GLP-1糖尿病治疗的新希望

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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 rangeMedian HbA1c (%) Conventional*GlibenclamideMetforminInsulinUKPDS 6789 Years from randomisation2 4 6 8 1007.58.56.5 Recommended 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):242743 Glibenclamide (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 years ADOPT: 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 w eight (kg)0150 3 6 9 12876432 Years0 1 2 3 4 59692880100 UKPDS 34. Lancet 1998:352:85465. n=at baseline;

4、 Kahn et al (ADOPT). NEJM 2006;355(23):242743 p0.05 glibenclamide vs. rosiglitazonePatients with hypoglycaemia* (%) 10 39051015202530354045RosiglitazoneMetformin Glibenclamide12Hypoglycaemia, events/patient/year* 051020 Glargine NPH *All symptomatic hypoglycaemic events 15 Riddle et al. Diabetes Car

5、e 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 antibody formation; Data on file; 2DeFronzo et al.

6、 Diabetes Care 2005;28:1092 人类 GLP-1 Liraglutide Exenatide 患者使用后抗体增加的比例 Liraglutide 1 020406080100 Exenatide + metformin243%8.6% liraglutide 抗体对疗效没有影响 Butler et al. Diabetes 2003Meier et al. Diabetologia 2005 Ritzel RA et al. Diabetes Care 2006; 29:717 M.A. Pfeifer et al. Am J Med 1981; 70:579-588 8

7、5 % Holst JJ ,et al.physiological reviews 87：1409-1439，2007Doyle 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 mass (mg/pancreas) ZDF rats16-week study 1. Sturis et a

8、l. Br J Pharmacol 2003;140:123132.2. Rolin et al. Am J Physiol Endocrinol Metab 2002; 283:E745E75205101520 Vehicle(n=7) Liraglutidep 0.05 p = 0.0019150 g/kg bid(n=8) 02468 Vehicle(n=10) Liraglutide200 g/kg bid(n=10)10 db/db mice22-week study Farilla et al. Endocrinology 2003; 144:5149-58 Fehse F et

9、al. J Clin Endocrinol Metab 2005;90(11):5991-5997 Healthy subjects, PlaceboType 2 diabetes, PlaceboType 2 diabetes, ExenatideExenatide vs HealthyExenatide vs PlaceboP=0.0002 P=0.0002P=0.0029 Time (min)Insulin secretion (pmol/kg/min)Mean (SE); N = 25. Insulin (pmol/L) (n = 7)(n = 7) Hyperglycaemic cl

10、amp (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 p0.0001p0.0001(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

11、 ratio versus baseline p0.02(n=11)-0.3-0.2-0.100.1 (n=21) (n=21)p0.01 Zander et al. Lancet 2002; 359:824-830mg Glucose per kg lean body weight per pmol/l Insulin Week 0Week 6 Slide No 21 Mean2SEGarber et al. Diabetes 2008;57(Suppl. 1):LB3 (LEAD 3) Slide No 22 Liraglutide 1.8 mgLiraglutide 1.2 mg% re

12、aching ADA target SU combinationLEAD 1 Metformin combinationLEAD 2 Met + TZD combinationLEAD 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 max

13、imum dose of 1 OAD (LEAD 3); or add-on to monotherapy (LEAD 2,1). Glimepiride Rosiglitazone GlargineData originally presented as Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1); Nauck et al. Diabetes 2008;57(Suppl. 1):A150 (LEAD 2); Garber et al. Diabetes 2008;57(Suppl. 1):LB3 (LEAD 3); Russell-

14、Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD 5); 26-week studies (LEAD 3=52 weeks). 70605040302010-0 51% 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 weight3.02.52.01.51.00.50.0 GLP-1 Saline 8h血糖 (GLP-1 组)体重持续皮下输注GL

15、P-1或盐水6周血糖 (mmol/L) 05101520250 1 2 3 4 5 6 7 8注射后（小时） 0周 1周 GLP-1 6周 GLP-1 900180270血糖 (mg/dL)360450 Zander et al. Lancet 2002;359:82430 T2DM (n = 20)观察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 + met G

16、limepiride + 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 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 2008;57(

17、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 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) Minutes10 0 60 120 180c4.3(77) 3.7(67) 3.0(54) 2.3(41)胰高血糖素 (pq/ml) Minutes0 60 120 180 2404080120160 4.3(77) 3.7(67) 3.0(54) 2.3(41) Slide No 26 Garber et al. Diabetes 2008;57(Suppl. 1):LB3 (LEAD 3) HbA1c, FPG 和 PPG 恶化治疗加强伴随着体重增加及低血糖细胞功能下降Incretin的治疗会改变这些状况吗？