内源性胰岛素分泌决定胰高血糖素反应强化血糖控制可增加重度低血糖发生率DCCT和UKPDS:强化血糖治疗与低血糖发生的风险为什么2型糖尿病胰岛素强化治疗的低血糖发生率较1型糖尿病少虽然胰高糖素反应受损，但是儿茶酚胺反应通常不受影响2型糖尿病患者存在胰岛素抵抗2型糖尿病患者存在残余的β细胞功能，可以调节自身胰岛素分泌量2型糖尿病患者较少接受胰岛素强化治疗，所以重度低血糖的发生风险较低，发生未察觉低血糖的可能性较低从基础到临床-强化治疗中全因死亡率的增加不能完全归咎于低血糖OBJECTIVE—Todeterminetheincidence,predisposingfactors,andcostsofemergencytreatmentofseverehypoglycemiainpeoplewithtype1andtype2diabetes.RESEARCHDESIGNANDMETHODS—Overa12-monthperiod,routinelycollecteddatasetswereanalyzedinapopulationof367,051people,including8,655peoplewithdiabetes,tomeasuretheincidenceofseverehypoglycemiathatrequiredemergencyassistancefromNinewellsHospitalandMedicalSchool(NHS)personnelincludingthoseinprimarycare,am-bulanceservices,hospitalaccidentandemergencydepartments,andinpatientcare.Associatedcostswiththeseepisodeswerecalculated.RESULTS—Atotalof244episodesofseverehypoglycemiawererecordedin160patients,comprising69(7.1%)peoplewithtype1diabetes,66(7.3%)withtype2diabetestreatedwithinsulin,and23(0.8%)withtype2diabetestreatedwithsulfonylureatablets.Incidencerateswere11.5and11.8eventsper100patient-yearsfortype1andtype2patientstreatedwithinsulin,respectively.Age,duration,andsocioeconomicstatuswereidenti?edasriskfactorsforseverehypoglycemia.Oneinthreecasesweretreatedsolelybytheambulanceservicewithnoothercontactfromhealthcareprofessionals.Thetotalestimatedcostofemergencytreatmentofseverehypoglycemiawas￡92,078inoneyear.CONCLUSIONS—Hypoglycemiarequiringemergencyassistancefromhealthservicepersonnelisascommoninpeoplewithtype2diabetestreatedwithinsulinasinpeoplewithtype1diabetes.ItisassociatedwithconsiderableNHSresourceusethathasasigni?canteconomicandpersonalcost.Toreportontheout-of-pocketexpensesincurredbyinsulin-treatedpatientstomanagebloodglucoselevels.thisretrospectivestudyininsulin-usingadultswithtype1ortype2diabeteswasconductedbetweenJuly7andDecember12,2003,in4Canadiancenters,usingapatientself-administeredquestionnaireandmedicalcharts.Thequesonnairecollecteddataregardingdurationofdiabetes;durationofinsulintherapy;typeofdiabetes;sourceofpaymentorinsulin,oralanthyperglycemicagentsandteststrips(i.e.insurancecompany[with%coverage],government,self);averagecostpermonthtotreathypoglycemia;frequencyofself-monitoringofbloodglucoseandinsulininjections;andfrequencyofdiabetes-relatedvisitstohealthcareprofessionals.METHODSAll335patientsenrolledcompletedthestudy;202(60.3%)hadtype1diabetesand133(39.7%)hadtype2diabetes;29patients(8.6%;27type1and2type2diabetespatients)usedpumptherapy.Themeanout-of-pocketcostperpersonforallpatientswas$2.21dailyor$807annually($891fortype1and$679fortype2diabetes).Insulinpumpusershadhigherannualaveragecoststhannon-pumpusers($1309vs.$797).At39.2%oftotalexpenses,glucosemonitoringteststripsaccountedforthegreatestcost,followedbymanagementofhypoglycemia(26.1%),insulin(15.8%),syringesandneedles(11.7%),andinsulinpumpandsupplies(3.9%).Thisstudyprovidesdirectdataconfirmingthatthecostsofmanagingbloodglucosearesignificantforpeoplewithdiabetestreatedwithinsulin.Ensuringthatpeoplewithdiabetesdonotreceivecompromisedcarebecauseoffinancialconstraintsisachallengethatwillrequireacoordinatedandthoughtfulresponsefromhealthcareproviders,alllevelsofgovernment,theinsuranceindustry,formularylistingbodiesandpatientadvocacygroups.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.‘轻微’低血糖的代价和负担在美国、英国和德国进行互联网调查N=6756名应答者报告患有糖尿病目的：调查在工作和非工作时间以及夜间发作的非重度低血糖对患者工作效率和糖尿病自我管理的影响Brodetal.ValueinHealth2011;14(5):665–71目的和研究概述‘轻微’低血糖的代价和负担焦虑增加担心再次出现低血糖事件而降低血糖控制标准生活质量降低和需要改变生活方式（如减少驾驶）Brodetal.ValueinHealth2011;14(5):665–71健康情况下降平均生产力丧失是~2300美元/人/年发生一次夜间低血糖后:23%上班迟到/不上班；32%错过会议/未按时完成任务；工作时间减少15小时生产力下降血糖监测次数增加：低血糖后7天内额外监测血糖5.6次发作低血糖后，25%的人联系了医疗服务提供者治疗成本增加重度低血糖经常需要入院和住院治疗每年需要医院服务的严重事件百分比Leeseetal.DiabetesCare2003;26:1176–80根据8655名糖尿病患者出现的244次事件救护车急诊入院91%63%21%对于使用胰岛素治疗的糖尿病患者而言，低血糖的管理相当于支出成本的一个重大部分每月个人用于糖尿病治疗的费用支出Harrisetal.CanJDiabetes2007;31(1):25–33806.73总体26.1210.71低血糖治疗3.326.47口服药3.931.08泵装置(泵使用者)11.794.58注射器/针头39.2316.51血糖监测试纸15.8127.38胰岛素占总体的比例(%)年费用（加元）总结证据表明低血糖很可能增加患者的死亡率由于生理保护反应减弱和反调节反应缺陷，2型糖尿病随病程延长更易发生低血糖低血糖通过不同的机制导致猝死对于低血糖高风险人群，我们应该考虑适当放宽强化血糖控制目标或采用一些较少引起低血糖的治疗方案针对患者特点选择合适的治疗方案，减少低血糖的发生成为临床医生需要关注的重点WeknowthattherisksofseverehypoglycaemiaarerelativelylowinthosewithType2diabetesevenduringintensivetherapy.ThesefiguresliftedfromJackGerich’srecentcommentaryintheLancet,showthatin3separatestudies,ratesofseverehypoglycaemiaexpressedasepisodesper100ptyareallbetween10.Notethatthemostintensive,usingpumptherapyisarounddoublethatoftheotherstudiesandisahintthatasonemightexpect,attemptstolowerglucosetonormallevelswillproducesimilarproblemsforpatientswithType2diabetesasforthosewithType1diabetes.Theincreasedriskofseverehypoglycaemiainpatientswithtype2diabeteswhoareintensivelytreatedwithinsulinseemstobemuchlowerthanitiswithtype1.IntheJapanesestudy2noseverehypoglycaemiawasobserved;andintheUKstudy,3theVeteransCooperativeStudy7andtheVeteransImplantableInsulinPumpStudy8severehypoglycaemiawasreportedtooccuratratesof2·3,3·0,and7·8per100patient-yearsrespectively,comparedwith62per100patient-yearsintheDCCT.1Thesituationisdifferentintype2diabetes.Firstofall,althoughglucagonresponsesarecommonlyimpaired,16,17catecholamineresponsesareusuallynormal18orincreased.16,17Second,thepatientsareinsulinresistant.Third,theyhavepersistent-cellfunction.Theabilitytomodulateinsulinsecretioncanactasabuffersinceendogenousinsulinsecretionwilldecreaseasplasmaglucosefalls;16thisopportunityisnotavailabletotype1patientswhoseinsulinavailabilityispredeterminedbytheamountalreadyinjected.Fourth,mosttype2patientsarenotonintensiveinsulinregimens,sotheyarelessatriskofhypoglycaemiaunawarenessasaresultofinsulinreactions.Finally,ofalltheoralagentsusedtotreattype2diabetes,onlyinsulinsecretogogues(sulphonylureassuchasglyburideandmeglitinidessuchasrepazlinide)havehypoglycaemiaasarecognizedside-effect。anobservationalstudyover9–12monthsinsixUKsecondarycarediabetescentres.Altogether383patientswereinvolved.Patientsweredividedintothefollowingthreetreatmentgroupsfortype2diabetes:(1)sulfonylureas,(2)insulinfor<2yearsand(3)insulinfor>5years,andintotwotreatmentgroupsfortype1diabetes,namely<5yearsdiseasedurationand>15yearsdiseaseduration.results:Mildhypoglycaemiaintype2diabeticpatientsoninsulinfor<2yearswaslessfrequentthanintype1patientswith<5yearsdiseaseduration(meanrate:4vs36episodespersubject-year,p<0.001).Intype2diabeticpatientstreatedwithsulfonylureasorinsulinfor<2years,nodifferenceswereobservedintheproportionexperiencingseverehypoglycaemia(7vs7%,difference0).mildsymptomatic(39vs51%,difference12)orinterstitialglucose<2.2mol/l(22vs20%,difference2).Severehypoglycaemiarateswerecomparableinpatientswithtype2diabetesonsulfonylureasorinsulin<2years(0.1and0.2episodespersubject-year)andfarlessfrequentthanintype1diabetes(<5yearsgroup,1.1;>15yearsgroup,3.2.episodespersubject-year).Type1<5yearsn=50Type1>15yearsn=57Type2sulfonylurean=108Type2<2yearsn=89Type2>5yearsn=77Durationofdiabetes(years)3.0(1.3–3.8)29.8(21.5–40.3)6.0(3.6–9.7)7.0(4.1–9.8)14.2(10.8–19.0)BaselineHbA1c(%)a7.3(1.02)7.8(0.73)7.5(0.84)7.4(0.89)7.7(0.90)Toevaluatetherolesofcounterregulatoryhormonesandinsulinantibodiesintheimpairmentofplasmaglucoserecoveryfromhypoglycemiaindiabetesmellitus,andtoassesstherelationshipbetweentheglucagonresponseanddurationofthedisease,21insulin-dependentdiabeticpatientsand10nondiabeticsubjectswerestudied.Thediabeticsconsistedof5patientswithrecentonsetofdiabetes(lessthan1mo);11with2.6+/-0.3(mean+/-SEM)yrdurationofdiabetes,5ofwhomhadinsulinantibodies;and5patientswithlong-termdiabetes(21+/-3yr),insulinantibodies,andautonomicneuropathy.Duringinsulin-inducedhypoglycemia(28mU/m2Xminfor60min)inpatientswithrecent-onsetdiabetes,plasmafreeinsulin,glucose,andcounterregulatoryhormoneconcentrationsdidnotdifferfromthoseofnondiabeticsubjects.Inpatientswithinsulinantibodies,thedisappearanceofinsulinafterinsulininfusionwasdelayed,andbothrestitutionofnormoglycemiaandplasmaglucagonresponsewerebluntedcomparedwithpatientswithoutantibodies.Whenglucagonwasinfused(80-130ng/m2Xmin)duringhypoglycemiaindiabeticswithimpairedglucagonresponsesinordertosimulatenormalglucagonresponses,plasmaglucoserecoverywasnormalizedinpatientswithoutantibodiesbutnotinthosewithantibodies.Inpatientswithlong-standingdiabetes,restitutionofnormoglycemiawasfurtherimpairedandthiswasassociatedwithanabsentplasmaglucagonresponseandadiminishedplasmaepinephrineresponse.Plasmaglucagonresponsestohypoglycemiawereinverselycorrelatedtothedurationofdiabetes(r=-0.943;Plessthan0.0005).ItisconcludedthatimpairedA-cellsecretionisthepredominantmechanismforthedelayedglucoserecoveryafterhypoglycemiaindiabeticpatientswithoutinsulinantibodiesandnormalepinephrineresponses.Sloweddisappearanceofinsulinduetothepresenceofinsulinantibodiesfurtherdelaystherestorationofnormoglycemia.Patientswithlong-standingdiabetesandautonomicneuropathyexhibitdecreasedepinephrinesecretion,whichleadstoanadditionalretardationofglucoserecovery.Sinceplasmaglucagonandepinephrineresponsestohypoglycemiawerenormalattheonsetofdiabetesbutdiminishedinlong-termdiabetes,itappearsthattheimpairedglucagonandepinephrineresponsestohypoglycemiaareacquireddefectsthatdevelopsubsequenttoB-cellfailure.Hyperinsulinemicsteppedhypoglycemicclamps(85,75,65,55,and45mg/dlsteps)wereperformedin13patientswithtype2diabetes—7treatedwithoralhypoglycemicagents(OHARX;meanHbA1c8.6%)and6requiringtherapywithinsulinforanaverageof5yearsandwithreducedC-peptidelevels(insulinRX,HbA1c7.5%)—and15nondiabeticcontrolsubjects.Theglucagonresponsetohypoglycemiawasvirtuallyabsent(P0.0252)intheinsulin-deficienttype2diabeticpatients(insulinRXmeanfinalvaluesof52vs.93pg/mlincontrolsubjectsand98pg/mlintype2diabeticpatients,OADRX).theglucagonresponsetohypoglycemiaisreducedinpatientswhoareapproachingtheinsulin-deficientendofthespectrumoftype2diabetesWetestedthehypothesesthattheglucagonresponsetohypoglycemiaisreducedinpatientswhoareapproachingtheinsulin-de?cientendofthespectrumoftype2diabetesandthatrecentantecedenthypoglycemiashiftstheglycemicthresholdsforautonomic(includingadrenomedullaryepinephrine)andsymptomaticresponsestohypoglycemiatolowerplasmaglucoseconcentrationsintype2diabetes.Hyperinsulinemicsteppedhypoglycemicclamps(85,75,65,55,and45mg/dlsteps)wereperformedontwoconsecutivedays,withanadditional2hofhypoglycemia(50mg/dl)intheafternoonofthe?rstday,in13patientswithtype2diabetes—7treatedwithoralhypoglycemicagents(OHARX;mean[SD]HbA1c8.61.1%)and6requiringtherapywithinsulinforanaverageof5yearsandwithreducedC-peptidelevels(insulinRX,HbA1c7.50.7%)—and15nondiabeticcontrolsubjects.Theglucagonresponsetohypoglycemiawasvirtuallyabsent(P0.0252)intheinsulin-de?cienttype2diabeticpatients(insulinRXmean[SE]?nalvaluesof5216vs.9315pg/mlincontrolsubjectsand9816pg/mlintype2diabeticpatients,OHARXonday1).Glucagon(P0.0015),epinephrine(P0.0002),andnorepinephrine(P0.0138)responsesandneurogenic(P0.0149)andneuroglycopenic(P0.0015)symptomresponsestohypoglycemiawerereducedonday2afterhypogly-cemiaonday1intype2diabeticpatients;theseresponseswerenoteliminated,buttheirglycemicthresholdswereshiftedtolowerplasmaglucoseconcen-trations.Inaddition,theglycemicthresholdsfortheseresponseswereathigher-than-normalplasmaglucoseconcentrations(P0.0082,0.0028,0.0023,and0.0182,respectively)atbaseline(day1)inOHARXtype2diabeticpatients,withrelativelypoorlycontrolleddiabetes.Becausetheglucagonresponsetofallingplasmaglucoselevelsisvirtuallyabsentandtheglycemicthresholdsforautonomicandsymptomaticresponsestohypoglycemiaareshiftedtolowerglucoseconcentra-tionsbyrecentantecedenthypoglycemia,patientswithadvancedtype2diabetes,likethosewithtype1diabetes,areatriskforhypoglycemia-associatedautonomicfailureandtheresultantviciouscycleofrecurrentiatrogenichypoglycemia.Diabetes51:724–733,2002Sevenpoorlycontrolledtype2diabetespatients(meanHbA1c,11.3+/-1.1%)werestudiedbysteppedhyperinsulinemichypoglycemicclamp(nadir,2.4mmol/l)beforeandafterimprovingglycemiccontrolwithinsulintreatment.results:Inpatientswithpoorlycontrolledtype2diabetes,counterregulatoryhormoneresponsesbeganathigherplasmaglucoselevelsthandidthoseinhealthysubjects(epinephrine,4.4+/-0.2vs.3.7+/-0.2mmol/l,P=0.011).Aftersignificantimprovementinglycemiccontrol(meanHbA1c,8.1+/-0.9%,P<0.001)wasachievedwithoutseverehypoglycemia,hormonalresponsesstartedatmuchlowerplasmaglucoselevels(e.g.,epinephrine,3.5+/-0.3mmol/l,P=0.005)andweresignificantlyreducedinmagnitude(e.g.,areaunderepinephrineresponsecurve,306+/-93vs.690+/-107nmol.min-1.l-1,P=0.012).RatesofhypoinACCORDwerecomparablewiththoseintype1diabetes,wherethereisevidencedatingbackseveralyearslinkingseverehypoglycaemiawithsuddendeath2.8vs1.2%HR1.41,1.03to1.93-95%CIandstandardarms3.7vs1.0%HR2.30,1.46to3.65wetestedthehypothesisthatantecedenthypogycaemiacouldaffectthephysiologicalresponsetosubsequentepisodes.Wetestedthephysiologicalresponsetohypoglycaemiaon2successivemorningsinnormalsubjectswithahypoglycaemicclampat2.5mMandintheafternooninducedanadditionalperiodofhypoglycaemia,2hat2.8mM.Theslideshowsthepeakepiandssscoresbeforeandaftertheperiodofhypoglycemia.Therewasamarkedreductioninbothresponsesfollowing2hoffairlymildhypoglycaemia.Notealsothatalthoughwetitledourpaper,1episodeofhypoglycaemia,thiswasnotstrictlyaccurateastheinitialmeasruementoftheresponseimposedanadditionalperiodofantecedenthypoglycaemia.ThismaybeimportantasIwilldiscusslateron.Therewasnoevidenceofinteractionamongseverehypoglycemia,theassignedglucoseloweringtreatment,andtheriskofdeath(P=0.30)Therewasnoevidenceofadose–responserelationshipbetweenrepeatedepisodesofseverehypoglycemiaandvascularoutcomesordeathKeymessage:Hypoglycaemiamaycauseabnormalitiesinthecardiovascularsystemthatmayincreasetheriskforcardiovasculareventsinpatientswithdiabetes.Hypoglycaemiamayaffectcardiovasculareventsthroughincreasedinflammation,endothelialdysfunction,abnormalsympathoadrenalresponsesandbloodcoagulationabnormalities.Inflammatoryresponsestriggerthereleaseofmultipleinflammatorymarkers(C-reactiveprotein,vascularendothelialgrowthfactorandinterleukin-6)andincreasetheoveralllevelsofinflammatorycytokinesthatcanleadtoendothelialinjuriesandabnormalitiesincoagulation.Theactivationofthefibrinolyticsystemandincreasedepinephrinelevelscanalsoleadtobloodcoagulationabnormalitiesthroughincreasedneutrophilactivation,plateletactivationandincreasedfactorVII.Thesympathoadrenalresponseleadstoincreasedcatecholaminerelease,whichincreasesmyocardialcontractility,workloadandcardiacoutput.Endothelialdysfunctioncanleadtodecreasedvasodilationandcanplaceanevengreaterstrainonthecardiovascularsystemandperpetuatetheinabilitytomeetoxygendemands.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.AimsToascertainthefrequencyandidentifypredictorsofself-reportedhypoglycaemiainType1andinsulin-treatedType2diabetes.MethodsArandomsampleof267peoplewithinsulin-treateddiabeteswererecruitedfromapopulation-baseddiabetesregisterinTayside,Scotland.Eachsubjectprospectivelyrecordedthenumberofmildandseverehypoglycaemicepisodesexperiencedovera1-monthperiod.Ordinallogisticregressionwasperformedtoidentifypotentialpredictorsofhypoglycaemia.ResultsFivehundredandseventy-twohypoglycaemiceventswerereportedby155patients.TheparticipantswithType1diabeteshadatotalof336hypoglycaemiceventswitharateof42.89eventsperpatientperyear.Ofthese,ninewereseverehypoglycaemicevents,witharateof1.15eventsperpatientperyear.Participantswithinsulin-treatedType2diabetesexperiencedatotalof236hypoglycaemiceventswitharateof16.37eventsperpatientperyear.Ofthese,fivewereseverehypoglycaemicevents,whichwouldbeequivalentto0.35eventsperpatientperyear.PredictorsofhypoglycaemiainType1diabeteswereahistoryofprevioushypoglycaemia(P=0.006)andco-prescribingofanyoraldrug(P=0.048).Inpatientswithinsulin-treatedType2diabetes,ahistoryofprevioushypoglycaemia(P<0.0001)anddurationofinsulintreatment(P=0.014)weresignificantpredictors.ConclusionTheincidenceofself-reportedseverehypoglycaemiaininsulin-treatedType2diabetesislowerthaninType1diabetesbutdoesoccurmoreoftenthanpreviouslyreportedandwithsufficientfrequencytocausesignificantmorbidity.Durationofinsulintreatmentisakeypredictorofhypoglycaemiaininsulin-treatedType2diabetes.Objectives:Hypoglycemiaisacommoncomplicationoftreatmentwithcertaindiabetesdrugs.Non-severehypoglycemicevents(NSHEs)occurmorefrequentlythansevereeventsandaccountforthemajorityoftotalevents.Theobjectiveofthismulti-countrystudywastoidentifyhowNSHEsinaworkingpopulationaffectproductivity,costs,andself-managementbehaviors.Methods:A20-minutesurveyassessingtheimpactofNSHEswasadministeredviatheInternettoindividuals(18yearsofage)withself-reporteddiabetesintheUnitedStates,UnitedKingdom,Germany,andFrance.TheanalysissampleconsistedofallrespondentswhoreportedanNSHEinthepastmonth.Topicsincluded:reasonsfor,durationof,andimpactofNSHE(s)onproductivityanddiabetesself-management.Results:Atotalof1404respondentswereincludedinthisanalysis.Lostproductivitywasestimatedtorangefrom$15.26to$93.47(USD)perNSHE,representing8.3to15.9hoursoflostworktimepermonth.AmongindividualsreportinganNSHEatwork(n972),18.3%missedworkforanaverageof9.9hours(SD8.4).AmongrespondentsexperiencinganNSHEoutsideworkinghours(includingnocturnal),22.7%arrivedlateforworkormissedafullday.ProductivitylosswashighestforNSHEsoccurringduringsleepwithanaverageof14.7(SD11.6)workinghourslost.IntheweekfollowingtheNSHE,respondentsrequiredanaverageof5.6extrabloodglucoseteststrips.Amongrespondentsusinginsulin,25%decreasedtheirinsulindosefollowingtheNSHE.Conclusions:NSHEsareassociatedwithsubstantialeconomicconsequencesforemployersandpatients.GreaterattentiontotreatmentsthatreduceNSHEscouldhaveamajor,positiveimpactonlostworkproductivityandoveralldiabetesmanagement.Keywords:costanalysis,diabetes,diseasemanagement,hypoglycemia.探索与反思——血糖达标与低血糖的再思考陈璐璐华中科技大学协和医院内容概要2型糖尿病中的低血糖流行病学病理生理学与1型糖尿病相比的异同低血糖致死的可能机制低血糖与死亡风险的再思考糖尿病低血糖风险随着疾病的进展而增加ns报告过至少一次严重低血糖的患者比例1.00.80.60.40.20 使用SU的T2DM T2DM<2年 T2DM>5年 T1DM<5年 T1DM>15年 Diabetologia.2007;50(6):1140-7n=50n=57n=77n=89n=108低血糖的原因低血糖的生理防御机制受损反调节激素释放受损对低血糖无感知不恰当的胰岛素浓度1型糖尿病随病程延长而出现进行性内分泌反调节激素反应受损050100150200250300350非糖尿病1个月1-5年14-31年020406080100120肾上腺素胰高糖素肾上腺素(pg/ml)胰高糖素(pg/ml)对胰岛素诱发低血糖(2.5mM)的激素反应峰值1型糖尿病患者BolliGetal.Diabetes1983P＜0.05随着2型糖尿病的进展，胰高糖素对低血糖的反应下降020406080100胰高糖素(pg/ml)非糖尿病对照组n=15使用OAD治疗的2型糖尿病n=7使用胰岛素治疗的2型糖尿病n=6血浆葡萄糖2.5mM时的胰高糖素反应Diabetes.2002;51(3):724-33P=0.0252胰岛素诱发的低血糖IV甲苯磺丁脲Peaceyetal.JClinEndocrinolMetab1997;82:1458-61.胰高血糖素门脉胰岛素α细胞对低血糖的反应在一定程度上取决于β细胞的功能01234567血糖2.5mM时的肾上腺素(nM)0510152025303540血糖2.5mM时的症状评分前后前后健康志愿者低糖钳夹2.5mM相隔1天测定的反应Diabetes.1991Feb;40(2):223-6先前1次低血糖发作对肾上腺素反应的影响P＜0.05P＜0.01严格血糖控制对2型糖尿病低血糖时肾上腺素反应的影响2345血浆葡萄糖(mmol/l)出现明显肾上腺素反应的血糖阈值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DiabetesCare.1998;;21(2):283-90.1.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重度低血糖事件发生率?(/100患者/年)P＜0.001Vs常规治疗P＜0.001P＜0.001P=0.001HbA1c7.97.17.27.36.57.56.48.46.9UKPDS(2型糖尿病)1.DCCTResearchGroup.Diabetes1997;46:271-286；2.UKPDSGroup(33).Lancet1998;352:837-853.DCCT(1型糖尿病)发生1次或1次以上严重低血糖的患者比例（%）54321003691215随机化后时间（年）强化组常规组研究期间HbA1C水平(%)100806040200567891011121314低血糖发作次数/100病人年强化组常规组糖尿病病程长严格血糖控制睡眠锻炼(药物–非选择性?受体阻滞剂,酒精)什么因素导致反调节防御反应受损和对低血糖无感知?睡眠是反调节反应受损和低血糖无感知的原因之一睡眠降低了:肾上腺素反应低血糖过程中的觉醒 Jonesetal,NEnglJMed1998 Banareretal,Diabetes2003仰卧位姿势减弱低血糖时的症状和肾上腺素反应 Hirschetal,ClinSci1992机制未明锻炼是导致机体对后续低血糖时交感肾上腺反应减弱的原因之一既往的体育锻炼降低了机体对后续低血糖发作的反调节反应，减少了自主神经症状（但不包括脑低血糖症状） Galassettietal,AmJPhysiol2001 McGregoretal,Diabetes2002机制未明使用胰岛素治疗的2型糖尿病患者低血糖发生率较1型糖尿病患者低00.20.40.60.81.01.2InsRxType2Type1每名患者年严重低血糖事件数1月余的预计记录;94名1型糖尿病,173名使用胰岛素的2型糖尿病DonnellyLAetal.DiabeticMed20051型糖尿病使用胰岛素的2型糖尿病2型糖尿病强化胰岛素治疗期间的低血糖事件较1型糖尿病少每100人年的事件发生数Okuboetal1995Abrairaetal1995Saudeketal1996DCCT1993Lancet.2000;356(9246):1946-7Lancet.2000;356(9246):1946-7内容概要2型糖尿病中的低血糖流行病学病理生理学与1型糖尿病相比的异同低血糖致死的可能机制低血糖与死亡风险的再思考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充分证据显示1型糖尿病低血糖与猝死有关Malins,1968TattersallandGill,1991Borch-JohnsenandHelwig-Larsen,1993SartorandDahlquist,1995ThordarsonandS?vik,1995S?vikandThordarson,1999Ramslietal.,2004Twiggetal.,2008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RobinsonRTetal.Diabetes.2003Jun;52(6):1469-74.低血糖低血钾交感神经活性增加心肌复极化异常QT间期延长QT离散度增加心律失常猝死（心肌梗死等）同一名糖尿病患者在两种不同情况下的非卧床心电图监测情况RobinsonRTetal.Diabetes.2003Jun;52(6):1469-74.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）曾有低血糖事件内容概要2型糖尿病中的低血糖流行病学病理生理学与1型糖尿病相比的异同低血糖致死的可能机制低血糖与死亡风险的再思考“ACCORD试验中观察到强化治疗组相对死亡风险增加不能用研究中出现的严重低血糖解释”BMJ.2010;340:b4909死亡率增加是由于低血糖吗?ACCORD试验研究者的观点00.5124强化组常规组HR2.30(1.46,3.65)死亡率%ACCORD严重低血糖和死亡风险的关系1次或多次严重低血糖发作无严重低血糖HR1.4195%CI(1.03,1.93)BMJ.2010;340:b4909026强化组常规组死亡率%ADVANCE严重低血糖和死亡风险的关系1次或多次严重低血糖发作无严重低血糖NEngJMed2010;363:1410-84无严重低血糖HR0.93(0.82,1.06)≥1次严重低血糖HR0.67(0.37,1.21)风险比(95%CI)0.512ADVANCEUKPDS0.92(0.78,1.10)0.93(0.82,1.05)有利于强化血糖控制有利于常规血糖控制风险比(95%CI)1.09(0.81,1.47)VADT1.28(1.06,1.54)ACCORDDiabetesResClinPract.2009;86:S57-62强化治疗过程中死亡率增加的可能原因特定药物体重增加低血糖一些重要因素影响对结果的解读：严重低血糖发作反映了交感肾上腺反应缺陷偶尔发作低血糖更容易产生强烈的交感肾上腺反应，该反应可能更加‘有致病性’，而ACCORD和其他胰岛素强化研究通常并不系统记录这类事件为何低血糖对未强化治疗的患者更危险?Sheet1
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