2defronzo et al. diabetes care 2005;28:1092 人类 glp-1 liraglutide exenatide 患者使用后抗体增加的比例 liraglutide1 0 20 40 60 80 100 exenatide + metformin2 43% 8.6% liraglutide 抗体对疗效没有 影响 butler et al. diabetes 2003 meier et al. diabetologia 2005 ritzel ra et al. diabetes care 2006;

7、 29:717 m.a. pfeifer et al. am j med 1981; 70:579-588 85 % holst jj ,et al.physiological reviews 87：1409-1439，2007 doyle me,egan jm. pharmacol ther 2007 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 1987 b-cell

8、 mass (mg/pancreas) zdf rats1 6-week study 1. sturis et al. br j pharmacol 2003;140:123132. 2. rolin et al. am j physiol endocrinol metab 2002; 283:e745e752 0 5 10 15 20 vehicle (n=7) liraglutide p 0.05p = 0.0019 150 g/kg bid (n=8) 0 2 4 6 8 vehicle (n=10) liraglutide 200 g/kg bid (n=10) 10 db/db mi

9、ce2 2-week study farilla et al. endocrinology 2003; 144:5149-58 fehse f et al. j clin endocrinol metab 2005;90(11):5991-5997 healthy subjects, placebo type 2 diabetes, placebo type 2 diabetes, exenatide exenatide vs healthy exenatide vs placebo p=0.0002p=0.0002 p=0.0029 time (min) insulin secretion

10、(pmol/kg/min) mean (se); n = 25. insulin (pmol/l) (n = 7) (n = 7) hyperglycaemic clamp (20 mmol/l) plus arginine arginine visbll et al. diabetic medicine 2008;25;152-6. vilsbll t et al. diabetes care 2007;30(6):1608-1610 改善homa beta p0.0001 p0.0001 (n=40) change in homa beta-cell function (%) versus

11、 baseline -40 0 40 80 120 160 (n=42)(n=41) 改善胰岛素原/胰岛素 median change in pro-insulin: insulin ratio versus baseline p0.02 (n=11) -0.3 -0.2 -0.1 0 0.1 (n=21)(n=21) p0.01 zander et al. lancet 2002; 359:824-830 mg glucose per kg lean body weight per pmol/l insulin week 0 week 6 slide no 21 mean2se garber

12、 et al. diabetes 2008;57(suppl. 1):lb3 (lead 3) slide no 22 liraglutide 1.8 mgliraglutide 1.2 mg % reaching ada target su combination lead 1 metformin combination lead 2 met + tzd combination lead 4 met + su combination lead 5 monotherapy lead 3 *p0.0001 *p0.001 vs. comparator; patients reaching hba

13、1c 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). glimepiriderosiglitazoneglargine data originally presented as marre et al. diabetes 2008;57(suppl. 1):a4 (lead 1); nauck et al. d

14、iabetes 2008;57(suppl. 1):a150 (lead 2); garber et al. diabetes 2008;57(suppl. 1):lb3 (lead 3); russell-jones et al. diabetes 2008;57(suppl. 1):a159 (lead 5); 26-week studies (lead 3=52 weeks). 70 60 50 40 30 20 10 -0 51% 43% 54% 52% 58% 57% 66% 53% 62% 58% 31% 56% 56% 36% 44% 28% * * * * * * * * *

15、placebo 体重变化 (kg) p=0.013 absolute values p=0.16 change in weight 3.0 2.5 2.0 1.5 1.0 0.5 0.0 glp-1 saline 8h血糖 (glp-1 组) 体重 持续皮下输注glp-1或盐水6周 血糖 (mmol/l) 0 5 10 15 20 25 012345678 注射后（小时） 0周 1周 glp-1 6周 glp-1 90 0 180 270 血糖 (mg/dl) 360 450 zander et al. lancet 2002;359:82430 t2dm (n = 20) 观察6周 slid

16、e no 24 体脂变化 dexa scan -4 -3 -2 -1 0 1 2 3 change 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 -15 5 0 5 10 -10 腹部皮下 change in pe

17、rcentage 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 2008;57(suppl. 1):a32. nauck et al. diabetes 2003;52(suppl 1):a128. data are mean sem 11名2型糖尿病患者 liraglutide或安慰剂注射后给 予阶梯式低糖钳夹实验 钳夹血糖水平钳夹血糖水平 mmol/l (mg/dl) liraglutide (7.5 g/kg体重) (n=11) placebo (n=11) 240 胰岛素分泌 (pmol/kg/min) m