GLP-1糖尿病治疗的新希望课件.ppt

1、GLP-1糖尿病患者的新希望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 p

2、ractice recommendations.UKPDS 34,n=1704UKPDS 34.Lancet 2019:352:85465;Kahn et al(ADOPT).NEJM 2019;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

3、 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 2019:352:85465.n=at baseline;Kahn et al(ADOPT).NEJM 2019;355(23):242743p0.05 gli

4、benclamide vs.rosiglitazonePatients with hypoglycaemia*(%)1039051015202530354045Rosiglitazone Metformin Glibenclamide12Hypoglycaemia,events/patient/year*051020GlargineNPH*All symptomatic hypoglycaemic events15Riddle et al.Diabetes Care 2019;26:3080;Kahn et al(ADOPT).NEJM 2019;355:2427432型糖尿病的进展过程:Hb

5、A1c,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？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 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.Diabe

6、tes Care 2019;28:1092 人类 GLP-1LiraglutideExenatide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 2019Meier et al.Diabetologia 2019Ritzel RA et al.Diabetes Care 2019;29:717M.A.Pfeifer et al.Am J Med 1981;70:579-58885%Holst JJ,et al.physiolo

7、gical reviews 87：1409-1439，2019Doyle ME,Egan JM.Pharmacol ther 2019 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 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 2019,Bulotta et al.J Mol Endocrinol 20

8、19,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b-cell mass(mg/pancreas)ZDF rats16-week study 1.Sturis et al.Br J Pharmacol 2019;140:123132.2.Rolin et al.Am J Physiol Endocrinol Metab 2019;283:E745E75205101520Vehicle(n=7)Liraglutidep 0.05p=0.0019150 g/kg bi

9、d(n=8)02468Vehicle(n=10)Liraglutide200 g/kg bid(n=10)10db/db mice22-week study Farilla et al.Endocrinology 2019;144:5149-58 Fehse F et al.J Clin Endocrinol Metab 2019;90(11):5991-5997Healthy subjects,PlaceboType 2 diabetes,PlaceboType 2 diabetes,ExenatideExenatide vs HealthyExenatide vs PlaceboP=0.0

10、002P=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 2019;25;152-6.Vilsbll T et al.Diabetes Care 2019;30(6):1608-1610改善HOMA betap0.0001p0.0001(n=40)Change in HOMA beta-cell

11、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 2019;359:824-830mg Glucose per kg lean body weightper pmol/l InsulinWeek 0Week 6Slide No 21Mean2SEGarber et al.Diabe

12、tes 2019;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 for overall population(

13、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 2019;57(Suppl.1):A4(LEAD 1);Nauck et al.Diabetes 2019;57(Suppl.1):A150(LEAD 2);Garber et al

14、.Diabetes 2019;57(Suppl.1):LB3(LEAD 3);Russell-Jones et al.Diabetes 2019;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 weight3.02.52.01.51.00.50.0GLP-1 Saline 8h血糖(GLP-

15、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 2019;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 mg+metGlimepiride+met

16、-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 2019;57(Suppl.1):A32.Nauck et al.Diabete

17、s 2019;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 2019;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？