糖尿病的口服药治疗

,糖尿病的口服药治疗,ADA/EASDconsensusalgorithmfortype2diabetesmellitus,Diagnosis,Lifestyleintervention+metformin,HbA1c7%,No,Yesa,Addbasalinsulinmosteffective,Addsulfonylurealeastexpensive,Addglitazonebnohypoglycemia,HbA1c7%,HbA1c7%,HbA1c7%,No,Yesa,No,Yesa,No,Yesa,Addglitazoneb,c,Intensifyinsulin,Addbasalinsulin,Addsulfonylureac,HbA1c7%,HbA1c7%,No,Yesa,No,Yesa,Intensiveinsulin+metformin+/glitazonec,Addbasalorintensifyinsulin,aCheckHbA1cevery3monthsuntilHbA1cis2500倍vs.DPP-8或9可逆性竞争性,ThornberryNA，etal.CurrTopicsinMedChem,2007;7:557-568,口服西格列汀100mg和600mg的峰浓度是747nM和7000nM可有效抑制DPP-4显著低于抑制DPP-8和DPP-9所需浓度,高度选择性保证了捷诺维无动物毒性反应,1.LeitingBetal.Presentedat64thScientificSessionsoftheAmericanDiabetesAssociation;2004.Abstract6-OR.2.LankasGKetal.Diabetes.2005;54:29882994.,捷诺维(西格列汀)给药24小时后有效抑制血浆DPP-4活性达80%,给药后时间（小时）,80%,50%,对DPP-4的抑制,与基线相比对血浆DPP-4的抑制程度(%),0,1,2,4,8,12,16,20,24,10,0,40,50,60,80,100,90,70,30,20,10,6,10,14,18,22,26,OGTT,西格列汀25mg(n=56)西格列汀200mg(n=56)安慰剂(n=56),HermanGA,etal.JClinEndocrinolMetab2006;91:4612-4619,目前治疗药物对细胞的作用,AdaptedfromBuchananTAetalDiabetes2002;51:27962803;OvalleF,BellDSDiabetesObesMetab2002;4(1):5659;WolffenbuttelBH,LandgrafRDiabetesCare1999;22(3):463467;DeFronzoRAAnnInternMed1999;131:281303;AhrnBCurrDiabRep2003;3:365372;DruckerDJExpertOpinInvestDrugs2003;12(1):87100;BuseJBetal.In:WilliamsTextbookofEndocrinology.10thed.Philadelphia:Saunders,2003:14271483;SkrumsagerBKetalJClinPharmacol2003;43(11):12441256.,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.,捷诺维(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.,捷诺维(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,捷诺维(西格列汀)和格列吡嗪对胰岛形态和功能的影响,Mu,Jetal.Diabetes,2006;55:1695-1704,(green=,red=),捷诺维(西格列汀)改善胰岛功能(离体胰腺),Mu,Jetal.Diabetes,2006;55:1695-1704,捷诺维(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,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：捷诺维（西格列汀）临床疗效安全性,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：捷诺维（西格列汀）临床疗效安全性,捷诺维(西格列汀)III期临床研究评估主要临床终点,降糖疗效:单药治疗与其他降糖药物联合细胞功能HOMA-胰岛素原/胰岛素比值安全性/耐受性临床不良事件体重改变低血糖发生率实验室不良事件,HbA1c(所有研究主要终点)FPGPPGHbA1c（7%或6.5%)达标率,捷诺维(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,捷诺维(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（PN040）,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),=,捷诺维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,捷诺维在亚洲人群(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%,HbA1c:基线水平越高，降幅越大,Least-squaresmean,placebo-subtracted.All-patients-treatedpopulation.Copyright2006AmericanDiabetesAssociation.FromDiabetesCare,Vol.29,2006;26322637ReprintedwithpermissionfromtheAmericanDiabetesAssociation,Monotherapy,24-weekplacebo-controlledstudy,MohanVetal.DiabetesResClinPract.2009;83:106116.,MonotherapystudyinAsia,单药治疗中捷诺维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,捷诺维(西格列汀)单药治疗：总结,显著降低HbA1c及其它血糖参数显著改善与细胞功能相关的指标降低胰岛素原/胰岛素比值升高平均HOMA-值这一胰岛素分泌的指标总体耐受性好，体重改变与低血糖发生率与安慰剂无显著差异,HOMA-=homeostasismodelassessment-.AdaptedfromAschneretal.DiabetesCare.2006;29:26322637;Razetal.Diabetologia.2006;49:25642571.MohanVetal.DiabetesResClinPract.2009;83:106116.,Monotherapy,捷诺维(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,24周与二甲双胍联合治疗研究捷诺维(西格列汀)与安慰剂对照-研究设计,ScreeningPeriod,Single-blindplacebo,Double-blindtreatmentperiod:Placeboorsitagliptin100mg/day,Continueorstartmetforminrun-intherapy,Week-2:EligibleifHbA1C7%to10%,IfonanAHAD/Cpatientsstartedonregimenofmonotherapy,Day1Randomization,Metformin1500mg/day,AHA=antihyperglycemicagent;D/C=discontinued;FPG=fastingplasmaglucose;MTT=mealtolerancetest.AdaptedfromCharbonneletal.DiabetesCare.2006;29:26382643.,主要终点HbA1c自基线的改变西格列汀的安全性和耐受性次要终点FPG进食标准餐后的血糖状况亚组患者在MTT后的胰岛素分泌指标,入选标准:接受口服降糖药物治疗(单药或低剂量联合)或未用药,Pioglitazonerescueforpatientsmeetingprespecifiedglycemiccriteria,Add-on1,24周与二甲双胍联合治疗研究HbA1c和FPG的改变情况,HbA1c(%SE),HbA1c,SE=standarderror.All-patients-treatedpopulation.LSMbetween-groupsdifferencesatweek24(95%CI):inHbA1Cvsplacebo=0.65%0.77,0.53(P0.001);inFPGvsplacebo=1.4mmol/L1.7,1.1(P0.001).ToconvertFPGfrommmol/Ltomg/dL,divideby0.05551Copyright2006AmericanDiabetesAssociation.FromDiabetesCare,Vol.29,2006;26322637ReprintedwithpermissionfromtheAmericanDiabetesAssociation.,FPG,Add-on1,-0.65%,-1.4mmol/L,Screening,Single-blindplacebo,Double-blindtreatmentperiod:Sulfonylureaorsitagliptin100mg/day,Metforminmonotherapy,Week2:EligibleifHbA1c6.5%to10%,IfonanOHA,D/CContinue/startmetformin,Day1Randomization,Week52,D/C=discontinued;OHA=oralantihyperglycemicagent;T2DM=type2diabetes.*Specifically,glipizide5mg/dayincreasedto20mg/day(dosenotuptitratediffingerstick110mg/dLorhypoglycemia).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研究设计,2型糖尿病患者随机，双盲，平行，活性对照，非劣效性研究(N=1172)治疗西格列汀100mg/day，二甲双胍1500mg/day磺脲*最大剂量20mg/day，二甲双胍1500mg/day,Metformin(stabledose1500mg/day),Add-on2,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，捷诺维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捷诺维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捷诺维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-on2,24周与吡格列酮联合治疗研究安慰剂对照与捷诺维(西格列汀)联用研究设计,AHA=antihyperglycemicagent;D/C=discontinued;FPG=fastingplasmaglucose.AdaptedfromRosenstocketal.ClinTher.2006;28:15561568.,主要终点HbA1c自基线的改变西格列汀的安全性和耐受性次要终点FPG,Add-on3,HbA1c,FPG,LSM=leastsquaresmean;SE=standarderror.All-patients-treatedpopulation.LSMbetween-groupsdifferenceatweek24:inHbA1Cvsplacebo=0.70%(95%CI,0.85,0.54;P0.001),inFPGvsplacebo=17.7mg/dL(95%CI,24.3,11.0;P0.001).ToconvertFPGfrommg/dLtommol/L,multiplyby0.05551AdaptedfromRosenstocketal.ClinTher.2006;28:15561568.,24周与吡格列酮联合治疗研究HbA1c和FPG改变情况,HbA1c(%),FPG(mg/dLSE),Add-on3,-0.7%,-0.98%,联合治疗中捷诺维改善细胞功能指标,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%).,捷诺维与二甲双胍或吡格列酮联合治疗总结,对血糖控制未达标的患者，捷诺维(西格列汀)与二甲双胍或吡格列酮联合治疗：显著降低HbA1c和其它血糖参数改善细胞功能指标总体耐受性好，低血糖发生率少不增加体重,AdaptedfromRosenstocketal.ClinTher.2006;28:15561568;Charbonneletal.DiabetesCare.2006;29:26382643.,Add-on,捷诺维(西格列汀)III期临床研究起始联合治疗,起始联合治疗54周数据：捷诺维(西格列汀)与二甲双胍起始联合治疗,InitialCombination,bid=twicedaily;qd=daily;R=randomization.Williams-HermanDetal.CurrMedResOpin.2009;25(3):569583.,Week2,Day1,Single-BlindPlaceboRun-InPeriod,EligibleifHbA1c7.5%11%,Week24,R,研究设计,Week54,24-Week(PhaseA),30-WeekContinuationPhase,InitialCombination,西格列汀与二甲双胍起始联合治疗HbA1c24周时自基线的改变,aLeastsquaresmeanchangefrombaselinewithadjustmentforplacebo.bWithin-groupmeanchangefrombaseline.bid=twicedaily;qd=daily.GoldsteinBetal.DiabetesCare.2007;30:19791987.Pleasenote:Dr.GoldsteiniscurrentlyaMerckemployeebutwasnotatthetimethisstudywasconductedorwhenthepublicationwaswritten.,Metformin1000mgbid,Sitagliptin100mgqd,Sitagliptin50mg+metformin500mgbid,Metformin500mgbid,Sitagliptin50mg+metformin1000mgbid,HbA1cChangeFromBaseline,%,3.5,3.0,2.5,2.0,1.5,1.0,0.5,0.0,0.5,178,177,183,178,175,n=,0.8a,1.0a,1.3a,1.6a,2.1a,24-WeekPlacebo-AdjustedResultsMeanHbA1c=8.8%,Open-LabelMeanChangeFromBaselineMeanHbA1c=11.2%,All-Patients-TreatedPopulation,HbA1cchangefrombaselineatweek24forplacebogroup(n=165)=0.17%,InitialCombination,西格列汀与二甲双胍起始联合治疗基线值高的患者HbA1c降幅更大,ContinuationAll-Patients-TreatedPopulation,BaselineHbA1c,8%Mean7.6%,n=172,8%to9%Mean8.4%,n=244,9%to10%Mean9.4%,n=163,10%Mean10.4%,n=78,0,3.0,2.0,1.0,MeanSEHbA1cChangeFromBaseline,%,3.5,2.5,1.5,0.5,0,3.0,2.0,1.0,3.5,2.5,1.5,0.5,Sitagliptin50mg+metformin1000mgbid,Metformin1000mgbid,Sitagliptin50mg+metformin500mgbid,Metformin500mgbid,Sitagliptin100mgqd,n=2832403933,n=4339534960,n=1930333843,n=161682117,bid=twicedaily;qd=daily;SE=standarderror.ReproducedwithpermissionfromWilliams-HermanDetal.CurrMedResOpin.2009;25(3):569583.,InitialCombination,西格列汀与二甲双胍起始联合治疗54周时改善细胞功能指标,Sita50mg+met1000mgbid,Sita50mg+met500mgbid,Met1000mgbid,Met500mgbid,Sita100mgqd,n=88,n=102,n=126,n=133,n=143,n=61,n=75,n=114,n=100,n=130,Proinsulin-to-InsulinRatio,n=88,n=102,n=126,n=133,n=143,HOMA-Change,bid=twicedaily;HOMA=homeostasismodelassessment;LSM=least-squaresmean;met=metformin;qd=daily;Sita=sitagliptin.Williams-HermanDetal.CurrMedResOpin.2009;25(3):569583.,ContinuationAll-Patients-TreatedPopulation,InitialCombination,西格列汀与二甲双胍起始联合治疗54周内持续降低HbA1c,Sita50mg+met1000mgbid(n=153),Met1000mgbid(n=134),Sita100mgqd(n=106),Sita50mg+met500mgbid(n=147),Met500mgbid(n=117),APT=all-patients-treated;bid=twicedaily;LSM=least-squaresmean;Met=metformin;qd=daily;Sita=sitagliptin.ReproducedwithpermissionfromWilliams-HermanDetal.CurrMedResOpin.2009;25(3):569583.,24-Week(PhaseA),30-WeekContinuationPhase,MeanSEChangeinHbA1c,%,6.0,6.5,7.0,7.5,8.0,8.5,9.0,0,6,12,18,24,30,38,46,54,Weeks,ContinuationAll-Patients-TreatedPopulation,InitialCombination,061218243038465462707891104,6,6.5,7,7.5,8,8.5,9,*CompleterspopulationSita=sitagliptin;Met=metformin,西格列汀与二甲双胍起始联合治疗持续2年降低HbA1c,Time(weeks),24-WeekPhase,ContinuationPhase,ExtensionPhase,HbA1c(LSmeanchange%),2008EASD,InitialCombination,捷诺维(西格列汀)III期临床研究三联治疗,三联治疗：52周与二甲双胍和磺脲联合治疗,TripleCombination,捷诺维联合格列吡嗪或格列吡嗪/二甲双胍,*=Pioglitazone30mgQD,入选病例：441例随机化病例，平均56岁，53%男性糖尿病平均病程为8.8年，平均基线A1C=8.34%,Add-ontoSU,TripleCombination,各组A1c自基线的改变Placebo-controlledAdd-ontoGlimepiride(+/-metformin)Study,*DifferenceinLSMeanchangefrombaseline,Weeks,A1C(%),AdaptedfromHermansenetal.DiabetesObesMetab2007;9:733-745,MeandurationofT2DM:8.8years,TripleCombination,Baseline(pmo