安心之道选择更安全的血糖达标之路内容简介美中不足---糖尿病治疗管理中的低血糖平衡之美---减少胰岛素治疗过程的低血糖风险强化控制血糖后重度低血糖发生率增加低血糖是糖尿病治疗血糖管理的重要因素。同时，低血糖已成为及时起始及优化胰岛素治疗的重要障碍！内容简介美中不足---糖尿病治疗管理中的低血糖平衡之美---减少胰岛素治疗过程的低血糖风险2010年《中国2型糖尿病防治指南》肯定了胰岛素类似物的临床优势临床试验证明，胰岛素类似物与人胰岛素相比控制血糖的能力相似，但在模拟生理性胰岛素分泌和减少低血糖发生的危险性方面，胰岛素类似物优于人胰岛素诺和锐?30每日2次注射－－有效的胰岛素起始治疗方案口服治疗不达标的患者起始诺和锐?30每日2次治疗——显著降低HbA1c水平口服治疗不达标的患者起始诺和锐?30每日2次治疗——有效降低血糖的同时，极少发生重度低血糖口服治疗不达标的患者起始诺和锐?30每日2次治疗——有效降低血糖的同时，较少发生轻度低血糖总结低血糖是糖尿病治疗血糖管理的重要因素低血糖可增加心血管意外事件的发生低血糖也成为及时起始及优化胰岛素治疗的重要障碍诺和锐?30是平衡安全性及有效性的胰岛素治疗方案口服药治疗不达标的T2DM患者起始诺和锐?30每日2次治疗可显著改善血糖控制且不增加低血糖风险诺和锐?30兼顾起始及强化治疗，有更广泛的适用人群，是符合中国指南推荐的预混胰岛素类似物－每日2次注射－有效的胰岛素起始治疗方案－每日3次注射－简单的胰岛素强化治疗方案重度低血糖(事件/患者/年)1.Raskinetal.DiabetesCare2005;28:260–5,2.Yangetal.Diabetescare2008;31:852-6,3.LieblAetal.Diabetes,Obes&Metab2009:11(1):45-52,4.Gaoetal.DiabetesObesMetab2009;11:33–40,5.Yangetal.CurrentMedicalResearch&Opinion2009;25:2643-54ΔHbA1c(%)2.82.500.01-4-3-2-1010.52.00.12.60.011.20INTITATE1Yang2IMPROVE5PRESENT4PREFER3为计算值，原文以事件/患者/30天表示。轻度低血糖(事件/患者/年)1.Raskinetal.DiabetesCare2005;28:260–5,2.Yangetal.Diabetescare2008;31:852-6,3.LieblAetal.Diabetes,Obes&Metab2009:11(1):45-52,4.Gaoetal.DiabetesObesMetab2009;11:33–40,5.Yangetal.CurrentMedicalResearch&Opinion2009;25:2643-54ΔHbA1c(%)2.82.51.2-4-3-2-102468102.01.273.41.943.682.62.8INTITATE1Yang2IMPROVE5PRESENT4PREFER3Meta分析结果：诺和锐?30较人胰岛素30R夜间低血糖显著降低50%DavidsonJA,etal.ClinTher.2009;31(8):1641-51.Meta分析结果：诺和锐?30较人胰岛素30R重度低血糖发生率显著降低55%DavidsonJA,etal.ClinTher.2009;31(8):1641-51.诺和锐?30每日3次注射－－简单的胰岛素起始治疗方案门冬胰岛素30具有更广泛的使用人群及更灵活的给药方案在2型糖尿病患者中，本品的推荐起始剂量为早餐前6单位，晚餐前6单位。本品每日一次使用时，晚餐前12单位。可通过每日两次给药方案的早餐前剂量分到早餐前和午餐前给药，安全的从每日两次给药方案转为每日三次给药方案灵活的治疗方案：诺和锐30说明书广泛的适用人群：本品可用于10岁及以上的儿童和青少年，6－9岁儿童临床数据有限本品可用于老年患者，但在75岁以上的患者中，本品与口服降糖药联合治疗的经验有限MethodsWeusedadverse-eventdatafromtheNationalElectronicInjurySurveillanceSystem–CooperativeAdverseDrugEventSurveillanceproject(2007through2009)toestimatethefrequencyandratesofhospitalizationafteremergencydepartmentvisitsforadversedrugeventsinolderadultsandtoassessthecontributionofspecificmedications,includingthoseidentifiedashigh-riskorpotentiallyinappropriatebynationalqualitymeasures.ResultsOnthebasisof5077casesidentifiedinoursample,therewereanestimated99,628emergencyhospitalizations(95%confidenceinterval[CI],55,531to143,724)foradversedrugeventsinU.S.adults65yearsofageoroldereachyearfrom2007through2009.Nearlyhalfofthesehospitalizationswereamongadults80yearsofageorolder(48.1%;95%CI,44.6to51.6).Nearlytwothirdsofhospitalizationswereduetounintentionaloverdoses(65.7%;95%CI,60.1to71.3).Fourmedicationsormedicationclasseswereimplicatedaloneorincombinationin67.0%(95%CI,60.0to74.1)ofhospitalizations:warfarin(33.3%),insulins(13.9%),oralantiplateletagents(13.3%),andoralhypoglycemicagents(10.7%).High-riskmedicationswereimplicatedinonly1.2%(95%CI,0.7to1.7)ofhospitalizations.ConclusionsMostemergencyhospitalizationsforrecognizedadversedrugeventsinolderadultsresultedfromafewcommonlyusedmedications,andrelativelyfewresultedfrommedicationstypicallydesignatedashigh-riskorinappropriate.Improvedmanagementofantithromboticandantidiabeticdrugshasthepotentialtoreducehospitalizationsforadversedrugeventsinolderadults.Althoughthecriteriafordefininghypoglycaemiamayvarysomewhat,associationguidelinesprovidesomeguidanceforstandardisationAmericanDiabetesAssociation(ADA)CanadianDiabetesAssociation(CDA)–definitionoflowplasmaglucoselevels(above)isforclinicaluseinpatientstreatedwithinsulinoraninsulinsecretagogueEuropeanAssociationfortheStudyofDiabetes(EASD)EuropeanMedicinesAgency(EMA)低血糖症状主要由神经组织缺糖引起，包括神经源性（自主神经）症状和神经组织糖缺乏症状两个方面，前者主要是心悸、颤抖、出汗等，后者主要包括神志的改变、性格变化、认知障碍、抽搐、昏迷等。RESEARCHDESIGNANDMETHODSSevenpoorlycontrolledtype2diabetespatients(meanHbA1c,11.3±1.1%)werestudiedbysteppedhyperinsulinemichypoglycemicclamp(2.4mmol/1)beforeandafterimprovingglycemiccontrolwithinsulintreatment.Counterregulatoryhormones,symptoms,andfour-choicereactiontimeweremeasuredateachglucoseplateau.RESULTSInpatientswithpoorlycontrolledtype2diabetes,counterregulatoryhormoneresponsesbeganathigherplasmaglucoselevelsthandidthoseinhealthysubjects(epinephrine,4.4±0.2vs.3.7±0.2mmol/1,P=0.011).Aftersignificantimprovementinglycemiccontrol(meanHbA1c,8.1±0.9%,P<0.001)wasachievedwithoutseverehypoglycemia,hormonalresponsesstartedatmuchlowerplasmaglucoselevels(e.g.,epinephrine,3.5±0.3mmol/1,P=0.005)andweresignificantlyreducedinmagnitude(e.g.,areaunderepinephrineresponsecurve,306±93vs.690±107nmol·min?1·l?1,P=0.012).Thiswasaccompaniedbyachangeintheplasmaglucosethresholdatwhichhypoglycemicsymptomsfirstdevelopedfrom3.6±0.2to3.0±0.2mmol/1(P=0.019).Incontrast,theplasmaglucosethresholdatwhichfour-choicereactiontimedeteriorateddidnotchangesignificantly(3.1±0.1vs.2.9±0.1mmol/1,P=0.125).CONCLUSIONSCounterregulatoryresponsesbeginatnormoglycemiainpoorlycontrolledtype2diabetes.Improvingglycemiccontrolwithinsulintherapynormalizeshormonalresponsesbutlowerstheplasmaglucoselevelsatwhichhypoglycemicsymptomsdeveloptolevelsassociatedwithimpairmentoffour-choicereactiontime,amarkerofcognitivefunction.Thisprocesspotentiallyincreasestheriskofseverehypoglycemia,buttoalesserextentthanoccursintype1disease.Keymessage:Multipleriskfactorscanleadtohypoglycaemiainpatientswithdiabetes.BackgroundDuringtheUnitedKingdomProspectiveDiabetesStudy(UKPDS),patientswithtype2diabetesmellituswhoreceivedintensiveglucosetherapyhadalowerriskofmicrovascularcomplicationsthandidthosereceivingconventionaldietarytherapy.Weconductedpost-trialmonitoringtodeterminewhetherthisimprovedglucosecontrolpersistedandwhethersuchtherapyhadalong-termeffectonmacrovascularoutcomes.MethodsOf5102patientswithnewlydiagnosedtype2diabetes,4209wererandomlyassignedtoreceiveeitherconventionaltherapy(dietaryrestriction)orintensivetherapy(eithersulfonylureaorinsulinor,inoverweightpatients,metformin)forglucosecontrol.Inpost-trialmonitoring,3277patientswereaskedtoattendannualUKPDSclinicsfor5years,butnoattemptsweremadetomaintaintheirpreviouslyassignedtherapies.Annualquestionnaireswereusedtofollowpatientswhowereunabletoattendtheclinics,andallpatientsinyears6to10wereassessedthroughquestionnaires.WeexaminedsevenprespecifiedaggregateclinicaloutcomesfromtheUKPDSonanintention-to-treatbasis,accordingtopreviousrandomizationcategories.ResultsBetween-groupdifferencesinglycatedhemoglobinlevelswerelostafterthefirstyear.Inthesulfonylurea–insulingroup,relativereductionsinriskpersistedat10yearsforanydiabetes-relatedendpoint(9%,P=0.04)andmicrovasculardisease(24%,P=0.001),andriskreductionsformyocardialinfarction(15%,P=0.01)anddeathfromanycause(13%,P=0.007)emergedovertime,asmoreeventsoccurred.Inthemetformingroup,significantriskreductionspersistedforanydiabetes-relatedendpoint(21%,P=0.01),myocardialinfarction(33%,P=0.005),anddeathfromanycause(27%,P=0.002).ConclusionsDespiteanearlylossofglycemicdifferences,acontinuedreductioninmicrovascularriskandemergentriskreductionsformyocardialinfarctionanddeathfromanycausewereobservedduring10yearsofpost-trialfollow-up.Acontinuedbenefitaftermetformintherapywasevidentamongoverweightpatients.Similarlywhenlookingattherateofminorhypos,theratesseeninPRESENTaresimilar.Keymessage:Inamanagedcaredatabaseanalysis,hypoglycaemiceventsledtoanincreasedriskforacutecardiovascularevents.Aretrospectiveobservationalanalysisof860,845USmanagedcarepatients≥18yearsofagewithT2DMexaminedtheimpactofhypoglycaemiceventsonacutecardiovasculareventsoverthecourseof2consecutiveyearsofdata(2006–2008).A1-yearbaselineperiodidentifiedeligiblepatientsandcollectedinformationonclinicalanddemographiccharacteristicsfromSeptember2006toSeptember2007.AnevaluationperiodidentifiedhypoglycaemiceventsandacutecardiovasculareventsfromOctober2007toOctober2008.ThestudyexaminedtheassociationbetweenICD-9codedoutpatienthypoglycaemiceventsandacutecardiovascularevents(acutemyocardialinfarction,coronaryarterybypassgrafting,revascularisation,percutaneouscoronaryinterventionandincidentunstableangina).Withintheevaluationtimeperiod,3.1%ofpatientsexperiencedhypoglycaemiceventsascodedbyICD-9.Aftercontrollingforimportantconfounders,thisstudyfoundthatpatientswithdocumentedoutpatienthypoglycaemiceventshada79%higherregression-adjustedodds(oddsratio=1.79;confidenceinterval=1.69-1.89)ofacutecardiovasculareventsthanpatientswithoutdocumentedhypoglycaemicevents.Furthervariablessuchasage,presenceofdiabeticcomplicationsandpriorcardiovasculareventsareshownabove.WhileoveralluseofmultipleOADtherapyand/orinsulinhasoftenbeenfoundtobeassociatedwithpoorglycaemiccontrol,Simonsetal.foundanassociationbetweenimmediateorrapidtransitiontotheuseofinsulinandimprovedHbA1ccontrolovertimeandareductionintheriskofmicro-andmacrovascularcomplicationsby27%,ascomparedtoothertreatmentstrategies,includingstepwiseOADtreatment.Thestudyalsoreportedadirectcorrelationbetweentheincreasingnumberoftreatmentintensificationstepsandagreaterriskofcomplications.Thesefindingssuggestthat,ingeneral,thenumberandintensityofmedicationsreflectsunderlyingdiseaseprogression,andthatpatientswhoarewillingandabletoinitiateinsulinearlierappeartohaveimprovedglycaemiccontrolandlowerriskofcomplications,perhapsasaresultofavoidingallsubsequentdelaysinappropriatetreatmentintensificationthatresultinprolongedperiodsofpoorglycaemiccontrol.BackgroundIntensiveglycaemiccontrolcanreducetheriskofmicrovascularcomplicationsinpeoplewithtype2diabetes.AimToexaminetheextentofmonitoringandglycaemiccontrolofpatientswithtype2diabetesprescribedoralagentsand/orinsulin,andtoinvestigatetransitiontoinsulin.DesignofstudyRetrospectivecohortstudy.SettingAtotalof154generalpracticesintheUKcontributingtotheDIN-LINKdatabasebetween1995and2005.MethodPeoplewithtype2diabeteswereidentifiedusingReadcodesandprescribingdata.Outcomemeasureswere:glycaemicmonitoringandcontrolonmultipleoralagentsand/orinsulin,andtransitiontoinsulin.ResultsAtotalof14824peoplewithtype2diabeteswereprescribedmultipleoralagentsconcurrently,ofwhom5064(34.16%)hadhaemoglobinA1c(HbA1c)assessments6monthsbeforeandfollowinginitiationoftheirlastoraltherapy.MeanHbA1cbeforetherapywas9.07%,whichdroppedto8.16%followingtherapy(meandifference0.91%,95%confidenceinterval[CI]=0.86to0.95,P<0.0001).OfthepatientswithHbA1cassessments,3153(62.26%)hadevidenceofpoorglycaemiccontrolfollowingtherapy.Mediantimetoinsulinforpatientsprescribedmultipleoralagentswas7.7years(95%CI=7.4to8.5years);1513peoplebeganinsulinduringthestudyandhadHbA1cassessments6monthsbeforeandfollowinginsulin.MeanHbA1cbeforeinsulinwas9.85%(standarddeviation[SD]1.96%)whichdecreasedby1.34%,(95%CI=1.24%to1.44%)followingtherapy,but1110people(73.36%)stillhadHbA1c≥7.5%.ConclusionManypeoplewithtype2diabetesreceivedinadequatemonitoringandhadpoorglycaemiccontrol.Intensivemanagementisrequiredtoreducetheriskofmicrovascularcomplications.5941ofthe6442patientsinitiatinginsulinwereregisteredforatleast3monthsfollowingtherapy,ofwhom5647(95.05%)hadaprescriptionforanOADduringthestudyperiod,and3597(60.55%)hadaprescriptionforanOADfollowingtheirfirstprescriptionforinsulin.Keymessage:althoughhigherratesofseverehypoglycaemiawereseenwithintensivetherapyintheselargeclinicaltrials,itisarelativelyuncommonevent.UKPDS:Arandomised,non-blindedclinicaltrialthatinvestigatedtheeffectsofintensivecontrolofbloodglucoseandbloodpressureonmicro-andmacrovascularcomplicationsofT2DM.Participants(n=5102;58%male)wereaged25–65yearsandhadfastingplasmaglucose>6mmol/L(108mg/dL)ontwooccasions.Participantswererandomisedtoeitherconventionaltherapy(dietaryrestriction)orintensivetherapy(eitherSUorinsulin,orinoverweightpatients,metformin).Severehypoglycaemiawasdefinedasaneventwhenpatientswereunabletotreatthemselvesunaidedandrequiredthird-partyhelpormedicalintervention.Significantlymorehypoglycaemicepisodeswereseenintheinsulingroupvs.theconventionalgroup(p<0.0001).1ADVANCE:DesignedtoassesstheeffectsonmajorvascularoutcomesofloweringHbA1ctoatargetof6.5%orlessinabroadcross-sectionofpatientswithT2DM.Inthisstudy,11,140patientswererandomisedtoreceiveeitherstandardcontrol(n=5569)orintensivecontrol(n=5571).Participantsentereda6-weekrun-inperiod,duringwhichtheycontinuedtheirusualmethodsofglucosecontrolandreceivedafixedcombinationofperindoprilandindapamide.Thosewhotoleratedandwereadherentwiththetreatmentduringtherun-inperiodwererandomlyassignedtoreceivecontinuedtherapywitheitherperindoprilandindapamideormatchingplaceboaswellasintensivetherapytocontrolHbA1cat≤6.5%orstandardglucosecontrol.Intensivetherapyconsistedofgliclazide(modifiedrelease,30–120mgdaily);patientswhowereassignedtothisstrategywererequiredtodiscontinueanyotherSU.Patientsrandomisedtoreceivestandardtherapyandwhoweretakinggliclazide(modifiedrelease)whentheyenteredthestudywererequiredtoreplacethisdrugwithanotherSUifcontinuedtherapywasrequired.Severehypoglycaemiawasmorecommonintheintensivetreatmentgroup(p<0.001vs.standardgroup).2ACCORD:Designedtodeterminewhetherintensivelyloweringbloodsugar(targetHbA1clevelsof<6%comparedwithtargetHbA1Clevelsof7–7.9%)inthesettingofaggressiveornormalbloodpressure(BP)control(systolicBP<120mmHg,orsystolicBP<140mmHg,respectively),oraggressivelow-densitylipoproteincholesterollowering,withorwithouttriglycerideloweringandhigh-densitylipoproteincholesterolincreasingmedication,wouldreducetheriskofCVeventssuchasheartattack,strokeorCVmortalityinpeoplewithT2DMwithhighriskofCVevents.Thehighrateofmortalityintheintensivetherapygroupledtotheearlyterminationofthetreatmentgroupat3.5years.Severehypoglycaemiawasdefinedasanyhypoglycaemiarequiringmedicalassistance.Severehypoglycaemiawasdefinedasbloodglucose<50mg/dLandtransientdysfunctionofthecentralnervoussystemwhowereunabletotreatthemselvesandrequiredhelpfromanotherperson.Asignificantlygreaterrateofhypoglycaemiaoccurredinpatientsintheintensivetherapygroup(p<0.001vs.standardtherapy).3VADT:Anopen-labelstudytargeting1791militaryveteranswhohadsuboptimalresponsetoT2DMtherapy.Theaverageageofpatientswas60.4years,andtheaveragediseasedurationwas11.5years.ParticipantswererandomisedtostandardorintensivetherapybasedonBMI.Patientswerestratifiedtooneoffourtreatmentgroups:1.intensivetherapytargetingHbA1c?6%,andobesity(BMI≥27kg/m2)onoralagentsalone;2.intensive,forleanpatients(BMI<27)onOAD;3.standardtherapytargetingHbA1c8–9%andobesity(BMI≥27)onOAD;4.standardtherapy,forleanpatients(BMI<27)onOAD.InsulinwasaddedforpatientsinthestandardgroupwhodidnothaveHbA1c<9%andintheintensivetherapygroup<6%.4Intensiveglycaemiccontrolwasdefinedasfollowsintheabovetrials:UKPDS1=bloodglucosecontrolwitheitherSUorinsulintoFPG<108mg/dLand,ininsulin-treatedpatients,premealglucoseof72–126mg/dL;ADVANCE2=useofgliclazideplusotherdrugsasrequiredtoachieveHbA1c≤6.5%;ACCORD3=comprehensivetherapytargetingHbA1c<6.0%;VADT4=intheintensivegroup,patientswerestartedonmaximaldosesof2OADs(metformin+rosiglitizoneifBMI≥27,glimepiride+rosiglitazoneifBMI<27)and,priortoanychangeinOAD,insulinwasaddedifHbA1c<6%wasnotachieved.ThegoalintheintensivegroupwasanabsolutereductioninHbA1cof1.5%comparedwiththestandardcontrolgroup.ReferencesUKPDSGroup.Lancet1998;352:837–53.Pateletal.;ADVANCECollaborativeGroup.NEnglJMed2008;358:2560–72.Gersteinetal.;ACCORDStudyGroup.NEnglJMed2008;358:2545–59.Duckworthetal.NEnglJMed2009;360:129–39.Keymessage:Hypoglycaemiamaycauseabnormalitiesinthecardiovascularsystemthatmayincreasetheriskforcardiovasculareventsinpatientswithdiabetes.Hypoglycaemiamayaffectcardiovasculareventsthroughincreasedinflammation,endothelialdysfunction,abnormalsympathoadrenalresponsesandbloodcoagulationabnormalities.Inflammatoryresponsestriggerthereleaseofmultipleinflammatorymarkers(C-reactiveprotein,vascularendothelialgrowthfactorandinterleukin-6)andincreasetheoveralllevelsofinflammatorycytokinesthatcanleadtoendothelialinjuriesandabnormalitiesincoagulation.Theactivationofthefibrinolyticsystemandincreasedepinephrinelevelscanalsoleadtobloodcoagulationabnormalitiesthroughincreasedneutrophilactivation,plateletactivationandincreasedfactorVII.Thesympathoadrenalresponseleadstoincreasedcatecholaminerelease,whichincreasesmyocardialcontractility,workloadandcardiacoutput.Endothelialdysfunctioncanleadtodecreasedvasodilationandcanplaceanevengreaterstrainonthecardiovascularsystemandperpetuatetheinabilitytomeetoxygendemands.诺和锐30是一种全新的预混胰岛素类似物，作用模式更接近生理性胰岛素分泌模式，其速效部分起效更快，达峰更高，可更好地控制餐后血糖，而中效部分吸收缓慢，作用持久，可提供有效的基础胰岛素水平。重要的是，速效部分回落快，与中效部分叠加少，因此低血糖发生风险较低。而且诺和锐30起效更快，可紧邻餐前注射。因而，与预混人胰岛素相比，诺和锐30更卓越的药代动力学特性，使其应用时更为有效、安全和方便。下面我将一一为您详细说明。这是杨文英教授领导的研究结果，该研究结果显示口服降糖药治疗血糖控制不佳的2型糖尿病患者在应用诺和锐30治疗后，随着注射次数增加，血糖达标率也逐渐增加。从图中可以看到，诺和锐30每日3次可使66%的患者HbA1c达标小于7%的控制目标，明显高诺和锐30每日2次注射。而达标率的增加是不是以低血糖发生率的增加及注射剂量的增加为代价的呢？该研究结果显示随着注射次射增加血糖达标率提高的同时，低血糖发生率及日治疗剂量没有显著性差异。如表中显示，无论是轻度低血糖，还是重度低血糖，诺和锐30每日3次注射与每日2次注射均无显著性差异。最新文献Budnitzetal.NewEnglandJournalofMedicine,Nov24th2011美国老年人因药物不良事件急诊入院情况数据来源于具有代表性的58家非儿科医院，分析2007-2009年12,666例病例，评价哪些药物种类容易发生药物不良事件Budnitzetal.NEnglJMed2011;365:21内分泌科药物成为由于药物不良事件所导致的急诊就诊和入院的主要原因之一Budnitzetal.NEnglJMed2011;365:21ADE:药物不良事件;ER,急诊室血液病药物内分泌药物心血管药物中枢神经系统药物抗感染药物抗肿瘤药物其他药物不明药物多重分类ADE导致的ER就诊（在>65岁的患者）(n=166174)ER就诊和入院例数导致入院的ER就诊例数(n=99628)降糖药物是导致急诊就诊和入院最常见的内分泌科药物Budnitzetal.NEnglJMed2011;365:21估计入院例数估计入院例数百分比华法令胰岛素口服抗血小板药物口服降糖药阿片类药物抗生素地高辛抗肿瘤药物抗肾上腺素能药物肾素-血管紧张素抑制剂镇静或安眠药物利尿剂抗惊厥药物在内分泌药物所导致的急诊就诊中，94.7%的患者伴有低血糖症状Budnitzetal.NEnglJMed2011;365:215.3%其他14%低血糖，伴其他或非特异性后遗症5.7%低血糖，伴虚弱或呼吸困难8.3%低血糖，伴心血管后遗症40.7%低血糖，伴精神状态改变或其他神经后遗症26.0%低血糖，伴意识丧失或癫痫发作事件比例诊断(AE表现)什么是低血糖?由于血浆葡萄糖水平降低导致的一种神经低血糖和/或神经性症状血浆葡萄糖水平降低定义为:≤70mg/dL(3.9mmol/L)(ADA)1<54.1mg/dL(3.0mmol/L)(EMA)2<72mg/dL(4.0mmol/L)(CDA)3给予碳水化合物后症状缓解31.ADA.DiabetesCare2005;28:1245–9;2.EMA.CPMP/EWP/1080/00.2006;3.Yaleetal.CanadianJDiabetes26:22–35ADA,美国糖尿病学会;CDA,加拿大糖尿病协会;EMA,欧洲药品管理局低血糖的危险因素低血糖的一般危险因素:1-4年龄/糖尿病治疗病程推迟或遗漏进餐/进餐量少于预计值/体育锻炼服用降糖药物/强化血糖控制同时服用其他药物/饮酒重度低血糖危险因素:4未察觉的低血糖睡眠先前发生过低血糖有重度低血糖史 1.Briscoe&Davis.ClinDiabetes2006;24:115–21;2.ADAWorkgrouponHypoglycemia.DiabetesCare2005;28:1245–9;3.Frier.DiabetesMetabResRev2008;24:87–92;4.Cryer.Diabetes2008;57:3169–761.UKPDSGroup.Lancet1998;352:837–53;2.Pateletal;ADVANCECollaborativeGroup.NEnglJMed2008;358:2560–72;3.Gersteinetal;ACCORDGroup.NEnglJMed2008;358:2545–59;4.Duckworthetal.NEnglJMed2009;360:129–39这些试验中强化控制血糖的定义不同。?降糖试验中需要任何帮助的低血糖。Conv,常规治疗;gly,格列本脲;HR,风险比;ins,胰岛素;int,强化治疗;std,标准治疗ConvGlyInsStdIntStdIntStdIntUKPDS1ADVANCE2ACCORD3VADT4严重低血糖事件发生率?(/100患者/年)P＜0.001Vs常规治疗P＜0.001P＜0.001P=0.001HbA1c7.97.17.27.36.57.56.48.46.9严格血糖控制可降低2型糖尿病患者低血糖时肾上腺素反应的影响2345血浆葡萄糖(mmol/l)肾上腺素反应明显的血糖阈值2型糖尿病患者非糖尿病对照组血糖控制差时严格控制后Korzon-BurakowskaAetal.DiabetesCare19984.4mmol/L3.7mmol/L与对照组相比P=0.011与血糖控制差时相比P=0.0053.5mmol/L低血糖对心血管的病理生理学影响Desouzaetal.DiabetesCare2010;33:1389–94CRP,C反应蛋白;IL-6,白细胞介素6;VEGF,血管内皮生长因子Sympathodarenal交感神经肾上腺低血糖致死的可能机制由于心脏复极异常导致高危患者(缺血性心脏病，心脏自主神经病变)心律失常血栓形成趋势增加/血栓溶解减少儿茶酚胺导致的心血管改变心率增加无症状性心肌缺血心绞痛和心肌梗死Desouzaetal.DiabetesCare2010;33:1389–94在2型糖尿病患者中，有低血糖事件的患者发生急性心血管事件的可能性比无低血糖事件的患者高79%Johnstonetal.DiabetesCare2011;34:1164–70风险比评价期间出现的低血糖事件年龄65+vs.18-34岁年龄55-64vs.18-34岁年龄45-54vs.18-34岁年龄35-44vs.18-34岁男性vs.女性周围血管病慢性肾脏病糖尿病周围神经病变糖尿病视网膜病变既往心血管事件风险增加一项回顾性、观察性研究(n=860,845)评价低血糖事件和急性心血管事件之间的相关性3.1%的患者在评价期间（1年）曾有低血糖事件UKPDS:良好的血糖控制可降低糖尿病慢性并发症的患病风险Holmanetal.NEnglJMed2008;359:1577–89任何糖尿病相关终点心肌梗死微血管疾病胰岛素是2型糖尿病重要治疗方法使用胰岛素后HbA1c显著改善1T2DM患者使用胰岛素后迅速改善血糖控制，降低并发症发生风险21.Calvertetal.BrJGenPract2007;57:455–460;2.Simonsetal.ExpClinEndocrinolDiabetes2006;114:520–526p<0.001OAD,口服降糖药;T2DM,2型糖尿病治疗前治疗后平均HbA1c(%)聚焦胰岛素治疗：2010《指南》对胰岛素治疗方案的推荐口服药治疗的患者应何时开始胰岛素治疗起始胰岛素治疗可选择何种治疗方案2010年《中国2型糖尿病防治指南》推荐应尽早起始并适时强化胰岛素治疗方案胰岛素起始治疗方案：胰岛素治疗方案应该模拟生理性胰岛素分泌的模式，包括基础胰岛素和餐时胰岛素两部分的补充。两种口服药联合治疗控制血糖不达标者可加用每日一次基础胰岛素或每日1-2次预混胰岛素。胰岛素强化治疗方案：在胰岛素起始治疗的基础上，经过充分的剂量调整，如患者的血糖水平仍未达标或出现反复的低血糖，需进一步优化治疗方案。可采用餐时+基础胰岛素或每日三次预混胰岛素类似物进行胰岛素强化治疗。2010《中国2型糖尿病防治指南》2010《中国2型糖尿病防治指南》从2007到2010，新《指南》增加预混胰岛素起始治疗的理由我国多数患者合并餐后高血糖，严格控制HbA1c达标，应同时针对空腹和餐后血糖东方患者血糖异常分布以餐后高血糖为主DECODEstudyDECODAstudyDECODAStudyGroup.Diabetologia2000;43(12):1470-1475东西患者血糖异常分布的差异西方东方Monnier研究：空腹及餐时血糖共同决定了HbA1c的水平MonnierLetal.DiabetesCare2003;26:881-885.50%线70%50%45%40%30%30%50%55%60%70%0%20%40%60%80%100%<7.37.3-8.48.5-9.29.3-10.2>10.2HbA1c的范围对HbA1c的贡献(%)空腹血糖餐后血糖FPG8-12mmol/LFPG12–15mmol/LFPG<8mmol/LFPG>18mmol/L正常人2型糖尿病病人0.401.000.800.600.200–300306090120150180210240时间(分钟)T2DM患者：存在程度不同的胰岛素早相分泌异常CoatesPAetal.DiabetesResClinPract1994;26:177–187胰岛素平均浓度（nmol/L）仅改善基础高血糖无法降低餐后血糖增幅adaptedfromMonnierLetal.DiabetesCare2003;26:881-885.100200300正常A1C5%血浆葡萄糖(mg/dL)0800120018000800TimeofDay降低基础血糖:A1C7%治疗前:A1C9%基础+餐时:A1C6%WoerleHJ,etal.DiabetesResClinPract2007.同时控制空腹与餐后血糖可有更多患者HbA1c达标达到HbA1c<7%的患者比例（％）单纯控制空腹血糖达标（<5.6mmol/l）同时控制餐后血糖达标（<7.8mmol/l）从2007到2010，新《指南》增加预混胰岛素起始及强化治疗的证据预混胰岛素作为起始及强化胰岛素治疗—有据可循相比预混人胰岛素诺和锐?30拥有更为优越的药代动力学特性McSorleyPT,etal.ClinTher2002;24(4):530-95.06.07.08.09.010.0HbA1c(%)6.77.57.06.99.28.59.59.76.88.7-2.8%-2.6%-1.0%-2.5%-1.9%INTITATE11-2-3study2Yang3Malone6IMPROVE5为推算值，原文未提及1.Raskinetal.DiabetesCare2005;28:260–5;2.Garberetal.DiabetesObesMetab2006;8:58–66;3.Yangetal.Diabetescare2008;31:852-6;4.LieblAetal.Diabetes,Obes&Metab2009:11(1):45-52;5.Yangetal.CurrentMedicalResearch&Opinion2009;25:2643-54;6.Ilagetal.ClinTher2007;29:1254-70.7.28.4-1.2%PREFER47.48.7-1.3%Malone6Sheet3
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Plasma(Whole)BolldGlucoseCategory,(mmol/L)
空腹血糖≥7.0并且餐后2小时血糖＜11.1
空腹血糖＜7.0并且餐后2小时血糖≥11.1
空腹血糖≥7.0并且餐后2小时血糖≥11.1
研究例数
年龄
BIM(kg/m2)
FPG≥7.0&2h-PPG＜11.1
FPG＜7.0&2h-PPG≥11.1
FPG≥7.0&2h-PPG≥11.1
00.00
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00.00
0.00
0.00
0.00
0.00
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0.00
FPG≥7.0&2h-PPG＜11.1
FPG＜7.0&2h-PPG≥11.1
FPG≥7.0&2h-PPG≥11.1
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Plasma(Whole)BolldGlucoseCategory,(mmol/L)
空腹血糖≥7.0并且餐后2小时血糖＜11.1
空腹血糖＜7.0并且餐后2小时血糖≥11.1
空腹血糖≥7.0并且餐后2小时血糖≥11.1
研究例数
年龄
BIM(kg/m2)
FPG≥7.0&2h-PPG＜11.1
FPG＜7.0&2h-PPG≥11.1
FPG≥7.0&2h-PPG≥11.1
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FPG≥7.0&2h-PPG＜11.1
FPG＜7.0&2h-PPG≥11.1
FPG≥7.0&2h-PPG≥11.1
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NPHplusshortactinginsulinplusmetformin
Dietalone
Metforminalone
Secretagoguealone
Metforminplussecretagogue
NPH-insulinalone
NPHplusmetformin
NPHplussecretagogue
Twiceinsulin
NPHplusshortactinginsulin
NPHplussecretagogeplusmetformin
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.00
0.00
0.00
.00
.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
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0.00
0.00
0.00
.00
.00
.00
0.00
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0.00
.00
0.00
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0.00
0.00
.00
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0.00
0.00
0.00
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0.00
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若要调整图表数据区域的大小，请拖拽区域的右下角。
基线
终点
BIAsp30
BHI30
.00
.00
.00
.00
基线
终点
9.50
7.00
BIAsp30
BIAsp30
BHI30
BHI30
.00
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