2型糖尿病治疗新进展

2型糖尿病治疗新进展临床一班李松埔201350312,概述,2型糖尿病：现状及挑战以肠促胰岛激素为基础的治疗：作用机制DPP-4抑制剂（西格列汀）对细胞的作用临床疗效安全性,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,2型糖尿病现有治疗选择,DeFronzoRA.BrJDiabetesVascDis,2003;3(Suppl1):S24-40,未解决,未解决,二甲双胍格列酮类,磺脲类格列奈类,-糖苷酶抑制剂,2型糖尿病的现状与挑战,尚无有效手段延缓2型糖尿病的进展保护胰岛细胞功能改善失调的细胞功能,2型糖尿病的现状与挑战,尚无有效手段延缓2型糖尿病的进展保护胰岛细胞功能改善失调的细胞功能由于降糖治疗的强度不断加大，带来的严重低血糖事件发生率加倍增加,反而影响了病人的达标率,2型糖尿病治疗的理想药物,、细胞双调节，有效地降低HbA1c，增加病人达标率能够延缓糖尿病的进程-改善细胞功能，改善胰岛素分泌不足-改善失调的细胞功能，增强对胰高糖素抑制-减缓慢性细胞功能衰竭减少副作用和改善依从性-减少常见的副作用：低血糖，体重增加，胃肠道反应-用药简单方便,概述,2型糖尿病：现状及挑战以肠促胰岛激素为基础的治疗：作用机制DPP-4抑制剂（西格列汀）对细胞的作用临床疗效安全性,Time,min,ControlSubjects(n=8),Time,min,IRInsulin,mU/L,180,60,120,0,Oralglucoseload,Intravenous(IV)glucoseinfusion,正常的肠促胰岛激素效应,IR=immunoreactiveAdaptedwithpermissionfromNauckMetal.Diabetologia1986;29:4652.Copyright1986Springer-Verlag.VilsbllT,HolstJJ.Diabetologia2004;47:357366.,正常个体的肠促胰岛激素效应,肠促胰岛激素调节胰岛素和胰高血糖素水平,GLP-1=胰高血糖素样肽1：GIP=葡萄糖依赖性促胰岛素分泌多肽.引自：KiefferT.EndocrineReviews.1999;20：876913.版权所有1999，TheEndocrineSociety.DruckerDJ.DiabetesCare.2003;26：29292940.NauckMAetal.Diabetologia.1993;36：741744.经允许引自：CreutzfeldtW.Diabetologia.1979;16：7585.版权所有1979Springer-Verlag.,13,肠促胰岛激素GLP-1和GIP的作用,由远端消化道L细胞分泌(回肠和结肠)以葡萄糖依赖的模式促进细胞释放胰岛素以葡萄糖依赖的模式抑制细胞分泌胰高糖素，从而抑制肝糖输出在动物模型及离体人类胰岛中增强beta细胞增殖和存活,由近端消化道K细胞分泌（十二指肠）以葡萄糖依赖的模式促进细胞释放胰岛素在胰岛细胞系中增强beta细胞增殖和存活,GLP-1（胰高糖素样肽1）,GIP（葡萄糖依赖性促胰岛素多肽）,AdaptedfromDruckerDJDiabetesCare2003;26:29292940;AhrnBCurrDiabRep2003;3:365372;DruckerDJGastroenterology2002;122:531544;FarillaLetalEndocrinology2003;144:51495158;TrmperAetalMolEndocrinol2001;15:15591570;TrmperAetalJEndocrinol2002;174:233246.,给2型糖尿病患者注射GLP-1后的葡萄糖依赖性调节胰岛素和胰高血糖素水平的作用,葡萄糖,胰高血糖素,当血糖水平达到正常值，胰高血糖素水平即回升。,当血糖水平达到正常值，胰岛素水平即下降。,*P0.052型糖尿病患者（N=10）,mmol/L,15.0,12.5,10.0,7.5,5.0,250,200,150,100,50,mg/dL,pmol/L,250,200,150,100,50,40,30,20,10,0,mU/L,注射,时间,pmol/L,20,15,10,5,0,60,120,180,240,pmol/L,20,15,10,5,胰岛素,2.5,0,0,0,0,0,引自：NauckMAetal.Diabetologia.1993;36：741744.版权所有1993Springer-Verlag.,30,15,Time,min,IRInsulin,mU/L,180,60,120,0,ControlSubjects(n=8),PatientsWithType2Diabetes(n=14),Time,min,IRInsulin,mU/L,180,60,120,0,Oralglucoseload,Intravenous(IV)glucoseinfusion,正常的肠促胰岛激素效应,减弱的肠促胰岛激素效应,IR=immunoreactiveAdaptedwithpermissionfromNauckMetal.Diabetologia1986;29:4652.Copyright1986Springer-Verlag.VilsbllT,HolstJJ.Diabetologia2004;47:357366.,2型糖尿病患者的肠促胰岛激素效应减弱,以肠促胰岛激素为基础的治疗:作用机制,DPP-IV=dipeptidylpeptidaseIVAdaptedfromDruckerDJExpertOpinInvestDrugs2003;12(1):87100;AhrnBCurrDiabRep2003;3:365372.,肠道GLP-1释放,无活性GLP-1(9-36),进餐,活性GLP-1(7-36),DPP-4酶抑制剂,DPP-4酶,GLP-1类似物,DPP-4抑制剂西格列汀(捷诺维)的作用机制,活性肠促胰岛激素GLP-1和GIP释放,餐前及餐后葡萄水平,摄食,胰高血糖素(GLP-1),肝糖生成,胃肠道,DPP-4酶,失活的GLP-1,X,西格列汀(DPP-4inhibitor),肠促胰岛激素GLP-1和GIP由肠道全天性释放，其水平在餐后升高,胰岛素(GLP-1GIP=glucose-dependentinsulinotropicpolypeptide.,西格列汀可升高活性肠促胰岛激素水平，从而增加和延长其活性作用,BetacellsAlphacells,外周组织对葡萄的摄取,DPP-4抑制剂：2型糖尿病治疗新选择,DPP4抑制剂,DeFronzoRA.BrJDiabetesVascDis,2003;3(Suppl1):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,磺脲类格列奈类,-糖苷酶抑制剂,DPP-4抑制剂与GLP-1类似物的差异,概述,2型糖尿病：现状及挑战以肠促胰岛激素为基础的治疗：作用机制DPP-4抑制剂（西格列汀）对细胞的作用临床疗效安全性,GLP-1在体外保护人胰岛细胞形态,第1天,GLP-1治疗的细胞,对照,第3天,第5天,AdaptedfromFarillaLetalEndocrinology2003;144:51495158.,加入GLP-1培养的胰岛细胞能够更长时间的保持其完整性.,西格列汀改善-细胞和-细胞数量,-细胞数量,-细胞数量,MU,Jetal.Diabetes,2006;55:1695-1704,HFD/STZmicetreatedwithDes-F-sitagliptinfor11-weeks.,西格列汀使细胞与细胞比例正常,Mu,Jetal.Diabetes,2006;55:1695-1704,HFD/STZmicetreatedwithDes-F-sitagliptinfor11-weeks.Greeninsulinpositiveb-cellRedglucagonpositivea-cell,西格列汀有效改善胰腺细胞功能,动物实验研究结果西格列汀增加-细胞数量，使细胞与细胞比例正常增加胰岛素阳性细胞数量增加胰腺内胰岛素含量改善葡萄糖刺激后胰岛素分泌（离体胰腺）,Mu,Jetal.Diabetes,2006;55:1695-1704,单药治疗中西格列汀显著改善细胞功能指标,All-patients-treatedpopulation.HOMA-=homeostasismodelassessment-.AdaptedfromRazetal.Diabetologia.2006;49:25642571.AdaptedfromAschneretal.DiabetesCare.2006;29:26322637.,AtWeek18(18-Week,Monotherapy,Placebo-ControlledStudy),AtWeek24(24-Week,Monotherapy,Placebo-ControlledStudy),Monotherapy,联合治疗中西格列汀改善细胞功能指标,Baseline:proinsulin-to-insulinratio(sitagliptin+pioglitazone=0.41pmol/L/pmol/L;placebo+pioglitazone=0.40pmol/L/pmol/L);HOMA-(sitagliptin=36.2%,placebo=39.6%).,Add-on,HOMA-=homeostasismodelassessment-;LSM=least-squaresmean.All-patients-treatedpopulation.AdaptedfromCharbonneletal.DiabetesCare.2006;29:26382643;AdaptedfromRosenstocketal.ClinTher.2006;28:15561568.,24周与二甲双胍联用研究,24周与吡格列酮联用研究,Baseline:Proinsulin-to-insulinratio(sitagliptin=0.357pmol/L/pmol/L,placebo=0.369pmol/L/pmol/L),HOMA-(sitagliptin=46.4%,placebo=45.1%).,Baseline(pmol/L/pmol/L):Sitagliptin=0.517;Placebo=0.491p=n.s.,三联治疗中西格列汀改善细胞功能指标,Sitagliptin,Placebo,Proinsulin/InsulinRatio,Baseline:Sitagliptin=50.7;Placebo=47.4*p=0.021,HOMA-b,*,AdaptedfromHermansenetal.DiabetesObesMetab2007;9:733-745,-0.08,-0.06,-0.04,-0.02,0.00,0.02,TripleCombination,概述,2型糖尿病：现状及挑战以肠促胰岛激素为基础的治疗：作用机制DPP-4抑制剂（西格列汀）对细胞的作用临床疗效安全性,西格列汀III期临床研究汇总,单药治疗18周安慰剂对照研究24周安慰剂对照研究12周日本人群安慰剂对照研究18周亚洲人群单药研究（PN040）与其它降糖药物联用与二甲双胍联用24周与二甲双胍联合治疗研究52周与二甲双胍联合治疗活性对照研究24周与吡格列酮联合治疗研究起始联合治疗二甲双胍和西格列汀对肠促胰岛激素的作用二甲双胍/西格列汀起始联合治疗三联治疗52周与磺脲或磺脲加二甲双胍联合治疗,西格列汀III期临床研究单药治疗,18周安慰剂对照研究24周安慰剂对照研究12周日本患者安慰剂对照研究18周亚洲患者单药研究,Monotherapy,AdaptedfromRazetal.Diabetologia.2006;49:25642571AdaptedfromAmericanDiabetesAssociation.FromDiabetesCare,Vol.29,2006;26322637AdaptedfromNonakaetal.Posterpresentedatthe66thScientificSessions,AmericanDiabetesAssociation,Washington,DC,June913,2006.,7.4,7.6,8.0,8.4,Placebo(n=244)Sitagliptin100mg(n=229),24-weekStudy,Time(weeks),0,6,12,18,24,-0.79%(p0.001),Japanese12-weekStudy,-1.05%(p0.001),Placebo(n=75)Sitagliptin100mg(n=75),Time(weeks),0,4,8,12,changevs.placebo*,18-weekStudy,Placebo(n=74)Sitagliptin100mg(n=168),Time(weeks),0,6,12,18,7.2,7.6,8.0,8.4,-0.6%(p0.001),=,西格列汀一天一次单药治疗持续显著降低HbA1C,Monotherapy,HbA1c(%SE),HbA1c(%SE),HbA1c(%SE),7.2,8.2,7.4,7.0,6.6,6.4,7.8,8.2,西格列汀在亚洲人群(中国、印度、韩国)降糖效果显著HbA1c从基线的改变(FASPopulation),9.2,9.0,8.8,8.6,8.4,8.2,8.0,7.8,0,6,12,18,Time,weeks,MeanSEChangeinHbA1c,%,FAS=fullanalysisset;qd=onceaday;SE=standarderror.,MohanVetal.DiabetesResClinPract.2009;83:106116.,Sitagliptin100mgqd(n=339),Placebo(n=169),Monotherapy,-1.03%,西格列汀III期临床研究联合治疗,1.与二甲双胍联用24周安慰剂对照，与二甲双胍联合治疗研究2.与二甲双胍联用52周活性对照研究（格列吡嗪），与二甲双胍联合治疗3.与吡格列酮联用24周安慰剂对照，与吡格列酮联合治疗研究,Add-on,HbA1c(%SE),LSMchangefrombaseline(forbothgroups):0.67%,达到首要假设：疗效非劣效于磺脲,LSM=least-squaresmean.aSpecifically,glipizide;bsitagliptin(100mg/day)withmetformin(1500mg/day);per-protocolpopulation.AdaptedfromNaucketal.DiabetesObesMetab.2007;9:194205.,52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究与二甲双胍联用时，西格列汀一天一次降糖效果不低于磺脲类(52周),Weeks,5.8,6.0,6.2,6.4,6.6,6.8,7.0,7.2,7.4,7.6,7.8,0,6,12,18,24,30,38,46,52,Sulfonylureaa+metformin(n=411),Sitagliptinb+metformin(n=382),Add-on2,aSpecifically,glipizide;bsitagliptin(100mg/day)withmetformin(1500mg/day);per-protocolpopulation.AdaptedfromNaucketal.DiabetesObesMetab.2007;9:194205.,Sulfonylurea+metformin,BaselineHbA1CCategory,ChangefrombaselineinHbA1c(%),n=117,n=117,112,179,167,82,82,33,21,7%,7to8%,8to9%,9%,-0.14,-0.59,-1.11,-1.76,-0.26,-0.53,-1.13,-1.68,-2.0,-1.8,-1.6,-1.4,-1.2,-1.0,-0.8,-0.6,-0.4,-0.2,0.0,Sitagliptinb+metformin,52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究基值越高，HbA1c降幅越大,Add-on2,PatientsatHbA1cgoal(%),HbA1c7%atweek52,*Specifically,glipizide.Per-protocolpopulation.MeanbaselineHbA1clevels:sitagliptin100mg,7.48%;glipizide,7.52%.AdaptedfromNaucketal.DiabetesObesMetab.2007;9:194205.,n=240,n=242,52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究西格列汀联合二甲双胍组更多的患者达到血糖控制目标,Add-on2,52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究西格列汀组体重下降且低血糖发生率显著低于对照组,Sulfonylurea+metformin(n=584),Sitagliptin100mg/day+metformin(n=588),Hypoglycemiab,LSMchangeinbodyweightovertimeb,体重(kgSE),LSM=least-squaresmean.aSpecifically,glipizide;ball-patients-treatedpopulation.LSMbetween-groupdifferenceatweek52(95%CI):inbodyweight=2.5kg3.1,2.0(P0.001);LSMchangefrombaselineatweek52:glipizide:+1.1kg;sitagliptin:1.5kg(P0.001).AdaptedfromNaucketal.DiabetesObesMetab.2007;9:194205.,Sulfonylurea+metformin(n=416)Sitagliptin100mg/day+metformin(n=389),Add-on2