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