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%upperlimitofnormalrange,MedianHbA1c(%),Conventional*,Glibenclamide,Metformin,Insulin,UKPDS,6,7,8,9,Yearsfromrandomisation,2,4,6,8,10,0,7.5,8.5,6.5,Recommendedtreatmenttarget15mmol/L;ADAclinicalpracticerecommendations.UKPDS34,n=1704,UKPDS34.Lancet1998:352:85465;Kahnetal(ADOPT).NEJM2006;355(23):242743,体重增加,Glibenclamide(n=277),Yearsfromrandomisation,Insulin(n=409),Metformin(n=342),Conventionaltreatment(n=411);dietinitiallythensulphonylureas,insulinand/ormetforminifFPG15mmol/L,UKPDS:upto8kgin12years,ADOPT:upto4.8kgin5years,Weight(kg),Rosiglitazone,0.7(0.6to0.8)Metformin,-0.3(-0.4to-0.2)*Glibenclamide,-0.2(-0.3to0.0)*,Changeinweight(kg),0,1,5,0,3,6,9,12,8,7,6,4,3,2,UKPDS34.Lancet1998:352:85465.n=atbaseline;Kahnetal(ADOPT).NEJM2006;355(23):242743,低血糖,Hypoglycaemia,events/patient/year*,*Allsymptomatichypoglycaemicevents,15,Riddleetal.DiabetesCare2003;26:3080;Kahnetal(ADOPT).NEJM2006;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,SlideNo8,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,Studyduration:Liraglutide26weeks;exenatide30weeks.1LEAD1,2,3,4,5meta-analysisofantibodyformation;Dataonfile;2DeFronzoetal.DiabetesCare2005;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,Butleretal.Diabetes2003Meieretal.Diabetologia2005,2型糖尿病细胞凋亡增加,RitzelRAetal.DiabetesCare2006;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.Pfeiferetal.AmJMed1981;70:579-588,对照,2型糖尿病,85%,HolstJJ,etal.physiologicalreviews87：1409-1439，2007DoyleME,EganJM.Pharmacolther2007,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-1mRNA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Ca2+增加可释放的胰岛素分泌囊泡数量,Farillaetal.Endocrinology2003,Bulottaetal.JMolEndocrinol2002,Holzetal.Nature1993;Druckeretal.ProcNatlAcadSciUSA1987,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-cellmass(mg/pancreas),ZDFrats16-weekstudy,1.Sturisetal.BrJPharmacol2003;140:123132.2.Rolinetal.AmJPhysiolEndocrinolMetab2002;283:E745E752,0,5,10,15,20,Vehicle(n=7),Liraglutide,p0.05,p=0.0019,150g/kgbid(n=8),0,2,4,6,8,Vehicle(n=10),Liraglutide,200g/kgbid(n=10),10,db/dbmice22-weekstudy,Vehicle,GLP-1,Farillaetal.Endocrinology2003;144:5149-58,Day1,Day3,Day5,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）,FehseFetal.JClinEndocrinolMetab2005;90(11):5991-5997,ExenatidevsHealthy,ExenatidevsPlacebo,P=0.0002,P=0.0002,P=0.0029,Time(min),Insulinsecretion(pmol/kg/min),Mean(SE);N=25.,Insulin(pmol/L),(n=7),(n=7),Hyperglycaemicclamp(20mmol/L)plusarginine,Arginine,Visblletal.DiabeticMedicine2008;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）,VilsbllTetal.DiabetesCare2007;30(6):1608-1610,改善胰岛素原/胰岛素,Medianchangeinpro-insulin:insulinratioversusbaseline,p0.02,(n=11),-0.3,-0.2,-0.1,0,0.1,(n=21),(n=21),p0.01,Zanderetal.Lancet2002;359:824-830,mgGlucoseperkgleanbodyweightperpmol/lInsulin,Week0,Week6,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,SlideNo21,Mean2SE,Garberetal.Diabetes2008;57(Suppl.1):LB3(LEAD3),Liraglutide迅速高效持久地降低HbA1c（单纯饮食控制者，单药治疗）,SlideNo22,加用liraglutide后血糖达到ADA标准的患者比例高,Liraglutide1.8mg,Liraglutide1.2mg,%reachingADAtarget,SUcombinationLEAD1,MetformincombinationLEAD2,Met+TZDcombinationLEAD4,Met+SUcombinationLEAD5,MonotherapyLEAD3,*p0.0001*pparator;PatientsreachingHbA1cADAtargetsforoverallpopulation(LEAD4,5)add-ontodietandexercisefailureoruptohalfofmaximumdoseof1OAD(LEAD3);oradd-ontomonotherapy(LEAD2,1).,Glimepiride,Rosiglitazone,Glargine,DataoriginallypresentedasMarreetal.Diabetes2008;57(Suppl.1):A4(LEAD1);Naucketal.Diabetes2008;57(Suppl.1):A150(LEAD2);Garberetal.Diabetes2008;57(Suppl.1):LB3(LEAD3);Russell-Jonesetal.Diabetes2008;57(Suppl.1):A159(LEAD5);26-weekstudies(LEAD3=52weeks).,*,*,*,*,*,*,*,*,*,Placebo,GLP-1可良好控制血糖、减轻体重,体重变化(kg),p=0.013absolutevalues,p=0.16changeinweight,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,Zanderetal.Lancet2002;359:82430,T2DM(n=20)观察6周,SlideNo24,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DEXAscan,-4,-3,-2,-1,0,1,2,3,Changeinbodyfat,kg(%),86%ofweightlosswasfattissue(liraglutide1.8mg),Liraglutide1.2mg+met,Glimepiride+met,-1.6*(-1.1%*),-2.4*(-1.2%*),+1.1kg(+0.4%),Liraglutide1.8mg+met,腹部vs.皮下脂肪CTscan,-25,-20,-15,5,0,5,10,-10,腹部,皮下,Changeinpercentagefat(%),-17.1,-16.4,-4.8,-7.8*,-8.5*,+3.4,DataaremeanSEM;*p0.05vs.glim+met;n=160.LEAD2substudy,originallypresentedasJendleetal.Diabetes2008;57(Suppl.1):A32.,Liraglutide血糖依赖性调节胰岛素和胰高血糖素分泌,Naucketal.Diabetes2003;52(Suppl1):A128.DataaremeanSEM,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(7.5g/kg体重)(n=11),Placebo(n=11),240,胰高血糖素(pq/ml),Minutes,SlideNo26,与格列美脲相比，liraglutide1.2mg/日和1.8mg/日组低血糖显著降低,Garberetal.Diabetes2008;57(Suppl.1):LB3(LEAD3),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,