GLP1糖尿病治疗的新希望.ppt

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1、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 6.2%upper limit of normal rangeMedian HbA1c(%)Conventional*GlibenclamideMetforminInsulinUKPDS6789Years from randomisation24681007.58.56.5Recommended treatment target 15 mmol/L;ADA clinical practice recomm

2、endations.UKPDS 34,n=1704UKPDS 34.Lancet 1998:352:85465;Kahn et al(ADOPT).NEJM 2006;355(23):242743Glibenclamide(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

3、 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):242743p0.05 glibenclamide vs.

4、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;355:242743大脑 胰岛素分泌(葡萄糖依赖)胰高血糖素分泌胰岛素合成

5、细胞量胰腺 肝脏 肝糖输出 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-1LiraglutideExenatide患者使用后抗体增加的比例 Liraglutide1 020406080100

6、Exenatide+metformin243%8.6%liraglutide 抗体对疗效没有影响Butler et al.Diabetes 2003Meier et al.Diabetologia 2005Ritzel RA et al.Diabetes Care 2006;29:717M.A.Pfeifer et al.Am J Med 1981;70:579-58885%Holst JJ,et al.physiological reviews 87：1409-1439，2007Doyle ME,Egan JM.Pharmacol ther 2007Farilla et al.Endocri

7、nology 2003,Bulotta et al.J Mol Endocrinol 2002,Holz et al.Nature 1993;Drucker et al.Proc Natl Acad Sci USA 1987b-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.

8、05p=0.0019150 g/kg bid(n=8)02468Vehicle(n=10)Liraglutide200 g/kg bid(n=10)10db/db mice22-week study Farilla et al.Endocrinology 2003;144:5149-58 Fehse F et al.J Clin Endocrinol Metab 2005;90(11):5991-5997Healthy subjects,PlaceboType 2 diabetes,PlaceboType 2 diabetes,ExenatideExenatide vs HealthyExen

9、atide 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.Vilsbll T et al.Diabetes Care 2007;30(6):1608-1610改善HOMA betap0.0001p0.0001(n=40)Chan

10、ge 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 6Slide No 21Mean

11、2SEGarber et al.Diabetes 2008;57(Suppl.1):LB3(LEAD 3)Slide No 22Liraglutide 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 fo

12、r 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

13、(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%*Placebo体重变化(kg)p=0.013 absolute valuesp=0.16 change in weight3.02.52.01.51.00.50.0G

14、LP-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 24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

15、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):A3

16、2.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 26Garber et al.Diabetes 2008;57(Suppl.1):LB3(LEAD 3)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？