浅析GLP受体激动剂与DPP抑制剂培训课件.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,浅析GLP受体激动剂与DPP抑制剂,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,浅析GLP受体激动剂与DPP抑制剂,*,浅析GLP受体激动剂与DPP抑制剂,GLP-1,与,2,型糖尿病,利拉鲁肽的研发和优势,肠促胰素类药物的比较,利拉鲁肽的储存和使用,主要内容,2,浅析GLP受体激动剂与DPP抑制剂,Adapted from Buse JB et al.In,Williams Textbook of Endocrinology.,10th ed.Philadelphia,Saunders,2003:14271483;Buchanan TA,Clin Ther,2003;25(suppl B):B32B46;Powers AC.In:,Harrisons Principles of Internal Medicine,.16th ed.New York:McGraw-Hill,2005:21522180;Rhodes CJ,Science,2005;307:380384.,2,型糖尿病的病理生理包括三方面主要缺陷,高血糖,肝脏,胰岛素不足,糖输出过多,胰岛素抵抗,(,葡萄糖摄取减少,),胰腺,肌肉和脂肪,过多胰高糖素,胰岛,胰岛素减少,胰岛素减少,细胞,产生过多胰高糖素,细胞,产生胰岛素减少,3,浅析GLP受体激动剂与DPP抑制剂,GLP-1,：,2,型糖尿病治疗新选择,GLP-1,DeFronzo RA.Br J Diabetes Vasc Dis,2003;3(Suppl 1):S24-40,胰岛素抵抗,胰高糖素,抑制不足,细胞,功能失调,胃肠道吸收,葡萄糖,慢性,细胞,功能衰竭,胰岛素,分泌不足,细胞,功能异常,二甲双胍,格列酮类,胰岛素、磺脲类,格列奈类,-,糖苷酶,抑制剂,4,浅析GLP受体激动剂与DPP抑制剂,6.2%,正常值上限,HbA,1c,中位数,(%),常规治疗,*,时间,(,年,),罗格列酮,格列苯脲,二甲双胍,胰岛素,UKPDS,6,7,8,9,随机化后时间（年）,2,4,6,8,10,0,7.5,8.5,6.5,推荐治疗达标目标,15 mmol/L,则加用磺脲类,胰岛素和,/,或二甲双胍,美国糖尿病学会临床实践指南,.,UKPDS,n=1704,5,浅析GLP受体激动剂与DPP抑制剂,以往的治疗增加体重和低血糖风险,体重（,kg,）,低血糖发生率*（,%,）,罗格列酮 二甲双胍 格列本脲,p,15 mmol/L,则加用磺脲类,胰岛素和,/,或二甲双胍,胰岛素,格列本脲,二甲双胍,12,年中体重增加最高达,8kg,6,浅析GLP受体激动剂与DPP抑制剂,胰高糖素样肽,-1(GLP-1),是重要的肠促胰素,一种由31个氨基酸组成的肽链,1,由,胃肠道,L-,细胞分泌的胰高糖素原剪切而成,1,由进食刺激分泌,(,直接腔内刺激和间接神经刺激,),2,肠促胰素家族成员,肠促胰素是天然血糖调节肽,GIP(,葡萄糖依赖的促胰岛素多肽）是另一种肠促胰素,2,1.Drucker et al.Proc Natl Acad Sci U.S.A 1987;84:34348;2.Drucker 368:16961705,7,浅析GLP受体激动剂与DPP抑制剂,胰腺,胃,心脏,大脑,肝,Adapted from Baggio&Drucker,.Gastroenterol,2007;132;213157,肠,心血管保护功能,饱腹感,学习能力和保护神经系统,(,动物实验,),胃排空,葡萄糖生成,葡萄糖依赖性胰岛素分泌,胰岛素合成,葡萄糖依赖性胰高糖素,分泌,GLP-1,具有多种重要生理作用,GLP-1,L,细胞分泌,GLP-1,被,DPP-4,分解,8,浅析GLP受体激动剂与DPP抑制剂,时间,(,分,),胰岛素反应（胰岛素，,mU/L,）,nmol/L,0.6,0.5,0.4,0.3,0.2,0.1,0,80,60,40,20,0,180,60,120,0,2,型糖尿病患者肠促胰素效应降低,对照组,(n=8),2,型糖尿病患者,(n=14),时间,(,分,),胰岛素反应（胰岛素，,mU/L,）,nmol/L,0.6,0.5,0.4,0.3,0.2,0.1,0,80,60,40,20,0,180,60,120,0,口服葡萄糖,静脉注射葡萄糖,肠促胰素效应,2,型糖尿病患者肠促胰素效应降低,Adapted with permission from Nauck M et al.Diabetologia.1986;29:4652.Copyright 1986 Springer-Verlag.,9,浅析GLP受体激动剂与DPP抑制剂,药理浓度的,GLP-1,可更好的恢复降糖作用,生理水平,GLP-1,1,(15 mM,高糖钳夹,),药理水平,GLP-1,2,(15 mM,高糖钳夹,),0,0,30,60,90,120,时间,(,分,),1000,2000,3000,4000,5000,6000,胰岛素,(pmol/L),GLP-1,输注时间,(0.5 pmol/kg/min),0,1000,2000,3000,4000,0,30,60,90,120,时间,(,分,),胰岛素,(pmol/L),5000,6000,GLP-1,输注时间,(1.0 pmol/kg/min),血浆,GLP-1:46 pM,健康人,血浆,GLP-1:41 pM,2,型糖尿病患者,血浆,GLP-1:126 pM,2,型糖尿病患者,Vilsbll et al.Diabetologia 2002;45:11119.,9,Hjberg et al.Diabetologia 2008,10,由于,2,型糖尿病患者,GLP-1,分泌量减少，需要体外补充药理浓度的,GLP-1,10,浅析GLP受体激动剂与DPP抑制剂,GLP-1,与,2,型糖尿病,利拉鲁肽的研发和优势,肠促胰素类药物的比较,利拉鲁肽的储存和使用,主要内容,11,浅析GLP受体激动剂与DPP抑制剂,2,型糖尿病患者,(n=6),正常人,(n=6),静脉推注,GLP-1(15 nmol/L),Intact GLP-1(pmol/L),时间,(,分钟,),5,5,15,35,45,0,500,1000,25,被,DPP-4,降解失活,7,37,9,Lys,His,Ala,Thr,Thr,Ser,Phe,Glu,Gly,Asp,Val,Ser,Ser,Tyr,Leu,Glu,Gly,Ala,Ala,Gln,Lys,Phe,Glu,Ile,Ala,Trp,Leu,Gly,Val,Gly,Arg,酶切,高清除率,(49 L/min),T,=1.52.1,分钟,(IV bolus 2.525.0 nmol/L),Adapted from Bjerre Knudsen.,J Med Chem,2004;47:412834;Vilsbll,.J Clin Endocrinol Metab,2003;88:2204,人,GLP-1,半衰期短，临床应用受限,12,浅析GLP受体激动剂与DPP抑制剂,在多个位点酰化,GLP-1,可实现一天一次注射,类似物,酰化位点,取代物,药性(pM),半衰期(小时),猪,GLP-1(7-37),55 19,1.2,K,18,R,26,34,-GLP-1,K,18,-Glu-C16,35.2 6.2,-,K,23,R,26,34,-GLP-1,K,23,-Glu-C16,30.1 3.3,20 2,R,34,-GLP-1,liraglutide,K,26,-Glu-C16,61.0 7.1,14 2,K,27,R,26,34,-GLP-1,K,27,-Glu-C16,36.3 0.3,-,R,26,-GLP-1,K,34,-Glu-C16,121 26,13,K,36,R,26,34,-GLP-1,K,36,-Glu-C16,36.4 2.1,12 1,K,38,R,26,34,-GLP-1,K,38,-Glu-C16,53.0 2.8,3,Bjerre Knudsen,et al.J Med Chem,2000;43:16649,13,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽是每日注射一次的人,GLP-1,类似物,Knudsen,et al.J Med Chem,2000;43:16649;Degn,et al.Diabetes,2004;53:118794,天然人,GLP-1,被,DPP-4,降解,利拉鲁肽,C-16,棕榈酰脂肪酸,与人,GLP-1,氨基酸同源性高达,97%,；,通过酰化与白蛋白结合；七聚物构型,皮下吸收缓慢,不易被,DPP-4,降解,半衰期达,13,小时,14,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽在皮下组织中吸收延迟,血液中的单体与白蛋白结合,避免被肾脏快速清除,肽链,脂肪酸,药物制剂和皮下组织中的七聚体,Steensgaard,et al.Diabetes,2008;57(,suppl,.1):A164(abstract 552-P),其机制为利拉鲁肽形成了七聚体的结构,15,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽,可达到稳定的高药理学浓度,Agers,et al.Diabetologia,2002;45:195202,单变量模式：给药,3,次后达到稳态,血浆利拉鲁肽,(pmol/L),时间,(,天,),2,12,6,8,10,4,6000,4000,2000,8000,9,11,7,3,1,5,13,30,个基准点制成的曲线模型,16,浅析GLP受体激动剂与DPP抑制剂,每日一次利拉鲁肽可,24h,控制血糖,安慰剂,利拉鲁肽,(6 g/kg,每日一次，皮下注射,),血糖,(mmol/L),注射,(08:00),注射后时间,(h),血糖,(mg/dL),0,0,4,8,12,16,20,24,6,8,10,12,14,100,180,220,260,140,Degn,et al.Diabetes,2004;53:118794,17,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽药代动力学特点,类似于天然GLP-1的代谢方式，代谢过程缓慢,DPP-4切断自N端的Ala8Glu9间位点,中性肽链内切酶（NEP）将利拉鲁肽降解为数个小片段代谢产物,体内代谢完全,仅6和5的代谢产物经尿液和粪便排出,泌尿系或胃肠道内未见完整的利拉鲁肽,Malm-Erjefalt M.Drug metabolism and disposition 2010;38(1944-53).,18,浅析GLP受体激动剂与DPP抑制剂,肾脏或肝脏受损患者体内利拉鲁肽药代动力学,1.Jacobsen L et al.,Diabetes 2007;56(Suppl.1):A137,2.Flint A et al.,Diabetes 2007;56(Suppl.1):A145,7000,5000,4000,3000,6000,2000,0,0,10,20,30,40,50,60,70,1000,注射后时间,(,小时,),10000,8000,6000,4000,2000,0,0,10,20,30,40,50,60,70,注射后时间,(,小时,),终末期,利拉鲁肽,浓度,(pmol/L),正常,轻度,中度,重度,肾组,肾脏受损,1,正常,轻度,中度,重度,肝脏组,肝脏受损,2,肝肾功能受损的患者利拉鲁肽药物暴露剂量未增加,19,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽3期临床试验涵盖了,T2DM,治疗的各个阶段,饮食,/,运动,开始一种口服药,增加第二种口服药,增加第三种口服药,或开始胰岛素,Liraglutide,monotherapy vs.SU,LEAD-3,Liraglutide+met vs.,SU+met,LEAD-2,Liraglutide+SU vs.,TZD+SU,LEAD-1,Liraglutide+met+TZD,vs.met+TZD,LEAD-4,Liraglutide+met+SU,vs.glargine+met+SU,LEAD-5,Liraglutide+met and/or SU,vs.exenatide+met and/or SU,LEAD-6,Liraglutide+met,vs.sitagliptin+met,Lira vs.DPP-4i,Marre,et al.Diabetic Medicine,2009;26;26878(LEAD-1);Nauck,et al.Diabetes Care,2009;32;8490(LEAD-2);Garber,et al.,Lancet,2009;373:47381(LEAD-3);Zinman,et al.,Diabetes Care,2009;,32:122430,(LEAD-4);Russell-Jones,et al.Diabetologia,2009;52:204655(LEAD-5);Buse,et al.Lancet,2009;374:3947(LEAD-6);,Pratley,et al,.,Lancet,2010:375;144756,(Lira vs.DPP-4i);1796 study,Novo Nordisk,data on file.,LEAD,Liraglutide Effect and Action in Diabetes;TZD,thiazolidinedione;met,metformin,Liraglutide+met,vs.SU+met,1796(China),20,浅析GLP受体激动剂与DPP抑制剂,与对照药物相比，利拉鲁肽可降低,HbA,1c,1.21.6%,LEAD-1,联合,SU,LEAD-2,联合,MET,LEAD-4,联合,MET+TZD,LEAD-5,联合,M,ET+SU,LEAD-3,单药治疗,*,*,*,*,*,HbA,1c,下降,(%),Change in HbA1c for overall population(LEAD-4,-5,-6,Lira vs Sita);add-on to,diet and exercise failure(LEAD-3);or add-on to previous OAD monotherapy(LEAD-2,-1).*,p,0.01,*,p,0.0001 vs,.,active comparator.Data from core trials,LEAD-6,联合,MET SU,*,Lira vs.sita,联合,MET,*,*,Liraglutide 1.8 mg,Liraglutide 1.2 mg,Glimepiride,Rosiglitazone,Glargine,Placebo,Exenatide,Sitagliptin,8.3,8.2,8.6,8.5,8.4,8.5,8.5,8.4,8.4,8.3,8.4,8.4,8.4,8.3,8.2,8.,1,8.4,8.4,8.5,8.3,8.4,8.3,基线,HbA,1c,(%),LEAD:Liraglutide Effect and Action in Diabetes.,Marre,et al.Diabet Med,2009;26;26878(LEAD-1);Nauck,et al.Diabetes Care,2009;32;8490(LEAD-2);Garber,et al.Lancet,2009;373:47381(LEAD-3);Zinman,et al.,Diabetes Care,2009;32:1224,30,(LEAD-4);Russell-Jones,et al.Diabetologia,2009;52:204655(LEAD-5);Buse,et al.Lancet,2009;374:39,47(LEAD-6);,Pratley,et al.Lancet,2010;375:1447,56(lira vs.sita),*,*,21,浅析GLP受体激动剂与DPP抑制剂,LEAD研究荟萃分析:仅利拉鲁肽可改善细胞功能的两个指标,*,p,0.0001,和*,p,0.05 vs.,利拉鲁肽,1.8 mg;,p,0.0001,和,p,0.001 vs.,利拉鲁肽,1.2 mg,BID,每日两次,;HOMA-B,-,细胞功能评价稳态模型；,OD,每日一次,;P/IR,胰岛素原：胰岛素比值,:,-,细胞压力测定,Matthews,et al.Diabetes,2010;59(Suppl 1):A401(1513-P),早期使用利拉鲁肽可以显著改善,2,型糖尿病的,细胞功能,治疗,利拉鲁肽,利拉鲁肽,罗格列酮,格列美脲,艾塞那肽,安慰剂,23,浅析GLP受体激动剂与DPP抑制剂,与对照药物相比，利拉鲁肽可降低体重达,3.4,kg,LEAD-1,联合,SU,LEAD-2,联合,MET,LEAD-4,联合,MET+TZD,LEAD-5,联合,MET+SU,LEAD-3,单药治疗,*,*,*,*,*,*,*,体重的变化,(kg),LEAD-6,联合,MET SU,*,Lira vs.Sita,联合,MET,*,*,*,*,*,p,0.01,*,p,0.0001 vs,.,active comparator;,p,0.01,p,0.0001 vs.placebo.Active comparators vs.placebo not shown.Data from core trials,Liraglutide 1.8 mg,Liraglutide 1.2 mg,Glimepiride,Rosiglitazone,Glargine,Placebo,Exenatide,Sitagliptin,LEAD:Liraglutide Effect and Action in Diabetes.,Marre,et al.Diabet Med,2009;26;26878(LEAD-1);Nauck,et al.Diabetes Care,2009;32;8490(LEAD-2);Garber,et al.Lancet,2009;373:47381(LEAD-3);Zinman,et al.,Diabetes Care,2009;32:1224,30,(LEAD-4);Russell-Jones,et al.Diabetologia,2009;52:204655(LEAD-5);Buse,et al.Lancet,2009;374:39,47(LEAD-6);,Pratley,et al.Lancet,2010;375:1447,56(lira vs.sita),24,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽降低收缩压可达6.7mmHg,Marre,et al.Diabetic Medicine,2009;26;26878(LEAD-1);Nauck,et al.Diabetes Care,2009;32;8490(LEAD-2);Garber et al.,Lancet,2009;373:47381(LEAD-3);Zinman,et al.,Diabetes Care,2009;32:,122430,(LEAD-4);Buse,et al.Lancet,2009;,374(9683):3947,(LEAD-6);,Colagiuri,et al.Diabetes,2008;57(Suppl.1):A16(LEAD-1-5),SBP,变化,(mmHg),与,SU,合用,LEAD-1,与,Met,合用,LEAD-2,与,Met+TZD,合用,LEAD-4,与,Met+SU,合用,LEAD-5,单药治疗,LEAD-3,1,5,6,7,4,3,2,1,0,2.8,2.6,2.8,6.7,利拉鲁肽,1.8 mg,利拉鲁肽,1.2 mg,5.6,4.0,2.3,2.1,3.6,*,*,*,*,*,*,与,MetSU,合用,LEAD-6,2.5,2.0,0.7,0.4,0.5,0.9,1.1,*vs.,对照药有显著差异,格列美脲,格列美脲,艾塞那肽,甘精胰岛素,安慰剂,罗格列酮,25,浅析GLP受体激动剂与DPP抑制剂,复合终点,(HbA,1c,7.0%,无体重增加和低血糖,),达标率高,0,5,10,15,20,25,30,35,40,45,达标比率,(%),利拉鲁肽,1.8 mg,(,n,=1363),利拉鲁肽,1.2 mg,(,n,=896),8%*,格列美脲,(,n,=490),6%*,罗格列酮,(,n,=231),15%*,甘精胰岛素,(,n,=232),艾塞那肽,(,n,=231),8%*,安慰剂,(,n,=524),利拉鲁肽,1.8 mg,(,n,=214),利拉鲁肽,1.2 mg,(,n,=210),14%*,西格列汀,(,n,=210),LEAD,研究,利拉鲁肽,vs.,西格列汀,Liraglutide 1.8 mg is superior(*,p,0.01;*,p,0.0001);Liraglutide 1.2 mg is superior(,p,0.0001),Percentages are from logistic regression model adjusted for trial,previous treatment and with baseline HbA,1c,and weight,Zinman,et al,Diabetologia,2009;52(Suppl 1):S292;,Pratley,et al.Lancet,2010;375:1447-56,50,39%,32%*,24%*,46%,35%*,26,浅析GLP受体激动剂与DPP抑制剂,GLP-1,与,2,型糖尿病,利拉鲁肽的研发和优势,肠促胰素类药物的比较,利拉鲁肽的储存和使用,主要内容,27,浅析GLP受体激动剂与DPP抑制剂,肠促胰素的两种治疗机制,Drucker.,Expert Opin Invest Drugs,2003;12:87100;Ahrn.,Curr Diab Rep,2003;3:36572,GLP-1,释放,食物摄入,活性的,GLP-1(7-36),DPP-4,抑制剂,DPP-4,GLP-1,受体激动剂,无活性的,GLP-1(9-36),28,浅析GLP受体激动剂与DPP抑制剂,Slide No,29,目前肠促胰素治疗的基本药物分类,人,GLP-1,类似物,如：利拉鲁肽,基于,exendin-4,治疗,如：艾塞那肽,GLP-1,受体,激动剂,DPP-IV,抑制剂,如：西格列汀等,基于肠促胰素的治疗,29,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽在多方面优于艾塞那肽,利拉鲁肽,艾塞那肽,用法,QD,BID,同源性,高(97%),低(53%),抗体是否影响降糖疗效,无影响,高滴度影响降糖,恶心持续时间,短,长,HbA,1C,降幅,大,较小,Buse JB et al.,Lancet,2009;374:39-47,30,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽疗效强于西格列汀,利拉鲁肽,西格列汀,用法,注射,口服,HbA,1C,降幅,大,较小,降低体重幅度,大,中性,恶心持续时间,稍长,短,低血糖发生率,低,低,Pratley R,et al.,The International Journal of Clinical Practice,2011,6,4,397-407,31,浅析GLP受体激动剂与DPP抑制剂,GLP-1,与,2,型糖尿病,利拉鲁肽的研发和优势,肠促胰素类药物的比较,利拉鲁肽的储存和使用,主要内容,32,浅析GLP受体激动剂与DPP抑制剂,利拉鲁肽使用简单方便,规格3ml：18mg/支（预填充注射笔）,每日应用一次，治疗剂量固定,可在任意时间注射，与进餐无关,根据诺和力,(,利拉鲁肽,),中文说明书,33,浅析GLP受体激动剂与DPP抑制剂,本品应冷藏于28,冰箱中（勿进冰箱冷冻室），不可冷冻,首次使用后，应在30,以下储藏或冷藏在28,冰箱中，不可冷冻,首次使用后的效期为一个月,盖上笔帽避光储存,利拉鲁肽注射液储存条件,34,浅析GLP受体激动剂与DPP抑制剂,总结,利拉鲁肽是人GLP-1类似物，半衰期长，与人GLP-1作用类似,葡萄糖浓度依赖性降糖，高效降糖同时低血糖发生率低,直接保护,细胞,降低体重达,3.4kg,持续降低收缩压可达,6.7mmHg,临床使用灵活方便,35,浅析GLP受体激动剂与DPP抑制剂,Thanks,36,浅析GLP受体激动剂与DPP抑制剂,