GLP-1糖尿病治疗的新希望.ppt

GLP-1 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 大血管并发症风险增加 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,2型糖尿病治疗面临的挑战,随着时间的延长，血糖控制逐渐恶化,6.2% upper limit of normal range,Median HbA1c (%),Conventional*,Glibenclamide,Metformin,Insulin,UKPDS,6,7,8,9,Years from randomisation,2,4,6,8,10,0,7.5,8.5,6.5,Recommended treatment target 7.0%,Time (years),0,2,3,4,5,1,ADOPT,Metformin,Glibenclamide,Rosiglitazone,*Diet initially then sulphonylureas, insulin and/or metformin if FPG15 mmol/L; ADA clinical practice recommendations. UKPDS 34, n=1704,UKPDS 34. Lancet 1998:352:85465; Kahn et al (ADOPT). NEJM 2006;355(23):242743,体重增加,Glibenclamide (n=277),Years from randomisation,Insulin (n=409),Metformin (n=342),Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG 15 mmol/L,UKPDS: up to 8 kg in 12 years,ADOPT: 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),0,1,5,0,3,6,9,12,8,7,6,4,3,2,UKPDS 34. Lancet 1998:352:85465. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):242743,低血糖,Hypoglycaemia, events/patient/year*,*All symptomatic hypoglycaemic events,15,Riddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM 2006;355:242743,2型糖尿病的自然进展病史导致的结果是： 逐步升级的治疗方法,人体的GLP-1具有多重生理作用,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,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. Diabetes Care 2005;28:1092,人类 GLP-1,Liraglutide,Exenatide,Liraglutide: 与人类GLP-1高度同源,患者使用后抗体增加的比例,liraglutide 抗体对疗效没有影响,Butler et al. Diabetes 2003 Meier et al. Diabetologia 2005,2型糖尿病细胞凋亡增加,Ritzel RA et al. Diabetes Care 2006; 29:717,细胞量与FPG之间的关系,正常 IFG 2型糖尿病,2型糖尿病1相分泌消失,M.A. Pfeifer et al. Am J Med 1981; 70:579-588,对照,2型糖尿病,85 %,Holst JJ ,et al.physiological reviews 87：1409-1439，2007 Doyle ME,Egan JM. Pharmacol ther 2007,增加细胞内的钙浓度可能加强胰岛素基因转录 GLP-1增加胰岛素mRNA 水平 通过调节胰岛素转录 通过稳定胰岛素mRNA 增加PDX-1 mRNA及蛋白 水平,快速作用,慢速作用,GLP-1对细胞的作用,与受体结合后激活腺苷酸环化酶形成cAMP 对细胞KATP通道的作用（关闭通道，提高细胞膜势，增加对葡萄糖的敏感性） 释放细胞内储存的Ca 2+ 增加可释放的胰岛素分泌囊泡数量,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 1987,GLP-1对细胞的调节 刺激再生，增加细胞量（动物模型）,liraglutide 治疗后增加细胞量 （糖尿病动物模型）,b-cell 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 0.05,p = 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 mice2 2-week study,Vehicle,GLP-1,Farilla et al. Endocrinology 2003; 144:5149-58,Day 1,Day 3,Day 5,在孤立的人胰岛GLP-1 治疗抑制细胞凋亡,快速输入GLP-1可恢复一相胰岛素分泌（T2DM）,Fehse F et al. J Clin Endocrinol Metab 2005;90(11):5991-5997,Exenatide vs Healthy,Exenatide vs Placebo,P=0.0002,P=0.0002,P=0.0029,Time (min),Insulin secretion (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.,胰岛素分泌能力增加到正常人的50%,liraglutide改善细胞功能（单药治疗）,Vilsbll T et al. Diabetes Care 2007;30(6):1608-1610,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,在肥胖的T2DM20例患者中进行高胰岛素正糖嵌夹试验,GLP-1治疗提高胰岛素敏感性,GLP-1对细胞作用小结,T2DM表现为 胰岛素1相分泌消失 细胞胰岛素量减少 细胞凋亡增加 在体外试验，动物模型及人类的研究中，均发现GLP-1对细胞具有多重阳性的有益作用 GLP-1受体激动剂在临床单药使用及联合治疗中 改善HOMA 细胞功能 减少胰岛素原/胰岛素 改善1相及最大胰岛素分泌 恢复细胞的敏感性,Slide No 21,Mean2SE,Garber et al. Diabetes 2008;57(Suppl. 1):LB3 (LEAD 3),Liraglutide迅速高效持久地降低HbA1c （单纯饮食控制者，单药治疗）,Slide No 22,加用liraglutide 后 血糖达到ADA标准的患者比例高,Liraglutide 1.8 mg,Liraglutide 1.2 mg,% reaching ADA target,SU combinationLEAD 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 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).,Glimepiride,Rosiglitazone,Glargine,Data 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-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD 5); 26-week studies (LEAD 3=52 weeks).,*,*,*,*,*,*,*,*,*,Placebo,GLP-1 可良好控制血糖、减轻体重,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),0,5,10,15,20,25,0,1,2,3,4,5,6,7,8,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,Slide No 24,体重的降低得益于腹部及皮下脂肪的减少 (所有试验组均加用二甲双胍),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 + met,Glimepiride + 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 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(Suppl. 1):A32.,Liraglutide血糖依赖性调节 胰岛素和胰高血糖素分泌,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