GLP1糖尿病治疗的新希望.ppt

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1、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,Recom

2、mended 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):24274

3、3,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

4、,-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 200

5、3;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

6、;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 2003Meier 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IFG2型糖尿病,2型糖尿病1相分泌消失,M.A.Pf

7、eifer et al.Am J Med 1981;70:579-588,对照,2型糖尿病,85%,Holst JJ,et al.physiological reviews 87：1409-1439，2007Doyle 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

8、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 rats16-week study,1.Sturis et al.Br J Pharmacol 2003;14

9、0:123132.2.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 mice22-week study,Vehicle,GLP-1,Farilla et al.Endocrinology 2003;144:5149-58,Day 1,Day 3,Day

10、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 a

11、rginine,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

12、2002;359:824-830,mg Glucose per kg lean body weightper 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,Garbe

13、r 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 combinationLEAD 2,Met+TZD combinationLEAD 4,Met+SU combination LEAD 5,Monotherapy

14、LEAD 3,*p0.0001*p0.001 parator;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.Diabet

15、es 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 val

16、ues,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

17、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

18、.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 mmol/l(mg/dl),Liraglutide(7.5 g/kg体重)(n=11),Placebo(n=11),240,胰高血糖素(pq/ml),Minutes,Slide No 26,与格列美脲相比，liraglutide 1.2 mg/日和1.8 mg/日组低血糖显著降低,Garber et al.Diabetes 2008;57(Suppl.1):LB3(LEAD 3),低血糖非常少(单药治疗),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？,看见曙光,2型糖尿病的进展过程,