GLP糖尿病治疗的新希望.pptx

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 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 rangeMedian HbA1c(%)Conventional*GlibenclamideMetforminInsulinUKPDS6789Years from randomisation24681007.58.56.5Recommended treatment target 15 mmol/L;ADA clinical practice recommendations.UKPDS 34,n=1704UKPDS 34.Lancet 1998:352:85465;Kahn et al(ADOPT).NEJM 2006;355(23):242743体重增加Glibenclamide(n=277)Years from randomisationInsulin(n=409)Metformin(n=342)Conventional treatment(n=411);diet initially then sulphonylureas,insulin and/or metformin if FPG 15 mmol/LUKPDS:up to 8 kg in 12 yearsADOPT: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 weight(kg)015036912876432Years0123459692880100UKPDS 34.Lancet 1998:352:85465.n=at baseline;Kahn et al(ADOPT).NEJM 2006;355(23):242743低血糖p0.05 glibenclamide vs.rosiglitazonePatients with hypoglycaemia*(%)1039051015202530354045Rosiglitazone Metformin Glibenclamide12Hypoglycaemia,events/patient/year*051020GlargineNPH*All symptomatic hypoglycaemic events15Riddle et al.Diabetes Care 2003;26:3080;Kahn et al(ADOPT).NEJM 2006;355:2427432型糖尿病的进展过程:HbA1c,FPG 和 PPG 恶化治疗加强伴随着体重增加及低血糖Beta细胞功能下降Incretin的治疗会改变这些状况吗？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 肝脏 肝糖输出 能量摄取胃肠道减少动力 Slide No 7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-1LiraglutideExenatideLiraglutide:与人类GLP-1高度同源患者使用后抗体增加的比例 Liraglutide1 020406080100Exenatide+metformin243%8.6%liraglutide 抗体对疗效没有影响Butler et al.Diabetes 2003Meier et al.Diabetologia 20052型糖尿病细胞凋亡增加Ritzel RA et al.Diabetes Care 2006;29:717细胞量与FPG之间的关系正常正常正常正常IFGIFG2 2型糖尿病型糖尿病型糖尿病型糖尿病2型糖尿病1相分泌消失M.A.Pfeifer et al.Am J Med 1981;70:579-588对照对照2 2型糖尿病型糖尿病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PDX1 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 1987X肥大凋亡新生增殖 红色箭头代表GLP-1的作用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;140:123132.2.Rolin et al.Am J Physiol Endocrinol Metab 2002;283:E745E75205101520Vehicle(n=7)Liraglutidep 0.05p=0.0019150 g/kg bid(n=8)02468Vehicle(n=10)Liraglutide200 g/kg bid(n=10)10db/db mice22-week study VehicleGLP-1Farilla et al.Endocrinology 2003;144:5149-58 Day 1Day 3Day 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):5991-5997Healthy subjects,PlaceboType 2 diabetes,PlaceboType 2 diabetes,ExenatideExenatide vs HealthyExenatide vs PlaceboP=0.0002P=0.0002P=0.0029Time(min)Insulin secretion(pmol/kg/min)Mean(SE);N=25.Insulin(pmol/L)(n=7)(n=7)Hyperglycaemic clamp(20 mmol/L)plus arginineArginineVisbll 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HOMA betap0.0001p0.0001(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 ratio versus baselinep0.02(n=11)-0.3-0.2-0.100.1(n=21)(n=21)p0.01Zander et al.Lancet 2002;359:824-830mg Glucose per kg lean body weightper pmol/l InsulinWeek 0Week 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 20Mean2SEGarber 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 21加用liraglutide 后血糖达到ADA标准的患者比例高Liraglutide 1.8 mgLiraglutide 1.2 mg%reaching ADA targetSU combinationLEAD 1 Metformin combinationLEAD 2 Met+TZD combinationLEAD 4 Met+SU combination LEAD 5 MonotherapyLEAD 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).GlimepirideRosiglitazoneGlargineData 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).70605040302010-051%43%54%52%58%57%66%53%62%58%31%56%56%36%44%28%*PlaceboGLP-1 可良好控制血糖、减轻体重体重变化(kg)p=0.013 absolute valuesp=0.16 change in weight3.02.52.01.51.00.50.0GLP-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)0510152025012345678注射后（小时）0周 1周 GLP-1 6周 GLP-1900180270血糖(mg/dL)360450 Zander et al.Lancet 2002;359:82430T2DM(n=20)观察6周Slide No 23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-4-3-2-10123Change in body fat,kg(%)86%of weight loss was fat tissue(liraglutide 1.8 mg)Liraglutide 1.2 mg+metGlimepiride+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(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 SEM11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)Minutes10060120180c4.3(77)3.7(67)3.0(54)2.3(41)胰高血糖素(pq/ml)Minutes06012018024040801201604.3(77)3.7(67)3.0(54)2.3(41)Slide No 25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