背景:胰岛素泵治疗的演变Dr.ArnoldKadish在1960年代早期设计了第一个胰岛素泵1-3闭环系统4由患者背在背后像一个背包大小4.由于不方便日常使用，很少受到关注4ImagereprintedwithpermissionfromMedscape.com,2011.Availableat:http://www.medscape.org/viewarticle/460365CopyrightheldbyMedscape.1Kadish.BiomedicalSciencesInstrumentation1963;1:171-176.2Kadish.Transactions-AmericanSocietyforArtificialInternalOrgans1963;9:363-367.3Kadish.AmericanJournalofMedicalElectronics1964;3:82-86.4Alsaleh.JClinPharmTher2010;35:127-138.背景：胰岛素泵治疗的沿革上世纪90年代代表了胰岛素泵发展的一个新时代1之前的问题90年代胰岛素泵的特点泵故障胰岛素泵不工作输注过量胰岛素胰岛素漏出解决了技术问题下列情况时安全报警：输注时堵管电量不足胰岛素余量不足导管问题堵管改善了导管材质很少发生堵管输注针头问题金属针头的输注系统针头输注位点的感染针头脱出塑料导管输注系统泵的尺寸问题尺寸过大，不宜使用缩小尺寸1Alsalehetal.JClinPharmTher2010;35:127-138.背景：胰岛素泵治疗的沿革胰岛素泵治疗进展:90年代晚期到现在举例:可调整设置的基础率餐时剂量计算器可调整餐时剂量的持续时间和给药模式内置的计量计算器可根据之前的剂量计算剩余计量可根据目前血糖值和估计进食量计算所需胰岛素用量可调整的记忆功能安全锁定功能远程控制改善使用的舒适性、灵活性和易用性的功能Alsalehetal.JClinPharmTher2010;35:127-138.背景：谁需要使用胰岛素泵？1Grunbergeretal.EndocrPract2010;16(5):746-762.建议适合胰岛素泵治疗的患者的临床特征1Class1Class2Class3使用最大剂量MDI方案治疗，血糖仍然不能达标的T1DM患者，尤其是?糖尿病病情不稳定（具有不稳定的和剧烈的血糖波动）?频发严重低血糖和/或未察觉的低血糖?具有明显的“黎明现象,”极端胰岛素敏感者。特殊人群(eg,孕前，妊娠期患者，儿童，饮食不规律青少年患者，需要参加比赛的运动员)以下T1DM患者：使用最大剂量的基础－餐时方案MDI(不管血糖水平控制如何)以及认为胰岛素泵有助于更灵活的生活方式(经过调查和仔细考量)符合以下条件之一的T2DM患者：C-肽分泌（+），经过最大剂量基础－餐时方案MDI治疗血糖仍控制不佳?具有明显的“黎明现象”?具有不规律的生活方式（eg.频繁的长途旅行，需要轮班工作，或经常有无法预测的工作和生活安排以致无法按时进餐）?严重胰岛素抵抗某些其它类型糖尿病(eg,胰腺切除术后)CSII=持续皮下胰岛素输注;MDI=每日多次注射背景：为什么使用胰岛素泵？优点1-3最接近生理的胰岛素输注方式可调整基础率可根据食物种类和进食时间调整不同的餐时给药选择有助于避免“黎明现象”更一致的每日血糖谱更好的HbA1c控制减少每日胰岛素用量改善生活质量缺点1导管移位/堵塞/泵故障可导致糖尿病酮症酸中毒易感性增加需要更频繁的血糖监测(4到7次/天)埋置针头位点存在感染风险输注系统组件可能引发局部过敏复杂精密的仪器需要患者有良好的认知能力，需要医护人员和技术专家支持和随访。1Weintrobetal.TheIsraelMedicalAssociationJournal2004;6:271-275.2Cumminsetal.HealthTechnolAssess2010;14(11):1-181.3Missoetal.CochraneDatabaseSystRev2010;20(1):CD005103.HCP=healthcareprovider糖尿病患者CSII治疗背景:胰岛素泵治疗的沿革赖脯胰岛素在CSII中的应用成人患者应用的临床有效性和安全性赖脯胰岛素vs人胰岛素谷赖vs门冬vs赖脯CSIIvsMDI物理和化学稳定性CSII=continuoussubcutaneousinsulininfusion赖脯胰岛素vs.常规人胰岛素在CSII中的应用（研究一）研究设计–Zinmanetal.19976个月,双盲交叉研究(交叉前、后各3个月)两种药物都通过CSII给药30例糖尿病患者(13例男性,17例女性),年龄在26到51岁T1DM患者,使用CSII治疗至少3个月基线时平均HbA1c:8.0%导入期：1个月常规人胰岛素治疗餐前即刻给予餐时胰岛素CSII=continuoussubcutaneousinsulininfusion，持续皮下胰岛素输注ZinmanBetal.Diabetes1997;46:440-443.ZinmanBetal.Diabetes1997;46:440-443.研究开始前患者HbA1c=8.03±0.13%(mean±SEM)p=0.0041HbA1c(%)CSII=continuoussubcutaneousinsulininfusion3个月治疗后两组HbA1c比较赖脯胰岛素组显著优于人胰岛素组餐后1h血糖赖脯胰岛素组显著低于人胰岛素组ZinmanBetal.Diabetes1997;46:440-443.p=0.006p=0.049p=0.03CSII=continuoussubcutaneousinsulininfusion低血糖发生频率（次/30天）两组的低血糖发生频率较基线都有显著下降ZinmanBetal.Diabetes1997;46:440-443.低血糖定义为血糖<3mmol/L或出现低血糖症状.证实的低血糖定义为实测血糖<3mmol/L.P<0.05与基线相比nsns研究设计–Melkietal.1998开放性、交叉研究39例糖尿病患者(22例男性,17例女性),平均年龄39岁T1DM患者导入期:4周人胰岛素治疗治疗期:3个月，然后交叉平均基线HbA1c:7.74%(赖脯胰岛素);7.97%(人胰岛素)餐时赖脯胰岛素于餐前0-5min给药;餐时人胰岛素于餐前20-30min给药MelkiVetal.DiabetesCare1998;21:977-982.赖脯胰岛素vs.常规人胰岛素在CSII中的应用（研究二）人胰岛素赖脯胰岛素P-值HbA1c(%)a7.97.1NotreportedHbA1c自基线的改变(%)a-0.09-0.620.01餐后血糖(mmol/L)b9.908.26<0.0001低血糖发生率(次/人/月）c7.947.03NSa第一治疗期结束时测量b每个治疗期最后30天测量c第一治疗期最后30天测量低血糖定义为BG<3.0mmol/LMelkiVetal.DiabetesCare1998;21:977-982.BG=bloodglucose;CSII=continuoussubcutaneousinsulininfusion;NS=notsignificant赖脯胰岛素组的HbA1c和BG改善更显著两组低血糖发生率无显著差异研究设计–Renneretal.1999开放性、交叉研究113例糖尿病患者(60例男性,53例女性),平均年龄37岁T1DM导入期:人胰岛素治疗4周治疗期：4个月，然后交叉4个月平均基线HbA1c:7.2%餐时赖脯胰岛素于餐前即刻给药;餐时人胰岛素于餐前30min给药RennerRetal.DiabetesCare1999;22:784-788.赖脯胰岛素vs.常规人胰岛素在CSII中的应用（研究三）人胰岛素赖脯胰岛素P-值终点HbA1c(%)6.906.77<0.02餐后血糖(mmol/L)早餐8.67.0<0.001午餐8.77.6<0.001晚餐8.37.2<0.001低血糖发生率(次/人/月)a13.413.20.690aMeasuredduringfinal30daysoftreatmentHypoglycemiadefinedasBG<3.3mmol/LFriedman’srank-sumtestwasusedifdatawerenotnormallydistributedRennerRetal.DiabetesCare1999;22:784-788.赖脯胰岛素组HbA1c和BG改善更显著两组低血糖发生率无显著差异研究设计–Raskinetal.20016个月,开放性、交叉研究58例患者(30例男性,28例女性),年龄13～60岁T1DM平均基线HbA1c：赖脯胰岛素-人胰岛素组:7.9%人胰岛素–赖脯胰岛素组:7.6%餐时胰岛素于餐前即刻给药在为期2-到4-周的导入期终点及每12周治疗期终点进行实验餐的管理RaskinPetal.JDiabetesComplications2001;15:295-300.CSII=continuoussubcutaneousinsulininfusion赖脯胰岛素vs.常规人胰岛素在CSII中的应用（研究四）治疗3个月时，HbA1c的变化赖脯胰岛素组显著优于人胰岛素HbA1c(%)基线终点 赖脯胰岛素7.9±1.17.41±0.97 人胰岛素7.6±0.87.65±0.85RaskinPetal.JDiabetesCompl2001;15:295-300.1st治疗期P<0.05，两治疗药物组间差异，根据两个治疗阶段综合结果比较基线人胰岛素赖脯胰岛素HbA1c(%)6.577.588.5Datasource:Johanssonetal.Zinmanetal.Renneretal.p=0.047p=0.004p<0.02Raskinetal.p=0.0041JohanssonUBetal.DiabetesMetab2000;26(3):192-196. 3RennerRetal.DiabetesCare1999;22:784-788.2ZinmanBetal.Diabetes1997;46:440-443. 4RaskinPetal.JDiabetesComplications2001;15:295-300.综合4个研究表明：与人胰岛素相比，赖脯胰岛素治疗后HbA1c有显著下降平均餐后血糖(mmol/l)作者赖脯胰岛素人胰岛素P-值Renneretal.a7.28.3<0.001Johanssonetal.b8.19.6<0.001Melkietal.c8.269.90<0.0001Raskinetal.d9.6412.530.001A晚餐后血糖B晚餐后2hC平均餐后2hD进食实验餐后2h数据以mmol/L表示MelkiVetal.DiabetesCare1998;21:977-982. RennerRetal.DiabetesCare1999;22:784-788.JohanssonUBetal.DiabetesMetab2000;26:192-196. RaskinPetal.JDiabetesComplications2001;15:295-300.综合4个研究表明：与人胰岛素相比，赖脯胰岛素治疗后餐后血糖有显著下降比较T1DM患者中赖脯胰岛素和人胰岛素在胰岛素泵中应用的研究，可以发现，赖脯胰岛素治疗可以:显著降低HbA1c1-5显著降低餐后血糖1-5两组低血糖发生率无显著差异1-51ZinmanBetal.Diabetes1997;46:440-443. 4JohanssonUBetal.DiabetesMetab2000;26(3):192-196. 2RaskinPetal.JDiabetesComplications2001;15:295-300. 5RennerR,etal.DiabetesCare1999;22:784-788. 3MelkiVetal.DiabetesCare1998;21:977-982. 小结：赖脯胰岛素vs.常规人胰岛素在CSII中的应用糖尿病患者CSII治疗背景:胰岛素泵治疗的沿革赖脯胰岛素在CSII中的应用成人患者应用的临床有效性和安全性赖脯胰岛素vs人胰岛素谷赖vs门冬vs赖脯胰岛素CSIIvsMDI物理和化学稳定性CSII=continuoussubcutaneousinsulininfusion赖脯胰岛素vs谷赖胰岛素vs门冬胰岛素在CSII中的使用研究设计–Sanofi-aventis(@NIH),2010每阶段13周,随机化分组，开放性,3阶段交叉研究288名患者(137名男性,151名女性),平均年龄44岁T1DM整个治疗期为39周(每种胰岛素治疗13周)患者被随机分入3种交叉序列研究组(交叉序列举例:谷赖胰岛素,然后赖脯胰岛素,然后门冬胰岛素)VanBonAc,etal.DiabetesTechnolTher2011,13:607-614CSII=continuoussubcutaneousinsulininfusion研究序列1研究序列2研究序列3第一阶段(13wks)谷赖门冬赖脯第二阶段(13wks)门冬赖脯谷赖第三阶段(13wks)赖脯谷赖门冬n=99入组n=95入组n=94入组研究序列分配治疗期VanBonAc,etal.DiabetesTechnolTher2011,13:607-614谷赖门冬赖脯研究起始7.31%±0.71%7.33%±0.71%7.28%±0.71%研究终末7.32%±?0.03%?7.25%?±?0.03%?7.33%±?0.03%?谷赖胰岛素与门冬胰岛素治疗组间，以及谷赖与赖脯胰岛素组间HbA1c无显著差异文章没有对赖脯与门冬胰岛素治疗组间进行比较三种药物治疗后的HbA1cVanBonAc,etal.DiabetesTechnolTher2011,13:607-614谷赖门冬赖脯症状性低血糖b同时PG≤3.9mmol/L(次/人-年)73.88±?4.74?65.06?±?4.74a?62.74?±?4.74a?严重症状性低血糖c(次/人-年)1.63?±?0.35?1.39±?0.35?1.07±?0.35?夜间症状性低血糖d(次/人-年)12.80?±?0.959.66±?0.95a?9.48±?0.95a?A与谷赖相比有显著差异b症状性低血糖定义为出现由低血糖导致的临床症状(经由血糖检测证实或否)，并可以通过进食碳水化合物及时恢复C严重症状性低血糖定义为出现由低血糖导致的临床症状，需要他人的帮助，并且血糖<2mmol/L；或者通过进食碳水化合物/静脉给予葡萄糖/胰高血糖素注射可以恢复的低血糖事件d夜间症状性低血糖定义为发生在患者睡眠时（就寝后到清早起床前）出现的由低血糖导致的临床症状(经由血糖检测证实或否)，并可以通过进食碳水化合物及时恢复PG=plasmaglucose低血糖谷赖胰岛素低血糖发生率高于另外两组VanBonAc,etal.DiabetesTechnolTher2011,13:607-614糖尿病患者CSII治疗背景:胰岛素泵治疗的沿革赖脯胰岛素在CSII中的应用成人患者应用的临床有效性和安全性赖脯胰岛素vs人胰岛素谷赖vs门冬vs赖脯CSIIvsMDI物理和化学稳定性CSII=continuoussubcutaneousinsulininfusion赖脯胰岛素在CSII中的应用vs.赖脯+甘精在MDI中的应用（一）研究设计–Leporeetal.20041年、开放性、平行对照研究48名T1DM患者(24名男性,24名女性)平均年龄:38岁(CSII组);41岁(MDI组)基线HbA1c:9.0%(CSII组);8.6%(MDI组)治疗:CSII:赖脯胰岛素作为基础量+餐时量MDI:餐时应用赖脯胰岛素+晚餐或睡前应用甘精胰岛素CSII=continuoussubcutaneousinsulininfusion;MDI=multipledailyinjectionsLeporeG.etal.DiabNutrMetab2004;17:84-89.MDI:甘精+赖脯CSII:赖脯HbA1c(%)Months6am81012141618202224Time(hr)血糖(mmol/L)1098703691214.9812.9810.988.997.544.99CSII=持续皮下胰岛素输注MDI=multipledailyinjections，每日多次注射两组分别与基线相比，都P<0.001HbA1c自基线到12个月的改变量在两组无差异CSIIvs.MDI两组HbA1c改变和血糖均无显著差异两组间无显著差异MDI:甘精+赖脯CSII:赖脯LeporeG.etal.DiabNutrMetab2004;17:84-89.LeporeG.etal.DiabetesNutrMeta2004;17:84-89.CSIIvs.MDI–血糖波动CSII显著降低血糖波动组间P<0.001CSII=持续皮下胰岛素输注;MDI=每日多次注射LeporeG.etal.DiabetesNutrMeta2004;17:84-89.CSIIvs.MDI–低血糖两组严重低血糖发生率无显著差异两组间无显著差异CSII=持续皮下胰岛素输注;MDI=每日多次注射赖脯胰岛素在CSII中的应用vs.赖脯+甘精在MDI中的应用（二）研究设计–Bollietal.200924周、开放性、平行对照研究50位T1DM患者(27位男性,23位女性)平均年龄:38岁(CSII组);42岁(MDI组)基线HbA1c:7.7%(CSII组);7.8%(MDI组)治疗:CSII:赖脯胰岛素MDI:餐时赖脯+晚间甘精两种治疗均瞄准同样的血糖目标值(FPG4.4-6.6mmol/L;其他餐前PG5.0-7.7mmol/L；2-hrPPG<7.7mmol/L；睡前PG6.1-8.3mmol/L)BolliG.etal.DiabetesCare2009;32(7):1170-1176.CSIIvs.MDI–血糖控制两组无显著差异参数MDI(n=26)CSII(n=24)HbA1c(%)7.2±0.77.0±0.8FPG(mmol/L)7.7±2.46.8±1.72-hrPPG(mmol/L)7.6±2.18.2±2.3MAGE(mmol/L)6.4±2.16.4±2.2终点时血糖控制指标以上血糖控制指标在两组无显著差异.BolliG.etal.DiabetesCare2009;32(7):1170-1176.CSII=continuoussubcutaneousinsulininfusion;FPG=fastingplasmaglucose;MAGE=meanamplitudeofglycemicexcursion;MDI=multipledailyinjections;PPG=postprandialplasmaglucoseCSIIvs.MDI–低血糖两组无显著差异低血糖(次/人)MDICSIIP-值总体35±3541±430.93非严重ab31±3235±370.97夜间c5±73±50.34症状性14±1513±120.84无症状性1.4±2.31.2±2.00.95A非严重低血糖定义为由低血糖引起的症状，无需他人救助，检测血糖<4.0mmol/LB两组各有1例患者发生了1次严重低血糖，严重低血糖定义为由低血糖导致的临床症状，需要他人救助，血糖<2.0mmol/L或经进食/静脉给予葡萄糖或应用胰高血糖素可以恢复c夜间定义为就寝后到清早起床前BolliG.etal.DiabetesCare2009;32(7):1170-1176.JohanssonUB,AdamsonUCK,LinsPES,WredlingRAM.Improvedbloodglucosevariability,HbA1cinsumanInfusat?andlessinsulinrequirementinIDDMpatientsusinginsulinlisproinCSII.TheSwedishMulticenterLisproInsulinStudy.DiabetesMetab2000;26(3):192-196.[Source:pg.192,Summary]ZinmanB,TildesleyH.ChiassonJL,etal.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:pg.1,Abstract,Results].RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:pg.1,Abstract,Results].RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.297,column2,Results,lastparagraph].DISCUSSIONAcross4studiesthatcomparedinsulinlisprowithregularinsulininCSIIandhadbothbaselineandendpointHbA1cvalues,allshowedasignificantlylowerHbA1cvalueatendpointforinsulinlisprotherapycomparedwiththeregularinsulintherapy.MelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:pg.978,column3,DailyBGmeasurements]JohanssonUB,AdamsonUCK,LinsPES,WredlingRAM.Improvedbloodglucosevariability,HbA1cinsumanInfusat?andlessinsulinrequirementinIDDMpatientsusinginsulinlisproinCSII.TheSwedishMulticenterLisproInsulinStudy.DiabetesMetab2000;26(3):192-196.[Source:pg.194,TableII]RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:pg.784,Abstract,Results]RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.299,Discussion,paragraph1]DISCUSSIONAcross5studiesthatcomparedinsulinlisprowithregularinsulininCSIIandmeasuredpostprandialbloodglucose,allshowedsignificantlylowermeanpostprandialbloodglucosewithinsulinlisprotherapycomparedwithregularinsulintherapy.1ZinmanB,TildesleyH,ChiassonJL,etal.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:Abstract].2RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.Abstract;pg.297,Results,paragraph4;pg.299,lastsentenceincolumn1]3MelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:pg.977,Abstract,Results;pg.978,column3,DailyBGmeasurements]4JohanssonUB,AdamsonUCK,LinsPES,WredlingRAM.Improvedbloodglucosevariability,HbA1cinsumanInfusat?andlessinsulinrequirementinIDDMpatientsusinginsulinlisproinCSII.TheSwedishMulticenterLisproInsulinStudy.DiabetesMetab2000;26:192-196.[Source:pg.194,TableII;pg.194,Results,paragraph1]5RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:pg.784,Abstract,Results][NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSION99patientswereassignedtoSequence1.Theytookinsulinglulisineforthefirst13weeks(Period1),theninsulinaspartforthesecond13weeks(Period2),theninsulinlisproforthelast13weeks(Period3).95patientswereassignedtoSequence2.TheytookinsulinaspartduringPeriod1,theninsulinlisproduringPeriod2,theninsulinglulisineduringPeriod3.94patientswereassignedtoSequence3.TheytookinsulinlisproduringPeriod1,theninsulinglulisineduringPeriod2,theninsulinaspartduringPeriod3.BACKGROUNDStudydesign–sanofi-aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female)meanage:44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSION本表格显示各个治疗组的治疗第一周以及最后一周的mean±SDHbA1c值(acrosseachofthethreeperiods）.BACKGROUNDStudydesign–sanofi-aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female)meanage:44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSIONAlthoughtherapywitheachinsulinlastedonly13weeks,hypoglycemiawasreportedasannualizedvalues(eventsperpatient-year).Insulinaspartandinsulinlisprobothhadsignificantlylowerhypoglycemiaratescomparedwithinsulinglulisineforsymptomaticandnocturnalsymptomatichypoglycemia.BACKGROUNDStudydesign–Sanofi-Aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female)meanage:44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)LeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabNutrMetab2004;17:84-89.[Source:MaterialsandMethods,p85]LeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabNutrMetab2004;17:84-89.[Source:pg.86,Figure1;pg.87,Figure2;pg.87,paragraph1]DISCUSSIONBothtreatmentregimensloweredHbA1csignificantlyfrombaseline.ThechangeinHbA1cfrombaselinetoendpointdidnotdifferbetweentreatmentregimens(MDI:-0.7±0.6%;CSII:-1.0±0.8%)(Notshownonslide)Althoughthebloodglucoseprofileswerenotsignificantlydifferentbetweengroups,themeanamplitudeofglycemicexcursionwassignificantlylowerfortheCSIIgroupthantheMDIgroup.(Notshownonslide)BACKGROUNDStudydesign–Leporeetal.20041-yearopen-labelparallelstudy48patients(24male,24female)withtype1diabetesMeanage:38years(CSIIgroup);41years(MDIgroup)BaselineA1C:9.0%(CSIIgroup);8.6%(MDIgroup)Treatment:CSII:insulinlisproatmultiplebasalrates+mealtimebolusesMDI:mealtimeinsulinlisproinjection+insulinglargineinjectionateveningmealorbedtimeLeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabetesNutrMetab2004;17:84-89.[Source:pg.87,1stparagraph;Tables2and3]DISCUSSION日内平均血糖波动幅度(MAGE)：计算血糖超过24小时期间的1SD幅度以上阶段的增加或减少的算术平均数.BACKGROUNDStudydesign–Leporeetal.20041-yearopen-labelparallelstudy48patients(24male,24female)withtype1diabetesMeanage:38years(CSIIgroup);41years(MDIgroup)BaselineA1C:9.0%(CSIIgroup);8.6%(MDIgroup)Treatment:CSII:insulinlisproatmultiplebasalrates+mealtimebolusesMDI:mealtimeinsulinlisproinjection+insulinglargineinjectionateveningmealorbedtimeLeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabetesNutrMetab2004;17:84-89.[Source:pg.87,1stparagraph;Tables2and3]BACKGROUNDStudydesign–Leporeetal.20041-yearopen-labelparallelstudy48patients(24male,24female)withtype1diabetesMeanage:38years(CSIIgroup);41years(MDIgroup)BaselineA1C:9.0%(CSIIgroup);8.6%(MDIgroup)Treatment:CSII:insulinlisproatmultiplebasalrates+mealtimebolusesMDI:mealtimeinsulinlisproinjection+insulinglargineinjectionateveningmealorbedtimeBolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1171,ResearchDesignandMethods;pg.1172,Table1]符合方案数据分析（Per-protocolpopulation）：所有符合试验方案，依从性好（实际服用药量占应服用药量80～120%），试验期间未服禁止用药，完成CRF表规定填写内容的病例BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1174,Table2]BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1172,Column3,Hypoglycemia]DISCUSSIONDatashownarethemean(±SD)numbersofeventsperpatientoverthecourseofthe24-weekstudy.BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1172,Column3,Costs]BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1172,Column3,TreatmentSatisfaction]DISCUSSIONTheDTSQscoreincreasedfrom24.0±6.3atbaselineto28.8±5.4atendpointfortheMDIgroupandfrom22.8±8.1atbaselineto31.5±4.9atendpointfortheCSIIgroup.BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)DeFelippisMR,BellMA,HeyobJA,StormsSM.Invitrostabilityofinsulinlisproincontinuoussubcutaneousinsulininfusion.DiabetesTechnolTher2006;8(3):358-368.[Source:pg.Abstract,Methods]DISCUSSION通过高温和机械搅动压力测试结合模拟基础/餐时给药来测试赖脯胰岛素在持续皮下胰岛素输注治疗中的稳定性.(本实验完全为体外试验.)胰岛素泵设置为以0.8U/hr(19.2U/day)持续给药;36-Unit剂量同时通过手动每日给药(18U/day).测试了效价,纯度，高分子量蛋白以及间甲酚含量还测试了pH,给药剂量以及药物物理外观DeFelippisMR,BellMA,HeyobJA,StormsSM.Invitrostabilityofinsulinlisproincontinuoussubcutaneousinsulininfusion.DiabetesTechnolTher2006;8(3):358-368.[Source:pg.362,Figure1].DISCUSSION本图显示了3个泵中的一个的实验数据，3种胰岛素泵的测试结果相似。本图显示了每天测试组和对照组的效价测试结果。结果显示，实验组和对照组的结果相似。两组的结果都符合规格(95.0%to105.0%).BACKGROUNDStudydesign–DeFelippisetal.2006Insulinlisprocontainedin3devices:MiniMed507cH-TRONplusD-TRONCSIISubjectedtostresstestwhileexposedto:Elevatedtemperature(98.6oF[37oC])Mechanicalagitation(shakingat100strokes/minute)for7dayscontinuouslyControlvialssubjectedtoelevatedtemperature,butnotagitationProgrammedforcontinuousinfusionat0.8U/hr(19.2U/day);36-Unitdosesalsomanuallydeliveredeachday(18U/day)Potency,purity,highmolecularweightproteinsandm-cresolcontentweredeterminedAdditionalevaluationsincludedpH,deliveredvolumeandformulationphysicalappearance解释：pH：试验期间，试验药物的ph波动符合可接受范围。聚合性：随着时间延长，化学降解产物的高分子蛋白略有增加，但是但仍低于规定上限（1.5%）纯度：随着时间延长，分子降解增加，但两组纯度都符合规定值抗菌剂（间甲酚）含量：两组的间甲酚含量都有下降，但仍高于规定下限（1.15mg/mL）给药量：衡量剂量准确性。实际给药量在理论给药量的±5%以内波动是ISO可接受的波动范围。本实验结果符合ISO要求的剂量准确性。DeFelippisMR,BellMA,HeyobJA,StormsSM.InVitroStabilityofInsulinLisproinContinuousSubcutaneousInsulinInfusion.DiabetesTechnolTher2006;8(3):358-368.[Source:pg.362,Figure1].DISCUSSIONOnDay1,themeanvolumesofinsulindeliveredwereslightlylessthan95%oftheoreticalfor2ofthe3pumps,andgreatervariabilitywasobservedinallcases.ThelowervaluesobtainedonDay1werenotconsideredtheresultofchangesinthephysicalpropertiesofinsulinlispro,butwereperhapsduetoequilibrationofthemechanicalandelectronicpumpcomponentswithintheenvironmentofextremetemperatureandagitation.BACKGROUNDStudydesign–DeFelippisetal.2006Insulinlisprocontainedin3devices:MiniMed507cH-TRONplusD-TRONCSIISubjectedtostresstestwhileexposedto:Elevatedtemperature(98.6oF[37oC])Mechanicalagitation(shakingat100strokes/minute)for7dayscontinuouslyControlvialssubjectedtoelevatedtemperature,butnotagitationProgrammedforcontinuousinfusionat0.8U/hr(19.2U/day);36-Unitdosesalsomanuallydeliveredeachday(18U/day)Potency,purity,highmolecularweightproteinsandm-cresolcontentweredeterminedAdditionalevaluationsincludedpH,deliveredvolumeandformulationphysicalappearanceInsulinGlulisine:Insulinshouldbediscardedifexposedtotemperatureshigherthan98.6oF(37oC)InsulinAspart:Insulinshouldbediscardedifexposedtotemperatureshigherthan98.6oF(37oC)InsulinLispro:Insulinlisprointheexternalpumpshouldnotbeexposedtotemperaturesabove37oC(98.6oF)Reference:PrescribingInformation,PhysiciansDeskReference2006.处方信息，医师参考手册2006[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.BACKGROUNDStudydesign–Sanofi-Aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female),meanage44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSIONTherewerenodifferencesbetweeninsulinsinthepercentagesofpatientswithunexplainedhyperglycemiaorinfusionsetocclusions.BACKGROUNDStudydesign–Sanofi-Aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female),meanage44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSIONNote:Nocomparisonsweremadebetweeninsulinaspartandinsulinlispro.没有进行门冬和赖脯之间的比较。BACKGROUNDStudydesign–sanofi-aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(151female)withtype1diabetesMeanage:44years39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)成人糖尿病患者中胰岛素泵使用及超短效胰岛素治疗教授医院PP-HI-CN-1074YellowCCI糖尿病患者CSII治疗背景:胰岛素泵治疗的沿革赖脯胰岛素在CSII中的应用成人患者应用的临床有效性和安全性赖脯胰岛素vs人胰岛素谷赖vs门冬vs赖脯CSIIvsMDI物理和化学稳定性CSII=continuoussubcutaneousinsulininfusion背景：胰岛素泵治疗的沿革CompanyConfidential?2014EliLillyandCompanyCompanyConfidential?2014EliLillyandCompanyCompanyConfidential?2014EliLillyandCompanyContinuousSubcutaneousInsulinInfusioninAdultPatientswithDiabetesPhotosource:LeeS(2003)availableat:http://cme.medscape.com/viewarticle/460365_print(accessed5-Jan-2011).1KadishAH.Aservomechanismforbloodsugarcontrol.BiomedicalScienceInstrumentation1963;1:171-176.2KadishAH.Automationcontrolofbloodsugar:aservomechanismforbloodglucosemonitoringandcontrol.Transactions-AmericanSocietyforArtificialInternalOrgans1963;9:363-367.3KadishAH.Automationcontrolofbloodsugar.I.Aservomechanismforglucosemonitoringandcontrol.AmericanJournalofMedicalElectronics1964;3:82-86.4AlsalehFM,SmithFJ,KeadyS,TaylorKMG.Insulinpumps:frominceptiontothepresentandtowardthefuture.JClinPharmTher2010;35:127-138.1AlsalehFM,SmithFJ,KeadyS,TaylorKMG.Insulinpumps:frominceptiontothepresentandtowardthefuture.JClinPharmTher2010;35:127-138.AlsalehFM,SmithFJ,KeadyS,TaylorKM.Insulinpumps:frominceptiontothepresentandtowardthefuture.JClinPharmTher2010;35(2):127-138.1GrunbergerG,BaileyTS,CohenAJ,FloodTM,HandelsmanY,HellmanR,Jovanovi?L,MoghissiES,OrzeckEA.StatementbytheAmericanAssociationofClinicalEndocrinologistsconsensuspaneloninsulinpumpmanagement.EndocrPract2010;16(5):746-762.1WeintrobN,ShalitinS,PhillipM.Whypumps?Continuoussubcutaneousinsulininfusionforchildrenandadolescentswithtype1diabetes.IsrMedAssocJ.2004;6(5):271-275.2CumminsE,RoyleP,SnaithA,GreeneA,RobertsonL,McIntyreL,WaughN.Clinicaleffectivenessandcost-effectivenessofcontinuoussubcutaneousinsulininfusionfordiabetes:systematicreviewandeconomicevaluation.HealthTechnolAssess2010;Feb;14(11):iii-iv,xi-xvi,1-181.3MissoML,EgbertsKJ,PageM,O''ConnorD,ShawJ.Continuoussubcutaneousinsulininfusion(CSII)versusmultipleinsulininjectionsfortype1diabetesmellitus.CochraneDatabaseSystRev.2010Jan20;(1):CD005103.ZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:ResearchDesignandMethodssection,pp440and441].ZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:pg.441,column2,Glycosylatedhemoglobin]DISCUSSIONHbA1csignificantlylowerwithinsulinlispro(7.66±0.13%vs8.00±0.16%)BACKGROUNDStudydesign–Zinmanetal.19976-month,double-blindcrossover(3monthsoneacharm)BothtreatmentsadministeredviaCSII30patients(13male,17female),age26to51yearsType1diabetes,atleast3monthsexperiencewithCSIIMeanHbA1catbaseline:8.0%1-monthrun-inperiodonregularhumaninsulinInsulinbolusdosesgivenimmediatelybeforemealsZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:Abstract].DISCUSSION1-hourpostprandialbloodglucosevaluessignificantlylowerwithinsulinlisprocomparedwithregularhumaninsulinBreakfastpostprandialbloodglucose:regularinsulin9.79mmol/L;insulinlispro8.35mmol/LLunchpostprandialbloodglucose:regularinsulin8.74mmol/L;insulinlispro7.58mmol/LDinnerpostprandialbloodglucose:regularinsulin9.01mmol/L;insulinlispro7.85mmol/LBACKGROUNDStudydesign–Zinmanetal.19976-month,double-blindcrossover(3monthsoneacharm)BothtreatmentsadministeredviaCSII30patients(13male,17female),age26to51yearsType1diabetes,atleast3monthsexperiencewithCSIIMeanHbA1catbaseline:8.0%1-monthrun-inperiodonregularhumaninsulinInsulinbolusdosesgivenimmediatelybeforemealsZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:Column2,p441,Hypoglycemia].DISCUSSIONThefrequencyofhypoglycemiawas12.7±1.6episodes/30daysbeforerandomizationintothestudy(andwas8.4±1.3episodes/30daysforconfirmedhypoglycemia).Hypoglycemiafrequencyper30daysdroppedsignificantlybelowbaselineforpatientsoninsulinlisproforhypoglycemiaunconfirmedbyabloodglucosereading(8.6±1.4episodes/30days)andforhypoglycemiaconfirmedbyabloodglucosereading(6.0±0.9episodes/30days).Therewasnodifferenceinhypoglycemiafrequencybetweeninsulinlisproandregularinsulin.BACKGROUNDStudydesign–Zinmanetal.19976-month,double-blindcrossover(3monthsoneacharm)BothtreatmentsadministeredviaCSII30patients(13male,17female),age26to51yearsType1diabetes,atleast3monthsexperiencewithCSIIMeanHbA1catbaseline:8.0%1-monthrun-inperiodonregularhumaninsulinInsulinbolusdosesgivenimmediatelybeforemealsMelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:ResearchDesignandMethods,p978;Table1,p978]MelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:Column3,p978;Columns2&3,p979]DISCUSSIONDailycapillarybloodglucosemeasurementswereperformedbypatientsbeforeand2hoursaftereachmeal,nightlyonceaweek,andduringanysymptomsofhypoglycemia.Glycemictargetswere3.9-6.6mmol/Lbeforemealsand6.6-10.0mmol/L2hoursaftermealsBACKGROUNDStudydesign–Melkietal.1998Open-labelcrossoverstudy39patients(17female)withtype1diabetes,meanage39yearsLead-in:4weeksonregularinsulinTreatment:3monthsthencrossoverMeanbaselineA1C:7.74(insulinlispro);7.97(regularinsulin)Insulinlisproboluses0-5minbeforemeals;regularinsulinboluses20-30minbeforemealsRennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:ResearchDesignandMethods,p785].RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:Tables2and3,p786].DISCUSSIONHbA1cdeterminationsweremadeatstudytreatmentendpoint(totalpopulation)usinganalysisofvariancewithpatient,treatmentandperiodterms.Postprandialbloodglucosechangesweredeterminedatstudytreatmentendpointusinganalysisofcovariancewithdependentvariables:treatmentperiod,premealglucose,insulindose,andbasalinsulinrecordedduringrun-inperiod.Postprandialbloodglucoseexcursionsweresignificantlyreducedduringtreatmentwithinsulinlispro(p<0.001).(Note:thisisnotshowninthetable.)BACKGROUNDStudydesign–Renneretal.1999Open-labelcrossoverstudy113patients(53female)withtype1diabetes,meanage37yearsLead-in:4weeksonregularinsulinTreatment:4monthsthencrossoverMeanbaselineA1C:7.2%Insulinlisproboluses0minbeforemeals;regularinsulinboluses30minbeforemealsRaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:Column2,p296;Table1,p296;Column1,p297]RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.297,Results,lastparagraph;pg.296,Table1]DISCUSSIONHbA1cchangefrombaselinewas+0.06%forregularinsulinand-0.34%forinsulinlisproattheendofthe1st12-weektreatmentperiodBACKGROUNDStudydesign–Raskinetal.20016-month,open-labelcrossoverstudy58patients(30male,28female),age13to60yearsType1diabetesMeanbaselineHbA1cInsulinlispro-regularinsulinsequencegroup:7.9%Regularinsulin-insulinlisprosequencegroup:7.6%BolusinsulindosesgivenimmediatelybeforemealsTestmealadministeredatendof2-to4-weeklead-inperiodandendofeach12-weektreatmentperiodCompanyConfidential?2014EliLillyandCompanyCompanyConfidential?2014EliLillyandCompanyCompanyConfidential?2014EliLillyandCompanyContinuousSubcutaneousInsulinInfusioninAdultPatientswithDiabetesPhotosource:LeeS(2003)availableat:http://cme.medscape.com/viewarticle/460365_print(accessed5-Jan-2011).1KadishAH.Aservomechanismforbloodsugarcontrol.BiomedicalScienceInstrumentation1963;1:171-176.2KadishAH.Automationcontrolofbloodsugar:aservomechanismforbloodglucosemonitoringandcontrol.Transactions-AmericanSocietyforArtificialInternalOrgans1963;9:363-367.3KadishAH.Automationcontrolofbloodsugar.I.Aservomechanismforglucosemonitoringandcontrol.AmericanJournalofMedicalElectronics1964;3:82-86.4AlsalehFM,SmithFJ,KeadyS,TaylorKMG.Insulinpumps:frominceptiontothepresentandtowardthefuture.JClinPharmTher2010;35:127-138.1AlsalehFM,SmithFJ,KeadyS,TaylorKMG.Insulinpumps:frominceptiontothepresentandtowardthefuture.JClinPharmTher2010;35:127-138.AlsalehFM,SmithFJ,KeadyS,TaylorKM.Insulinpumps:frominceptiontothepresentandtowardthefuture.JClinPharmTher2010;35(2):127-138.1GrunbergerG,BaileyTS,CohenAJ,FloodTM,HandelsmanY,HellmanR,Jovanovi?L,MoghissiES,OrzeckEA.StatementbytheAmericanAssociationofClinicalEndocrinologistsconsensuspaneloninsulinpumpmanagement.EndocrPract2010;16(5):746-762.1WeintrobN,ShalitinS,PhillipM.Whypumps?Continuoussubcutaneousinsulininfusionforchildrenandadolescentswithtype1diabetes.IsrMedAssocJ.2004;6(5):271-275.2CumminsE,RoyleP,SnaithA,GreeneA,RobertsonL,McIntyreL,WaughN.Clinicaleffectivenessandcost-effectivenessofcontinuoussubcutaneousinsulininfusionfordiabetes:systematicreviewandeconomicevaluation.HealthTechnolAssess2010;Feb;14(11):iii-iv,xi-xvi,1-181.3MissoML,EgbertsKJ,PageM,O''ConnorD,ShawJ.Continuoussubcutaneousinsulininfusion(CSII)versusmultipleinsulininjectionsfortype1diabetesmellitus.CochraneDatabaseSystRev.2010Jan20;(1):CD005103.ZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:ResearchDesignandMethodssection,pp440and441].ZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:pg.441,column2,Glycosylatedhemoglobin]DISCUSSIONHbA1csignificantlylowerwithinsulinlispro(7.66±0.13%vs8.00±0.16%)BACKGROUNDStudydesign–Zinmanetal.19976-month,double-blindcrossover(3monthsoneacharm)BothtreatmentsadministeredviaCSII30patients(13male,17female),age26to51yearsType1diabetes,atleast3monthsexperiencewithCSIIMeanHbA1catbaseline:8.0%1-monthrun-inperiodonregularhumaninsulinInsulinbolusdosesgivenimmediatelybeforemealsZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:Abstract].DISCUSSION1-hourpostprandialbloodglucosevaluessignificantlylowerwithinsulinlisprocomparedwithregularhumaninsulinBreakfastpostprandialbloodglucose:regularinsulin9.79mmol/L;insulinlispro8.35mmol/LLunchpostprandialbloodglucose:regularinsulin8.74mmol/L;insulinlispro7.58mmol/LDinnerpostprandialbloodglucose:regularinsulin9.01mmol/L;insulinlispro7.85mmol/LBACKGROUNDStudydesign–Zinmanetal.19976-month,double-blindcrossover(3monthsoneacharm)BothtreatmentsadministeredviaCSII30patients(13male,17female),age26to51yearsType1diabetes,atleast3monthsexperiencewithCSIIMeanHbA1catbaseline:8.0%1-monthrun-inperiodonregularhumaninsulinInsulinbolusdosesgivenimmediatelybeforemealsZinmanB,TildesleyH,ChiassonJL,TsuiE,StrackT.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:Column2,p441,Hypoglycemia].DISCUSSIONThefrequencyofhypoglycemiawas12.7±1.6episodes/30daysbeforerandomizationintothestudy(andwas8.4±1.3episodes/30daysforconfirmedhypoglycemia).Hypoglycemiafrequencyper30daysdroppedsignificantlybelowbaselineforpatientsoninsulinlisproforhypoglycemiaunconfirmedbyabloodglucosereading(8.6±1.4episodes/30days)andforhypoglycemiaconfirmedbyabloodglucosereading(6.0±0.9episodes/30days).Therewasnodifferenceinhypoglycemiafrequencybetweeninsulinlisproandregularinsulin.BACKGROUNDStudydesign–Zinmanetal.19976-month,double-blindcrossover(3monthsoneacharm)BothtreatmentsadministeredviaCSII30patients(13male,17female),age26to51yearsType1diabetes,atleast3monthsexperiencewithCSIIMeanHbA1catbaseline:8.0%1-monthrun-inperiodonregularhumaninsulinInsulinbolusdosesgivenimmediatelybeforemealsMelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:ResearchDesignandMethods,p978;Table1,p978]MelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:Column3,p978;Columns2&3,p979]DISCUSSIONDailycapillarybloodglucosemeasurementswereperformedbypatientsbeforeand2hoursaftereachmeal,nightlyonceaweek,andduringanysymptomsofhypoglycemia.Glycemictargetswere3.9-6.6mmol/Lbeforemealsand6.6-10.0mmol/L2hoursaftermealsBACKGROUNDStudydesign–Melkietal.1998Open-labelcrossoverstudy39patients(17female)withtype1diabetes,meanage39yearsLead-in:4weeksonregularinsulinTreatment:3monthsthencrossoverMeanbaselineA1C:7.74(insulinlispro);7.97(regularinsulin)Insulinlisproboluses0-5minbeforemeals;regularinsulinboluses20-30minbeforemealsRennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:ResearchDesignandMethods,p785].RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:Tables2and3,p786].DISCUSSIONHbA1cdeterminationsweremadeatstudytreatmentendpoint(totalpopulation)usinganalysisofvariancewithpatient,treatmentandperiodterms.Postprandialbloodglucosechangesweredeterminedatstudytreatmentendpointusinganalysisofcovariancewithdependentvariables:treatmentperiod,premealglucose,insulindose,andbasalinsulinrecordedduringrun-inperiod.Postprandialbloodglucoseexcursionsweresignificantlyreducedduringtreatmentwithinsulinlispro(p<0.001).(Note:thisisnotshowninthetable.)BACKGROUNDStudydesign–Renneretal.1999Open-labelcrossoverstudy113patients(53female)withtype1diabetes,meanage37yearsLead-in:4weeksonregularinsulinTreatment:4monthsthencrossoverMeanbaselineA1C:7.2%Insulinlisproboluses0minbeforemeals;regularinsulinboluses30minbeforemealsRaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:Column2,p296;Table1,p296;Column1,p297]RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.297,Results,lastparagraph;pg.296,Table1]DISCUSSIONHbA1cchangefrombaselinewas+0.06%forregularinsulinand-0.34%forinsulinlisproattheendofthe1st12-weektreatmentperiodBACKGROUNDStudydesign–Raskinetal.20016-month,open-labelcrossoverstudy58patients(30male,28female),age13to60yearsType1diabetesMeanbaselineHbA1cInsulinlispro-regularinsulinsequencegroup:7.9%Regularinsulin-insulinlisprosequencegroup:7.6%BolusinsulindosesgivenimmediatelybeforemealsTestmealadministeredatendof2-to4-weeklead-inperiodandendofeach12-weektreatmentperiodJohanssonUB,AdamsonUCK,LinsPES,WredlingRAM.Improvedbloodglucosevariability,HbA1cinsumanInfusat?andlessinsulinrequirementinIDDMpatientsusinginsulinlisproinCSII.TheSwedishMulticenterLisproInsulinStudy.DiabetesMetab2000;26(3):192-196.[Source:pg.192,Summary]ZinmanB,TildesleyH.ChiassonJL,etal.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:pg.1,Abstract,Results].RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:pg.1,Abstract,Results].RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.297,column2,Results,lastparagraph].DISCUSSIONAcross4studiesthatcomparedinsulinlisprowithregularinsulininCSIIandhadbothbaselineandendpointHbA1cvalues,allshowedasignificantlylowerHbA1cvalueatendpointforinsulinlisprotherapycomparedwiththeregularinsulintherapy.MelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:pg.978,column3,DailyBGmeasurements]JohanssonUB,AdamsonUCK,LinsPES,WredlingRAM.Improvedbloodglucosevariability,HbA1cinsumanInfusat?andlessinsulinrequirementinIDDMpatientsusinginsulinlisproinCSII.TheSwedishMulticenterLisproInsulinStudy.DiabetesMetab2000;26(3):192-196.[Source:pg.194,TableII]RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:pg.784,Abstract,Results]RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.299,Discussion,paragraph1]DISCUSSIONAcross5studiesthatcomparedinsulinlisprowithregularinsulininCSIIandmeasuredpostprandialbloodglucose,allshowedsignificantlylowermeanpostprandialbloodglucosewithinsulinlisprotherapycomparedwithregularinsulintherapy.1ZinmanB,TildesleyH,ChiassonJL,etal.InsulinlisproinCSII:resultsofadouble-blindcrossoverstudy.Diabetes1997;46(3):440-443.[Source:Abstract].2RaskinP,HolcombeJH,TamborlaneWV,MaloneJI,StrowigS,AhernJA,LaventF.Acomparisonofinsulinlisproandbufferedregularhumaninsulinadministeredviacontinuoussubcutaneousinsulininfusionpump.JDiabetesCompl2001;15(6):295-300.[Source:pg.Abstract;pg.297,Results,paragraph4;pg.299,lastsentenceincolumn1]3MelkiV,RenardE,Lassmann-VagueV,BoivinS,GuerciB,Hanaire-BroutinH,BringerJ,BelicarP,JeandidierN,MeyerL,BlinP,Augendre-FerranteB,TauberJP.ImprovementofHbA1candbloodglucosestabilityinIDDMpatientstreatedwithlisproinsulinanaloginexternalpumps.DiabetesCare1998;21(6):977-982.[Source:pg.977,Abstract,Results;pg.978,column3,DailyBGmeasurements]4JohanssonUB,AdamsonUCK,LinsPES,WredlingRAM.Improvedbloodglucosevariability,HbA1cinsumanInfusat?andlessinsulinrequirementinIDDMpatientsusinginsulinlisproinCSII.TheSwedishMulticenterLisproInsulinStudy.DiabetesMetab2000;26:192-196.[Source:pg.194,TableII;pg.194,Results,paragraph1]5RennerR,PfutznerA,TrautmannM,HarzerO,SauterK,LandgrafR.Useofinsulinlisproincontinuoussubcutaneousinsulininfusiontreatment.ResultsofaMulticenterTrial.GermanHumalog-CSIIStudyGroup.DiabetesCare1999;22(5):784-788.[Source:pg.784,Abstract,Results][NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSION99patientswereassignedtoSequence1.Theytookinsulinglulisineforthefirst13weeks(Period1),theninsulinaspartforthesecond13weeks(Period2),theninsulinlisproforthelast13weeks(Period3).95patientswereassignedtoSequence2.TheytookinsulinaspartduringPeriod1,theninsulinlisproduringPeriod2,theninsulinglulisineduringPeriod3.94patientswereassignedtoSequence3.TheytookinsulinlisproduringPeriod1,theninsulinglulisineduringPeriod2,theninsulinaspartduringPeriod3.BACKGROUNDStudydesign–sanofi-aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female)meanage:44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSION本表格显示各个治疗组的治疗第一周以及最后一周的mean±SDHbA1c值(acrosseachofthethreeperiods）.BACKGROUNDStudydesign–sanofi-aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female)meanage:44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSIONAlthoughtherapywitheachinsulinlastedonly13weeks,hypoglycemiawasreportedasannualizedvalues(eventsperpatient-year).Insulinaspartandinsulinlisprobothhadsignificantlylowerhypoglycemiaratescomparedwithinsulinglulisineforsymptomaticandnocturnalsymptomatichypoglycemia.BACKGROUNDStudydesign–Sanofi-Aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female)meanage:44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)LeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabNutrMetab2004;17:84-89.[Source:MaterialsandMethods,p85]LeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabNutrMetab2004;17:84-89.[Source:pg.86,Figure1;pg.87,Figure2;pg.87,paragraph1]DISCUSSIONBothtreatmentregimensloweredHbA1csignificantlyfrombaseline.ThechangeinHbA1cfrombaselinetoendpointdidnotdifferbetweentreatmentregimens(MDI:-0.7±0.6%;CSII:-1.0±0.8%)(Notshownonslide)Althoughthebloodglucoseprofileswerenotsignificantlydifferentbetweengroups,themeanamplitudeofglycemicexcursionwassignificantlylowerfortheCSIIgroupthantheMDIgroup.(Notshownonslide)BACKGROUNDStudydesign–Leporeetal.20041-yearopen-labelparallelstudy48patients(24male,24female)withtype1diabetesMeanage:38years(CSIIgroup);41years(MDIgroup)BaselineA1C:9.0%(CSIIgroup);8.6%(MDIgroup)Treatment:CSII:insulinlisproatmultiplebasalrates+mealtimebolusesMDI:mealtimeinsulinlisproinjection+insulinglargineinjectionateveningmealorbedtimeLeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabetesNutrMetab2004;17:84-89.[Source:pg.87,1stparagraph;Tables2and3]DISCUSSION日内平均血糖波动幅度(MAGE)：计算血糖超过24小时期间的1SD幅度以上阶段的增加或减少的算术平均数.BACKGROUNDStudydesign–Leporeetal.20041-yearopen-labelparallelstudy48patients(24male,24female)withtype1diabetesMeanage:38years(CSIIgroup);41years(MDIgroup)BaselineA1C:9.0%(CSIIgroup);8.6%(MDIgroup)Treatment:CSII:insulinlisproatmultiplebasalrates+mealtimebolusesMDI:mealtimeinsulinlisproinjection+insulinglargineinjectionateveningmealorbedtimeLeporeG,DodesiniA,NosariI,TrevisanR.Effectofcontinuoussubcutaneousinsulininfusionvsmultipledailyinsulininjectionwithglargineasbasalinsulin:Anopenparallellong-termstudy.DiabetesNutrMetab2004;17:84-89.[Source:pg.87,1stparagraph;Tables2and3]BACKGROUNDStudydesign–Leporeetal.20041-yearopen-labelparallelstudy48patients(24male,24female)withtype1diabetesMeanage:38years(CSIIgroup);41years(MDIgroup)BaselineA1C:9.0%(CSIIgroup);8.6%(MDIgroup)Treatment:CSII:insulinlisproatmultiplebasalrates+mealtimebolusesMDI:mealtimeinsulinlisproinjection+insulinglargineinjectionateveningmealorbedtimeBolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1171,ResearchDesignandMethods;pg.1172,Table1]符合方案数据分析（Per-protocolpopulation）：所有符合试验方案，依从性好（实际服用药量占应服用药量80～120%），试验期间未服禁止用药，完成CRF表规定填写内容的病例BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1174,Table2]BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1172,Column3,Hypoglycemia]DISCUSSIONDatashownarethemean(±SD)numbersofeventsperpatientoverthecourseofthe24-weekstudy.BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1172,Column3,Costs]BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)BolliGB,KerrD,ThomasR,TorloneE,Sola-GazagnesA,VitacolonnaE,SelamJL,HomePD.Comparisonofamultipledailyinsulininjectionregimen(basalonce-dailyglargineplusmealtimelispro)andcontinuoussubcutaneousinsulininfusion(lispro)intype1diabetes:arandomizedopenparallelmulticenterstudy.DiabetesCare2009;32:1170-1176.[Source:pg.1172,Column3,TreatmentSatisfaction]DISCUSSIONTheDTSQscoreincreasedfrom24.0±6.3atbaselineto28.8±5.4atendpointfortheMDIgroupandfrom22.8±8.1atbaselineto31.5±4.9atendpointfortheCSIIgroup.BACKGROUNDStudydesign–Bollietal.,200924-weekopen-labelparallelstudy50patients(27male,23female)withtype1diabetes(perprotocolpopulation)Meanage:38years(CSIIgroup);42years(MDIgroup)BaselineHbA1c:7.7%(CSIIgroup);7.8%(MDIgroup)Treatment:CSII:insulinlisproMDI:mealtimeinsulinlisproinjection+eveninginsulinglargineinjectionBothtreatmentstitratedtosameglucosetargets(FPG4.4-6.6mmol/L;2-hrPPG<7.7mmol/L)DeFelippisMR,BellMA,HeyobJA,StormsSM.Invitrostabilityofinsulinlisproincontinuoussubcutaneousinsulininfusion.DiabetesTechnolTher2006;8(3):358-368.[Source:pg.Abstract,Methods]DISCUSSION通过高温和机械搅动压力测试结合模拟基础/餐时给药来测试赖脯胰岛素在持续皮下胰岛素输注治疗中的稳定性.(本实验完全为体外试验.)胰岛素泵设置为以0.8U/hr(19.2U/day)持续给药;36-Unit剂量同时通过手动每日给药(18U/day).测试了效价,纯度，高分子量蛋白以及间甲酚含量还测试了pH,给药剂量以及药物物理外观DeFelippisMR,BellMA,HeyobJA,StormsSM.Invitrostabilityofinsulinlisproincontinuoussubcutaneousinsulininfusion.DiabetesTechnolTher2006;8(3):358-368.[Source:pg.362,Figure1].DISCUSSION本图显示了3个泵中的一个的实验数据，3种胰岛素泵的测试结果相似。本图显示了每天测试组和对照组的效价测试结果。结果显示，实验组和对照组的结果相似。两组的结果都符合规格(95.0%to105.0%).BACKGROUNDStudydesign–DeFelippisetal.2006Insulinlisprocontainedin3devices:MiniMed507cH-TRONplusD-TRONCSIISubjectedtostresstestwhileexposedto:Elevatedtemperature(98.6oF[37oC])Mechanicalagitation(shakingat100strokes/minute)for7dayscontinuouslyControlvialssubjectedtoelevatedtemperature,butnotagitationProgrammedforcontinuousinfusionat0.8U/hr(19.2U/day);36-Unitdosesalsomanuallydeliveredeachday(18U/day)Potency,purity,highmolecularweightproteinsandm-cresolcontentweredeterminedAdditionalevaluationsincludedpH,deliveredvolumeandformulationphysicalappearance解释：pH：试验期间，试验药物的ph波动符合可接受范围。聚合性：随着时间延长，化学降解产物的高分子蛋白略有增加，但是但仍低于规定上限（1.5%）纯度：随着时间延长，分子降解增加，但两组纯度都符合规定值抗菌剂（间甲酚）含量：两组的间甲酚含量都有下降，但仍高于规定下限（1.15mg/mL）给药量：衡量剂量准确性。实际给药量在理论给药量的±5%以内波动是ISO可接受的波动范围。本实验结果符合ISO要求的剂量准确性。DeFelippisMR,BellMA,HeyobJA,StormsSM.InVitroStabilityofInsulinLisproinContinuousSubcutaneousInsulinInfusion.DiabetesTechnolTher2006;8(3):358-368.[Source:pg.362,Figure1].DISCUSSIONOnDay1,themeanvolumesofinsulindeliveredwereslightlylessthan95%oftheoreticalfor2ofthe3pumps,andgreatervariabilitywasobservedinallcases.ThelowervaluesobtainedonDay1werenotconsideredtheresultofchangesinthephysicalpropertiesofinsulinlispro,butwereperhapsduetoequilibrationofthemechanicalandelectronicpumpcomponentswithintheenvironmentofextremetemperatureandagitation.BACKGROUNDStudydesign–DeFelippisetal.2006Insulinlisprocontainedin3devices:MiniMed507cH-TRONplusD-TRONCSIISubjectedtostresstestwhileexposedto:Elevatedtemperature(98.6oF[37oC])Mechanicalagitation(shakingat100strokes/minute)for7dayscontinuouslyControlvialssubjectedtoelevatedtemperature,butnotagitationProgrammedforcontinuousinfusionat0.8U/hr(19.2U/day);36-Unitdosesalsomanuallydeliveredeachday(18U/day)Potency,purity,highmolecularweightproteinsandm-cresolcontentweredeterminedAdditionalevaluationsincludedpH,deliveredvolumeandformulationphysicalappearanceInsulinGlulisine:Insulinshouldbediscardedifexposedtotemperatureshigherthan98.6oF(37oC)InsulinAspart:Insulinshouldbediscardedifexposedtotemperatureshigherthan98.6oF(37oC)InsulinLispro:Insulinlisprointheexternalpumpshouldnotbeexposedtotemperaturesabove37oC(98.6oF)Reference:PrescribingInformation,PhysiciansDeskReference2006.处方信息，医师参考手册2006[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.BACKGROUNDStudydesign–Sanofi-Aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female),meanage44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSIONTherewerenodifferencesbetweeninsulinsinthepercentagesofpatientswithunexplainedhyperglycemiaorinfusionsetocclusions.BACKGROUNDStudydesign–Sanofi-Aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(137male,151female),meanage44yearsType1diabetes39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3Sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)[NIH]NationalInstitutesofHealthClinicalTrials.govwebsite.EffectofInsulinGlulisineComparedtoInsulinAspartandInsulinLisproWhenAdministeredbyContinuousSubcutaneousInsulinInfusion(CSII)onSpecificPumpParametersinPatientWithType1DiabetesMellitus(PUMP).ClinicalTrials.govIdentifier:NCT00607087.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00607087?term=lispro%2C+glulisine+and+aspart+and+CSII&rank=1.AccessedMarch4,2011.DISCUSSIONNote:Nocomparisonsweremadebetweeninsulinaspartandinsulinlispro.没有进行门冬和赖脯之间的比较。BACKGROUNDStudydesign–sanofi-aventis(@NIH),201013-weekrandomized,open-label,3-periodcrossoverstudy288patients(151female)withtype1diabetesMeanage:44years39weekstotaltreatmentduration(13weeksoneachinsulintype)Patientsrandomlyassignedto1of3sequences (Examplesequence:insulinglulisine,theninsulinlispro,theninsulinaspart)Sheet1
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人胰岛素
赖脯胰岛素
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3个月治疗后的两组HbA1c
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血糖(mg/dL)
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基线
人胰岛素
赖脯胰岛素
低血糖
证实的低血糖
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发生频率（次/30天）
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人胰岛素
赖脯胰岛素
早餐
中餐
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血糖(mmol/L)
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人胰岛素
赖脯胰岛素
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严重低血糖事件
(次/人-年)
严重低血糖发生率
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MDI
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TotalTreatment
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平均每位患者的花费(€)
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Baseline
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DTSQScore
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