相见不相识掀开2型糖尿病低血糖的面纱内容低血糖的定义和症状低血糖现状和危害低血糖的影响因素和管理低血糖的经典定义低血糖是一组多种病因引起的以血糖浓度过低，临床上以交感神经兴奋和脑细胞缺乏葡萄糖为主要特点的综合征用于诊断的Whipple三联征出现与低血糖相符的临床症状确切的低血糖值血糖水平恢复后症状迅速缓解Joslin糖尿病学（14版）；内科学（人卫第7版）；中国2型糖尿病防治指南（2017版）2018年ADA指南对低血糖的定义怀疑低血糖(或常规血糖检测)患者是否能自行处理?是否血糖监测具有重要临床意义的低血糖血糖水平<3.0mmol/L严重低血糖与严重认知功能障碍相关需他人帮助的低血糖事件低血糖警戒值血糖水平≤3.9mmol/L及时给予碳水化合物、胰高糖素、或采取其他纠正措施.ADA,美国糖尿病学会;DiabetesCare.2018Jan;41(Suppl1):S55-S64InternationalHypoglycaemiaStudyGroup.DiabetesCare.2017;40(1):155-157.低血糖的生理应答——血糖阈值抑制内源性胰岛素分泌低血糖“警戒值”3.9mmol/L3.8mmol/L负反馈调节激素：胰高糖素肾上腺素具有临床意义的低血糖3.0mmol/L3.2-2.8mmol/L3.0-2.8mmol/L症状发作：自主性神经症状神经性低血糖认知功能障碍：无法执行复杂的任务血糖浓度（mmol/l）严重神经性低血糖：意识模糊抽搐昏迷<1.5mmol/LHypoglycaemiainClinicalDiabetes.3rded.Frier,Heller&McCrimmon(Eds),pp114-44.低血糖的常见症状非特异性头疼恶心出汗心悸颤抖饥饿精神不集中嗜睡行为怪异语言迟钝步态不稳自主神经症状神经性低血糖症状McAulayV,etal.DiabetMed.2001;18:690-705.低血糖症状具有年龄特性儿童（青春期前）成年人老年人自主神经症状自主神经症状自主神经症状神经性低血糖症状神经性低血糖症状神经性低血糖症状行为改变非特异性神经性的改变虚弱易怒具有攻击性视力障碍功能失调平衡受损HypoHypoHypoMcAulayV,etal.DiabetMed.2001;18:690-705.低血糖症状随病程延长改变出汗和/或震颤1神经性低血糖/自主神经症状2神经低血糖症状/自主神经症状比例患者（%）糖尿病病程（年）糖尿病病程（年）数据：中位数和95%CI症状随着时间改变自主神经症状减弱神经性低血糖症状持续且显著1.Prammingetal.DiabeticMed1991；8:217-22；2.Olsenetal.DiabetMed2014;31:1210-7内容低血糖的定义和症状低血糖现状和危害低血糖的影响因素和管理糖尿病患者低血糖发生率高于预期全球北欧/加拿大东欧拉丁美洲中东俄国东南亚T2DM患者前瞻期总体低血糖估算的年发生率(事件/患者年)发生率(事件/患者年)HAT研究：非干预性、全球性、6个月回顾期研究和1个月前瞻期研究；n=27,585；(T1DM:8022,T2DM:19,563)总体低血糖指全部非严重低血糖，严重低血糖和夜间低血糖KhuntiK,etal.DiabetesObesMetab.2016;18(9):907-15；KhuntiK,etal.PresentedatEASD2014,Vienna,Austria.低血糖事件经常未被患者发现T2DM(n=31)T2DM(n=30)低血糖事件47%T2DM患者通过CGM检测到未被患者发现的低血糖通过CGM检测到的低血糖事件，83%?未被患者发现其中，57%是夜间低血糖?24/30低血糖事件.CGM,continuousglucosemonitoring1.ChicoAetal.DiabetesCare2003;26:1153–7;2.WeberKKetal.ExpClinEndocrinolDiabetes2007;115:491–4严重低血糖在睡眠时更易发生60平均值CGM5040严重低血糖事件(%)3020100睡眠中1夜间(00:00–08:00)12型糖尿病患者的低血糖–CGM:36%发生在夜间2DCCT研究显示：55%的严重低血糖发生在睡眠时，43%发生在00:00-08:001.TheDCCTResearchGroup.AmJMed1991;90:450-459.2.Pazos-Couseloetal.CanJDiabetes.2015Oct;39(5):428-433低血糖的短期危害短期急性症状情绪改变认知损害工作表现驾驶水平扰乱日常活动死亡：急性事件肌肉骨骼跌倒，意外事故骨折驾驶事故心血管心肌缺血心律失常心力衰竭脑昏迷，癫痫认知紊乱心理影响FrierBM.NatRevEndocrinol.2014;10(12):711-22.低血糖的长期危害长期短期降低生活质量就业；驾驶许可认知功能减退糖尿病和/或血管并发症恶化急性症状情绪改变认知损害工作表现驾驶水平扰乱日常活动死亡率：急性事件FrierBM.NatRevEndocrinol.2014;10(12):711-22.低血糖的不良结局大脑认知功能障碍黑朦,癫痫、昏迷心理影响心脏心肌梗死心律失常循环系统跌倒,意外事故,交通事故骨折脱臼炎症凝血异常血液动力学改变内皮功能紊乱Desouzaetal.DiabetesCare2010;33:1389–94;Frier.NatRevEndocrinol2014;10:711–22骨骼肌多项研究显示低血糖与不良临床结局相关在多项心血管结局试验中，严重低血糖与MACE、全因死亡发生率升高相关ACCORDADVANCEEXAMINELEADERDEVOTEMACE,主要不良心血管事件BondsDE,etal.BMJ2010;340:b4909;ZoungasS,etal.NEnglJMed.2010;363(15):1410-8;HellerSR,etal.DiabetesObesMetab.2017;19(5):664-671;ZinmanB,etal.DiabetesCare.2018;41(8):1783-1791;PieberTR,etal.Diabetologia.2018Jan;61(1):58-65ACCORD研究：经历过严重低血糖的患者死亡率增加既往无低血糖至少经历过一次低血糖HR:2.30[1.46;3.65]HR:1.41[1.03;1.93]任何需要第三方援助（药物或非药物）的低血糖事件HR校正下列基线变量：年龄、性别、吸烟史、心血管病史、心衰史、外周神经病变、尿蛋白肌酐比、心率、QT评分（心电图）、视力评分、他汀类药物使用、磺脲类药物使用、降糖治疗方案、是否参加血脂、血压试验、强化血压控制组、贝特类药物使用;HR,风险比BondsDE,etal.BMJ2010;340:b4909ADVANCE研究：严重低血糖与多种不良临床结局显著相关无严重低血糖(n=10,909)有严重低血糖(n=231)发生事件患者数(%)事件HR[95%CI]主要大血管事件33(15.9%)1114(10.2%)3.53[2.41;5.17]主要微血管事件24(11.5%)1107(10.1%)2.19[1.40;3.45]全因死亡45(19.5%)986(9.0%)3.27[2.29;4.65]CVD死亡22(9.5%)520(4.8%)3.79[2.36;6.08]23(10.0%)466(4.3%)2.80[1.64;4.79]非CVD死亡1.010.00.1HR基于校正模型计算;HR,风险比;CI,置信区间;CVD,心血管疾病ZoungasS,etal.NEnglJMed.2010;363(15):1410-8.EXAMINE研究：低血糖与MACE发生风险增加相关MACE发生率%校正HR(95%CI)MACE95%CI无严重低血糖(n=609)参考严重低血糖(n=12)无低血糖(n=557)参考任何低血糖(n=64)HR校正基线年龄、性别、治疗方案、HbA1c、降糖药物（胰岛素、二甲双胍、磺脲类），并根据筛查时的肾功能和区域分层;MACE,主要不良心血管事件;HR,风险比;CI,置信区间;HellerSR,etal.DiabetesObesMetab.2017;19(5):664-671.LEADER研究：严重低血糖与MACE、全因死亡相关有vs.无严重低血糖的患者发生全因死亡风险有vs.无严重低血糖的患者发生MACE风险任何时间≤365天以后≤180天≤90天≤60天≤30天≤15天≤7天HR[95%CI]HR[95%CI]MACE,主要不良心血管事件;HR,风险比;CI,可信区间ZinmanB,etal.DiabetesCare.2018;41(8):1783-1791DEVOTE研究：严重低血糖与全因死亡、心血管死亡相关HR[95%CI]发生事件之前有严重低血糖发生事件之前无严重低血糖NRNR首次3-点MACE1.38[0.96;1.96]326.346494.57首次4-点MACE1.37[0.99;1.91]377.447685.47MACE的各项组成非致死性心肌梗死0.74[0.36;1.49]81.573052.13非致死性卒中1.81[0.92;3.57]91.761410.97心血管死亡(包括不确定原因)2.14[1.37;3.35]214.052571.76需住院的不稳定心绞痛1.34[0.59;3.04]61.181390.96全因死亡2.51[1.79;3.50]387.323852.64风险比[95%CI]发生严重低血糖后MACE/全因死亡风险更高3点MACE事件定义为心血管死亡、非致死性心梗、非致死性卒中；4点MACE事件定义为3点MACE事件或因不稳定心绞痛住院；N：患者数；R：MACE、MACE各组分、全因死亡发生率/100患者-年；HR,风险比;CI,可信区间PieberTR,etal.Diabetologia.2018Jan;61(1):58-65低血糖与交通事故相关使用OAD的患者交通事故发生率P<0.05,来自美国保险数据由于低血糖引发的交通事故导致住院或者急诊InksterBandFrierBM,DiabetesObesMetab2013;15(9):775–783低血糖影响患者生活质量英国T2DM与低血糖调查60患者报告低血糖事件对于日常活动的影响能力影响受影响的患者(%)5047%4037%35%35%35%3020100社交活动体育活动精神状态睡眠家务DiabetesUK.Type2diabetesandhypoglycaemiasurvey2009;N=1954http://www.diabetes.org.uk/Documents/survey/Type2hypoOct09/DiabetesUKhypossurveyinfull.pdfhttphttp://www.diabetes.org.uk/Documents/survey/Type2hypoOct09/DiabetesUKhypossurveyinfull.pdf://www.diabetes.org.uk/Documents/survey/Type2hypoOct09/DiabetesUKhypossurveyinfull.pdf(AccessedDec.2018)对低血糖的担忧是积极治疗糖尿病的重要障碍如果没有对低血糖的担心，我会更积极地治疗我的患者2因低血糖事件减少胰岛素剂量的患者比例1T1DM(n=202)T2DM(n=133)内科/全科/家庭医师(n=650)糖尿病/内分泌专家(n=600)非严重事件严重事件医生比例(%)1.LeiterLA,etal.CanJDiabetes.2005;29:186–92;2.PeyrotM,etal.DiabetMed2012;29(5):682–9严重低血糖意味着巨大的经济负担包括救护车服务、医务人员及住院护理费用1一次严重低血糖事件(如患者直接住院)的总费用预计为7317美元2严重低血糖事件通常需要收住院且进行院内治疗1基于8655名糖尿病患者，发生244次需要医护人员帮助的事件救护车急诊住院1.LeeseGP,etal.DiabetesCare.2003;26(4):1176-80;2.CurkendallSM,etal.JCOM.2011;18(10):455–62内容低血糖的定义和症状低血糖现状和危害低血糖的影响因素和管理低血糖的风险因素医学干预事件生活方式严格的血糖控制运动量增加既往严重低血糖史生活方式不规律糖尿病病程长饮酒注射部位脂肪增生年龄增加低血糖感知受损孕早期糖尿病治疗方案哺乳血糖变异性高睡眠肝肾功能不全终期病患胃肠手术https://www.diabetes.org.uk/Documents/About%20Us/Our%20views/Care%20recs/JBDS%20hypoglycaemia%20position%20(2013).pdfhttps://www.diabetes.org.uk/Documents/About%20Us/Our%20views/Care%20recs/JBDS%20hypoglycaemia%20position%20(2013).pdfQuYetal.DiabetesTechnolTher.2012;14:1008–1012.FrierBM.NatRevEndocrinol.2014;10(12):711-22.国际低血糖研究小组对低血糖管理的推荐若发生低血糖，医务人员使用SU/格列奈类和胰岛素治疗的患者考虑危险因素提供系统的健康教育如果可能，避免使用SUs若需要使用胰岛素，选择胰岛素类似物，或胰岛素泵和CGM达到不发生严重低血糖的最低HbA1c水平低血糖教育SMPG≤3.9mmol/L时进行干预，避免低血糖进展常规询问低血糖情况，包括低血糖症状和血糖水平InternationalHypglycaemiaStudyGroup,DiabetesCare2015;38:1583–1591系统教育改善低血糖对于T1DM进行为期5天的课程，主要关于根据碳水化合物摄入量以及自行血糖监测来调整胰岛素剂量p<0.05比较DAFNE之前和之后的平均值；DAFNE,DoseAdjustmentforNormalEating;针对正常饮食剂量调整HopkinsDetal,DiabetesCare2012;35:1638–1642基础胰岛素逐步更新换代，使得疗效与安全性不断加强胰岛素类似物人胰岛素NPH德谷胰岛素地特胰岛素甘精胰岛素动物胰岛素PZI安全性灵活性免疫原性有效性安全性人胰岛素和动物胰岛素的临床使用专家意见,药品评价.2014年第11卷第15期:8-10页.中国2型糖尿病防治指南(2017年版).中华糖尿病杂志.2018;10(1):4-67.SWITCH2研究：试验设计研究特点：RCT双盲交叉治疗达标设计721例T2DM患者德谷胰岛素OD±OADs德谷胰岛素OD±OADs甘精胰岛素OD±OADs甘精胰岛素OD±OADs剂量调整期216周剂量调整期116周剂量维持期216周剂量维持期116周主要终点:在剂量维持期，严重低血糖或血糖确证的症状性低血糖事件（总体症状性低血糖事件）发生率治疗期2治疗期1患者入组标准：年龄≥18岁，2型糖尿病≥26周，基础胰岛素±OADs≥26周，至少有一个低血糖危险因素；继续使用入组前的口服降糖药WyshamC,etal.JAMA.2017Jul4;318(1):45-56.德谷胰岛素有效降糖，低血糖风险降低SWITCH2结果HbA1c严重低血糖CROSSOVER累积事件数/患者德谷胰岛素甘精胰岛素46%NS0.00.0治疗期开始后时间(周)总体症状性低血糖夜间症状性低血糖累积事件数/患者累积事件数/患者30%(p<0.001)42%(p<0.001)治疗期开始后时间(周)治疗期开始后时间(周)WyshamCH,etal.JAMA2017;318:45–56德谷胰岛素不同定义的低血糖风险均降低SWITCH2事后分析剂量维持期全部治疗期率比[95%CI]0.70[0.61;0.80],p<0.0001总体症状性低血糖(BG<3.1mmol/L)0.77[0.70;0.85],p<0.00010.76[0.67;0.85],p<0.05总体症状性或无症状低血糖(BG<3.1mmol/L)0.83[0.77;0.90],p<0.050.85[0.79;0.92],p<0.05ADA定义的症状性低血糖(BG≤3.9mmol/L)0.92[0.87;0.96],p<0.050.54[0.21;1.42],NS严重低血糖0.49[0.26;0.94],p=0.03060.58[0.46;0.74],p<0.0001夜间症状性低血糖(BG<3.1mmol/L)00:01am-05:59am0.75[0.64;0.89],p=0.0070.62[0.50;0.78],p<0.05夜间症状性低血糖(BG<3.1mmol/L)10.01pm-07.59am睡眠中发生0.88[0.76;1.03],NS0.60[0.48;0.75],p<0.05夜间症状性或无症状低血糖(BG<3.1mmol/L)00:01am-05:59am0.74[0.64;0.86],p<0.05德谷胰岛素更优甘精胰岛素更优德谷胰岛素降低HbA1c水平时低血糖风险增加更少SWITCH2事后分析HbA1c水平每下降1%，甘精胰岛素治疗增加低血糖发生率增加67%，德谷胰岛素增加45%甘精胰岛素德谷胰岛素低血糖发生率增加（%）HbA1c水平下降（%）低血糖为严重低血糖或经血糖确证的症状性低血糖Philis-TsimikasA,etal.Oralpresentation200-ORatADA,25June2018,Orlando,Florida.德谷胰岛素血糖达标(HbA1c<7%)情况下，低血糖风险降低BEGIN荟萃分析率比[95%CI]剂量维持期全部治疗期0.77[0.58;1.02]总体确证的低血糖汇总未使用过胰岛素的T2DM0.88[0.69;1.10]0.74[0.61;0.89]汇总T2DM0.80[0.68;0.93]0.49[0.30;0.81]夜间确证的低血糖汇总未使用过胰岛素的T2DM0.56[0.38;0.84]0.53[0.39;0.72]汇总T2DM0.56[0.44;0.72]德谷胰岛素更优甘精胰岛素更优BEGIN3a期荟萃分析；基于95%CI，差异具有统计学意义;Einhornetal.EndocrPract2015;21(8):917-926德谷胰岛素血糖达标（FPG<7.2mmol/L)，且无低血糖患者比例更高BEGIN荟萃分析比值比[95%CI]FPG达标汇总未使用过胰岛素的T2D1.55[1.22;1.96]汇总T2D1.51[1.26;1.81]2.82[1.82;4.36]汇总未使用过胰岛素的T2D1.47[1.18;1.84]FPG达标且无夜间低血糖汇总T2D1.49[1.24;1.78]甘精胰岛素更优德谷胰岛素更优数值来自维持期每次随访Meneghinietal.Diabetes2016;PresentedatADA,NewOrleansRCT到真实世界研究验证德谷胰岛素低血糖风险降低Estimatedrateratio[95%CI]RCTsPhase3a1总体确证的低血糖0.83[0.74;0.94]夜间确证的低血糖0.68[0.57;0.82]严重低血糖0.81[0.42;1.56]SWITCH22总体症状性低血糖0.77[0.70;0.85]夜间症状性低血糖0.75[0.64;0.89]严重低血糖0.49[0.26;0.94]DEVOTE3夜间严重低血糖0.47[0.31;0.73]严重低血糖0.60[0.48;0.76]真实世界研究EU-TREAT4总体低血糖0.39[0.27;0.58]非严重夜间低血糖0.10[0.06;0.16]严重低血糖0.08[0.01;0.43]德谷胰岛素更优甘精胰岛素更优具有统计学差异，数据来自全部治疗期/6个月(EU-TREAT)RCT,randomisedcontrolledtrial1.Ratneretal.DiabetesObesMetab2013;15:175–84;2.Wyshametal.JAMA2017;318:45–56;3.Marsoetal.NEnglJMed2017;377:723–32;4.SiegmundT,etal.DiabetesObesMetab.2018Mar;20(3)689-697总结低血糖症状多样呈年龄特异性和个体异质性低血糖发生率高于预期，与众多不良临床结局相关需关注低血糖的风险因素，采取措施减少低血糖多项研究验证德谷胰岛素与甘精胰岛素相比，显著减少低血糖风险THANKS！BurdenofhypoRevisedD3_19Oct2018年ADA指南最新发布的低血糖的定义，血糖水平≤3.9mmol/L作为低血糖警戒值，需要速效碳水化合物治疗，并调整降糖治疗剂量血糖水平<3.0mmol/L，是具有重要临床意义的低血糖，需要在临床试验中评估。严重低血糖无具体的血糖切点，与严重认知功能障碍相关的低血糖症，需要他人帮助在不同的血糖阈值，机体会有相应的生理应答Thisthree-factormodel,referredtoasthe‘EdinburghHypoglycaemiaScale’,incorporatesthe11mostcommonlyreportedsymptomsofhypoglycaemia.McAulay,V.DiabetMed2001;18:690–705低血糖的症状还有年龄特性，在不同的年龄表现各异。在儿童除了上述的症状外，会表现为行为改变，而老年人会表现神经性的改变。低血糖症状随病程延长也会改变，早在1991年就有研究显示，T1DM患者的低血糖症状随时间而变化，长病程（≥40年）患者中低血糖最常见提示症状（出汗、发抖）仅有25%，而相对短病程（<10年）患者的出现比例为70%。另外也有研究显示，随着病程延长，自主神经评分减少，但是神经低血糖持续存在且显著。。Southeast(SE)Asia:IndiaandMalaysia)ZINMANPatientsrecruitedtotrial(n=267)wereinsulintreated.AbstractAimsToascertainthefrequencyandidentifypredictorsofself-reportedhypoglycaemiainType1andinsulin-treatedType2diabetes.MethodsArandomsampleof267peoplewithinsulin-treateddiabeteswererecruitedfromapopulation-baseddiabetesregisterinTayside,Scotland.Eachsubjectprospectivelyrecordedthenumberofmildandseverehypoglycaemicepisodesexperiencedovera1-monthperiod.Ordinallogisticregressionwasperformedtoidentifypotentialpredictorsofhypoglycaemia.Participatingpatientswereinstructedontheuseofadiarytorecordhypoglycaemicevents,whichincludedthedate,time,circumstancesandcontemporaneousbloodglucose(patientswereencouragedtousetheirownglucosemetertotaketheirrecording),togetherwiththenatureoftheremedialactiontakenandwhethertheepisoderequiredassistanceofathirdparty(i.e.severehypoglycaemia)foreachepisodeofsymptomatichypoglycaemia.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.MajorhypoglycemiaoccursmorefrequentlyduringsleepKeymessage:InDCCT,moremajorepisodesofhypoglycaemiaoccurredduringsleepinpatientswithT1DM—43%ofallepisodesoccurredbetweenmidnightand08:00,and26%between4-8AMTheDiabetesControlandComplicationsTrial(DCCT)wasamulticentre,randomisedclinicaltrial,whichcomparedintensivevs.conventionaltherapywithregardtoeffectsondevelopmentandprogressionofearlyvascularandneurologiccomplications.ParticipantsenrolledinDCCT(N=1441;aged13–39years)hadT1DM.After6.5yearsmeanfollow-up,DCCTwasterminatedduetothebenefitsofintensivetherapy.Majorhypoglycaemiawasdefinedasbloodglucose<2.8mmol/Lrequiringthird-partyassistance.1,2Inthistrial,216participantswithT1DMreported714episodesofmajorhypoglycemia,themajorityofwhichoccurredduringsleep(55%),and43%ofallepisodesoccurredbetweenmidnightand08:00.2ReferencesDCCTResearchGroup.Theeffectofintensivetreatmentofdiabetesonthedevelopmentandprogressionoflong-termcomplicationsininsulin-dependentdiabetesmellitus.TheDiabetesControlandComplicationsTrialResearchGroup.NEnglJMed1993;329(14):977–86.DCCTResearchGroup.Epidemiologyofmajorhypoglycemiainthediabetescontrolandcomplicationstrial.AmJMed1991;90(4):450–9.低血糖对机体的危害包括短期危害，急性症状、情绪改变、认知损害、工作表现下降、驾驶水平下降、扰乱日常活动已经导致死亡等急性事件，另外包括对于机体各器官的影响。低血糖的长期危害也众多。Theconsequencesofhypoglycemiaarecomplexandvaried,includingcognitivedysfunction,cardiaccomplications,fallsandinflammation.Frierabstract:Hypoglycaemiaisafrequentadverseeffectoftreatmentofdiabetesmellituswithinsulinandsulphonylureas.Fearofhypoglycaemiaaltersself-managementofdiabetesmellitusandpreventsoptimalglycaemiccontrol.Mild(self-treated)andsevere(requiringhelp)hypoglycaemiaepisodesaremorecommonin1型糖尿病mellitusbutpeoplewithinsulin-treated2型糖尿病mellitusarealsoexposedtofrequenthypoglycaemicevents,manyofwhichoccurduringsleep.Hypoglycaemiacandisruptmanyeverydayactivitiessuchasdriving,workperformanceandleisurepursuits.Inadditiontoaccidentsandphysicalinjury,themorbidityofhypoglycaemiainvolvesthecardiovascularandcentralnervoussystems.Whereascomaandseizuresarewell-recognizedneurologicalsequelaeofhypoglycaemia,muchinterestiscurrentlyfocusedonthepotentialforhypoglycaemiatocausedangerousandlife-threateningcardiaccomplications,suchasarrhythmiasandmyocardialischaemia,andwhetherrecurrentseverehypoglycaemiacancausepermanentcognitiveimpairmentorpromotecognitivedeclineandacceleratetheonsetofdementiainmiddle-agedandelderlypeoplewithdiabetesmellitus.Preventionofhypoglycaemiaisanimportantpartofdiabetesmellitusmanagementandstrategiesincludepatienteducation,glucosemonitoring,appropriateadjustmentofdietandmedicationsinrelationtoeverydaycircumstancesincludingphysicalexercise,andtheapplicationofnewtechnologiessuchasreal-timecontinuousglucosemonitoring,modifiedinsulinpumpsandtheartificialpancreasACCORD:ActiontoControlCardiovascularRiskinDiabetes10251participantsenrolled.Meandurationoffollow-upatthetimetheintensiveinterventionwasstoppedwas3.5yearsduetoincreasedmortalityintheintensivearm.Symptomatic,severehypoglycaemiawasassociatedwithanincreasedriskofdeathwithineachstudyarm.However,amongparticipantswhoexperiencedatleastoneepisodeofhypoglycaemia,theriskofdeathwaslowerinsuchparticipantsintheintensivearmthaninthestandardarm.Theunderlyingcauseoftheincreasedmortalityintheintensivearmwasunclearatthetimethattheinterventionwasstopped,althoughseveralhypotheseswereproposed,includingseverehypoglycaemia.Althoughhypoglycaemiacannotbeexcludedasapossiblecontributortodeathinsomeofthefatalcases,theincreasedrelativeriskofmortalityobservedintheintensivetreatmentgroupintheACCORDtrialcannotbeexplainedbyseverehypoglycaemiaasitwasmeasuredinthestudy.Susceptibilitytoseverehypoglycaemiamaybeamarkerforanunderlyingdisorderthatincreasestheriskfordeathinpatientswithdiabetes,evenwhenglycaemiaiscontrolledaccordingtocurrentguidelines.Severehypoglycemicevents(<2.8mmol/l(50mg/dl)orrecoverywithcarbohydratetreatment)weredividedintotwogroups:-Symptomatic,severehypoglycaemiceventrequiringmedicalassistance:episodeofseverehypoglycemiainwhichtheyhadreceivedcareatahospital,atanemergencyroom,orfrommedicalpersonnel.-Symptomatic,severehypoglycaemiceventrequiringanyassistance:episodeofsymptomatic,severehypoglycaemiainwhichtheparticipantreportedreceivingeithermedicalcareorassistancefromanotherindividual.Thehazardratiorepresentstheriskofanadverseclinicaloutcomeordeathamongpatientsreportingseverehypoglycemiaascomparedwiththosenotreportingseverehypoglycemia.Thecentersofthesquaresareplacedatthepointestimates,andthehorizontallinesrepresentthecorresponding95%confidenceintervals.Theestimateswereadjustedforthebaselinecovariatesofage,sex,treatmentassignment,durationofdiabetes,presenceorabsenceofahistoryofmacrovasculardisease,presenceorabsenceofahistoryofmicrovasculardisease,andsmokingstatusandforthetime-dependentcovariatesoftheuseofdiabetestreatment,useofantihypertensivetherapy;glycatedhemoglobin;body-massindex;creatininelevel;ratioofurinaryalbumintocreatinine;andsystolicbloodpressure.Inconclusion,ourstudyshowsthatseverehypoglycemiaisstronglyassociatedwithincreasedrisksofabroadrangeofadverseclinicaloutcomesinpatientswithlong-standingtype2diabetes,includingvasculareventsanddeath.Neitheraclosetemporalrelationshipnoradose–responserelationshipwasobserved.Althoughourfindingscannotexcludethepossibilitythatseverehypoglycemiahasadirectcausallinkwiththeseoutcomes,theysuggestthatitisaslikelytobeamarkerofvulnerabilitytoawiderangeofadverseclinicaloutcomes.Ineithercase,thepresenceofseverehypoglycemiashouldraiseclinicalsuspicionofthepatient’ssusceptibilitytoadverseoutcomesandpromptactiontoaddressthispossibility.TheEXAMINEtrialrandomized5380patientswithtype2diabetes(T2DM)andarecentacutecoronarysyndrome(ACS)event,in49countries,todouble-blindtreatmentwithalogliptinorplaceboinadditiontostandardofcare.Adjustingforbaselinecovariatesandstudytreatment,therewasasignificantassociationofMACEwithpatientswhohadanepisodeofserioushypoglycaemia(12/34[35.3%])vsthosewhodidnot(609/5346[11.4%];adjustedHR2.42,95%CI1.27-4.60;P=.007[Figure4A]).AnassociationwithMACEwasalsofoundforpatientswithanyhypoglycaemia(64/354[18.1%])vsthosewithout(557/5026[11.1%];adjustedHR1.38,95%CI1.05-1.80;P=.019).LEADER研究证实严重低血糖与MACE、全因死亡相关，且均具有时间相关性，即短期内发生过严重低血糖的患者，发生全因死亡或MACE的风险更高。IntheLEADERcardiovascular(CV)outcomestrial(N=9340;NCT01179048),theriskofCVandhypoglycemiaeventswasreducedwithliraglutidetreatmentvs.placebo,whenaddedtostandardofcare,inpatientswithtype2diabetesandhighriskforCVevents.Thispost-hocanalysisexaminesthepotentialassociationsbetweenseverehypoglycemiaandtimetofirstMACE(CVdeath,non-fatalmyocardialinfarctionornon-fatalstroke),CVdeathandall-causedeath;comparingpatientswith/withoutseverehypoglycemia,andadjustedfordifferentperiodsoffollow-upandrandomizedtreatment.Duringthetrial,267patientsexperiencedseverehypoglycemia(liraglutiden=114,placebon=153;rateratio,0.69;95%CI:0.51;0.93).ThesepatientsweremorelikelythanthosewithoutseverehypoglycemiatoexperienceMACE,CVdeathandall-causedeath,withaconsiderablyhigherriskupto60daysafterthehypoglycemicepisode(Table),irrespectiveoftreatmentgroup.TheprotectiveeffectofliraglutideonriskofMACEwasunchangedwhenpatientswithseverehypoglycemiawereexcludedfromtheanalysis(patientswithseverehypoglycemiaaccountedfor5%ofallMACEinthetrial).Inconclusion,patientsexperiencingseverehypoglycemiawereatgreaterriskofCVeventsanddeath,particularlyearlyafterthehypoglycemicepisode.Reducingseverehypoglycemiaremainsacornerstoneofdiabetesmanagement.严重低血糖与全因死亡、及MACE组份之一的心血管死亡相关“AMEDLINEsearch(1946–2012)wasconductedinOctober2012bycombiningthefollowingsubjectterms:diabetesmellitus,diabetesmellitustype1,diabetesmellitustype2,automobiledriving,trafficaccidents,automobiles,whiplashinjuries,motorvehiclesandautomobiledriverexamination.Limitsof‘human’and‘Englishlanguage’wereimposed,andthecitationswerethenconsideredforrelevance.Papersfromtheauthors''personalfileswereincluded,andlistsofpublishedreferenceswerecheckedtoidentifyanyotherrelevantmaterial.”Inkster,BandFrier,BM.DiabetesObesMetab2013;15(9):775–783另外低血糖的还影响患者及医务人员对于糖尿病管理，患者由于低血糖事件减少胰岛素剂量，医务人员如果没有对低血糖的担心，会更积极地治疗患者。低血糖也带来了巨大的经济负担。基于8655名糖尿病患者，发生244次需要医护人员帮助的事件，91%的事件需要救护车，63%需要急诊，21%需要住院治疗。来自美国的数据显示，一次严重低血糖事件，导致患者直接住院的费用预计为7317美元。这是一项为期2×32周的两阶段、随机对照、双盲、交叉的治疗达标研究，721名低血糖高风险的T2DM患者，1:1随机分配到IDeg或IGlar组，并联合入组前的OAD，其中IDeg或IGlar使用瓶装胰岛素和注射器以保持双盲。研究的主要终点为在剂量维持期（治疗期的后16周），严重低血糖或血糖证实的症状性低血糖事件（总体证实的症状性低血糖事件）发生率。其中血糖证实的症状性低血糖事件定义为血糖低于3.1mmmol/L且具有低血糖症状，夜间低血糖为发生在0.01-5.59期间的低血糖事件，严重低血糖与ADA标准一致，为需要第三方协助的低血糖事件。结果显示，德谷胰岛素相较于甘精胰岛素，A1C控制相似，严重低血糖，总体症状性低血糖和夜间症状性低血糖均降低，AbstractWyshametal.JAMA2017;318:45–56Importance:Hypoglycemia,aseriousriskforinsulin-treatedpatientswithtype2diabetes,negativelyaffectsglycemiccontrol.Objective:TotestwhethertreatmentwithbasalinsulindegludecisassociatedwithalowerrateofhypoglycemiacomparedwithinsulinglargineU100inpatientswithtype2diabetes.Design,Setting,andParticipants:Randomized,double-blind,treat-to-targetcrossovertrialincludingtwo32-weektreatmentperiods,eachwitha16-weektitrationperiodanda16-weekmaintenanceperiod.Thetrialwasconductedat152UScentersbetweenJanuary2014andDecember2015in721adultswithtype2diabetesandatleast1hypoglycemiariskfactorwhowerepreviouslytreatedwithbasalinsulinwithorwithoutoralantidiabeticdrugs.Interventions:Patientswererandomized1:1toreceiveonce-dailyinsulindegludecfollowedbyinsulinglargineU100(n?=?361)ortoreceiveinsulinglargineU100followedbyinsulindegludec(n?=?360)andrandomized1:1tomorningoreveningdosingwithineachtreatmentsequence.MainOutcomesandMeasures:Theprimaryendpointwastherateofoverallsymptomatichypoglycemicepisodes(severeorbloodglucoseconfirmed[<56mg/dL])duringthemaintenanceperiod.Secondaryendpointsweretherateofnocturnalsymptomatichypoglycemicepisodes(severeorbloodglucoseconfirmed,occurringbetween12:01amand5:59am)andtheproportionofpatientswithseverehypoglycemiaduringthemaintenanceperiod.Results:Ofthe721patientsrandomized(mean[SD]age,61.4[10.5]years;53.1%male),580(80.4%)completedthetrial.Duringthemaintenanceperiod,theratesofoverallsymptomatichypoglycemiaforinsulindegludecvsinsulinglargineU100were185.6vs265.4episodesper100patient-yearsofexposure(PYE)(rateratio?=?0.70[95%CI,0.61-0.80];P?
Chart1
f_mean_hba1c_pct_p2_fas
TRTPN
TRTP
PLNDTRWN
_MEAN
_STDERR
N_SUBJ
ERROR_UPPER
ERROR_LOWER
ORD
IDeg
IGlar
TOPIC_CD
HBA1C_BLOOD
1.00
.00
6.98
313.00
7.04
6.92
.00
1.00
12.00
7.04
.06
301.00
7.10
6.97
12.00
1.00
16.00
7.05
.07
301.00
7.12
6.98
16.00
1.00
20.00
7.07
.07
299.00
7.14
7.01
20.00
1.00
24.00
7.09
.07
298.00
7.15
7.02
24.00
1.00
28.00
7.11
.07
296.00
7.18
7.04
28.00
1.00
32.00
7.08
.07
303.00
7.15
7.01
32.00
2.00
.00
7.06
308.00
7.12
7.00
.00
2.00
12.00
7.04
.06
287.00
7.10
6.98
12.00
2.00
16.00
7.02
.06
287.00
7.09
6.96
16.00
2.00
20.00
7.01
.06
280.00
7.08
6.95
20.00
2.00
24.00
7.12
.07
279.00
7.19
7.05
24.00
2.00
28.00
7.09
.07
280.00
7.16
7.03
28.00
2.00
32.00
7.11
.07
295.00
7.17
7.04
32.00
IDeg
IGlar
HbA1c(%)
IDeg
IGlar
.00
.00
12.00
12.00
16.00
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32.00
32.00
6.98
7.06
1.#R
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7.04
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f_sev_main_mcf_sas
Chart1
f_sev_main_mcf_sas
EVENT_WEEKS
IDEG
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SEQ
X_AXIS_WEEKS
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.43
1.62E-03
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3.24E-03
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17.43
1.71
4.87E-03
4.87E-03
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17.71
2.71
6.51E-03
5.00
18.71
2.86
8.14E-03
6.00
18.86
3.14
1.60E-03
7.00
19.14
3.57
3.20E-03
3.20E-03
8.00
19.57
4.86
9.78E-03
9.78E-03
9.00
20.86
5.71
4.81E-03
4.81E-03
10.00
21.71
5.86
.01
.01
11.00
21.86
6.57
6.41E-03
12.00
22.57
6.71
.01
13.00
22.71
7.14
8.02E-03
14.00
23.14
7.57
9.63E-03
9.63E-03
15.00
23.57
7.86
.02
.02
16.00
23.86
8.29
.02
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24.29
8.43
.02
18.00
24.43
10.00
.02
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19.00
26.00
10.57
.02
20.00
26.57
11.29
.01
.01
21.00
27.29
12.00
.03
.03
22.00
28.00
12.86
.01
23.00
28.86
13.86
.03
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24.00
29.86
15.14
.01
25.00
31.14
16.00
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32.00
IDEG
IGLAR
Severehypoglycemia
(cumulativeeventsperpatient)
IDEG
IGLAR
16.00
16.00
16.43
16.43
17.43
17.43
17.71
17.71
18.71
18.71
18.86
18.86
19.14
19.14
19.57
19.57
20.86
20.86
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22.57
22.57
22.71
22.71
23.14
23.14
23.57
23.57
23.86
23.86
24.29
24.29
24.43
24.43
26.00
26.00
26.57
26.57
27.29
27.29
28.00
28.00
28.86
28.86
29.86
29.86
31.14
31.14
32.00
32.00
.00
.00
1.62E-03
3.24E-03
4.87E-03
6.51E-03
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1.60E-03
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4.81E-03
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f_hypo_main_mcf_sas
Chart1
f_hypo_main_mcf_sas
EVENT_WEEKS
IDEG
IDEG_
IGLAR
IGLAR_
SEQ
X_AXIS_WEEKS
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1.14
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.09
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17.29
1.43
.07
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11.00
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1.57
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.10
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1.71
.07
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1.86
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9.71
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10.86
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11.71
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27.71
11.86
.42
.57
84.00
27.86
12.00
.42
.42
.58
.58
85.00
28.00
12.14
.43
.59
86.00
28.14
12.29
.43
.60
87.00
28.29
12.43
.44
.60
88.00
28.43
12.57
.44
.60
89.00
28.57
12.71
.45
.60
90.00
28.71
12.86
.46
.62
91.00
28.86
13.00
.47
.63
92.00
29.00
13.14
.48
.64
93.00
29.14
13.29
.64
94.00
29.29
13.43
.48
.65
95.00
29.43
13.57
.48
.66
96.00
29.57
13.71
.49
.67
97.00
29.71
13.86
.49
.68
98.00
29.86
14.00
.50
.50
.69
.69
99.00
30.00
14.14
.50
.70
100.00
30.14
14.29
.50
.70
101.00
30.29
14.43
.50
.71
102.00
30.43
14.57
.51
.72
103.00
30.57
14.71
.52
.72
104.00
30.71
14.86
.52
.73
105.00
30.86
15.00
.52
.74
106.00
31.00
15.14
.52
.75
107.00
31.14
15.29
.53
.76
108.00
31.29
15.43
.53
.77
109.00
31.43
15.57
.54
.77
110.00
31.57
15.71
.55
.79
111.00
31.71
15.86
.56
.81
112.00
31.86
16.00
.56
.56
.82
.82
113.00
32.00
IDEG
IGLAR
SevereorBGconfirmed
symptomatichypoglycemia
(cumulativeeventsperpatient)
IDEG
IGLAR
16.00
16.00
16.14
16.14
16.29
16.29
16.43
16.43
16.57
16.57
16.71
16.71
16.86
16.86
17.00
17.00
17.14
17.14
17.29
17.29
17.43
17.43
17.57
17.57
17.71
17.71
17.86
17.86
18.00
18.00
18.14
18.14
18.29
18.29
18.43
18.43
18.57
18.57
18.71
18.71
18.86
18.86
19.00
19.00
19.14
19.14
19.29
19.29
19.43
19.43
19.57
19.57
19.71
19.71
19.86
19.86
20.00
20.00
20.14
20.14
20.29
20.29
20.43
20.43
20.57
20.57
20.71
20.71
20.86
20.86
21.00
21.00
21.14
21.14
21.29
21.29
21.43
21.43
21.57
21.57
21.71
21.71
21.86
21.86
22.00
22.00
22.14
22.14
22.29
22.29
22.43
22.43
22.57
22.57
22.71
22.71
22.86
22.86
23.00
23.00
23.14
23.14
23.29
23.29
23.43
23.43
23.57
23.57
23.71
23.71
23.86
23.86
24.00
24.00
24.14
24.14
24.29
24.29
24.43
24.43
24.57
24.57
24.71
24.71
24.86
24.86
25.00
25.00
25.14
25.14
25.29
25.29
25.43
25.43
25.57
25.57
25.71
25.71
25.86
25.86
26.00
26.00
26.14
26.14
26.29
26.29
26.43
26.43
26.57
26.57
26.71
26.71
26.86
26.86
27.00
27.00
27.14
27.14
27.29
27.29
27.43
27.43
27.57
27.57
27.71
27.71
27.86
27.86
28.00
28.00
28.14
28.14
28.29
28.29
28.43
28.43
28.57
28.57
28.71
28.71
28.86
28.86
29.00
29.00
29.14
29.14
29.29
29.29
29.43
29.43
29.57
29.57
29.71
29.71
29.86
29.86
30.00
30.00
30.14
30.14
30.29
30.29
30.43
30.43
30.57
30.57
30.71
30.71
30.86
30.86
31.00
31.00
31.14
31.14
31.29
31.29
31.43
31.43
31.57
31.57
31.71
31.71
31.86
31.86
32.00
32.00
.00
.00
.01
.01
.03
.02
.03
.03
.04
.04
.04
.06
.04
.06
.05
.08
.06
.08
.06
.09
.07
.09
.07
.10
.07
.11
.08
.12
.08
.13
.09
.13
.10
.10
.14
.10
.14
.11
.15
.11
.16
.11
.17
.12
.17
.12
.18
.13
.19
.13
.19
.14
.20
.14
.21
.14
.22
.15
.22
.15
.22
.16
.23
.16
.23
.17
.24
.17
.25
.18
.25
.18
.25
.26
.19
.19
.26
.19
.27
.20
.29
.21
.29
.21
.30
.21
.22
.30
.22
.30
.23
.31
.23
.32
.24
.32
.24
.33
.25
.33
.25
.34
.25
.35
.26
.35
.26
.36
.27
.37
.28
.38
.28
.38
.28
.39
.29
.39
.30
.41
.31
.42
.33
.43
.33
.44
.33
.44
.33
.45
.34
.45
.34
.45
.35
.47
.35
.48
.36
.48
.36
.48
.37
.49
.37
.50
.38
.51
.38
.52
.39
.53
.40
.54
.40
.55
.40
.55
.41
.55
.41
.56
.42
.57
.42
.58
.43
.59
.43
.60
.44
.60
.44
.60
.45
.60
.46
.62
.47
.63
.48
.64
.64
.48
.65
.48
.66
.49
.67
.49
.68
.50
.69
.50
.70
.50
.70
.50
.71
.51
.72
.52
.72
.52
.73
.52
.74
.52
.75
.53
.76
.53
.77
.54
.77
.55
.79
.56
.81
.56
.82
f_mean_hba1c_pct_p1_fas
Chart1
f_mean_hba1c_pct_p1_fas
ERROR_UPPER
ERROR_LOWER
ORD
IDeg
HBA1C_BLOOD
IGlar
TRTPN
TRTP
TOPIC_CD
PLNDTRWN
_MEAN
_STDERR
N_SUBJ
1.00
.00
7.60
.06
360.00
7.66
7.54
.00
1.00
8.00
7.21
.06
332.00
7.26
7.15
8.00
1.00
12.00
7.14
.06
326.00
7.20
7.08
12.00
1.00
16.00
7.07
.06
321.00
7.13
7.01
16.00
1.00
20.00
7.09
.06
320.00
7.15
7.02
20.00
1.00
24.00
7.09
.06
316.00
7.16
7.03
24.00
1.00
28.00
7.12
.07
309.00
7.18
7.05
28.00
1.00
32.00
7.06
.06
308.00
7.12
7.00
32.00
2.00
.00
7.57
.06
360.00
7.63
7.51
.00
2.00
8.00
7.24
.06
334.00
7.30
7.18
8.00
2.00
12.00
7.09
.06
329.00
7.15
7.03
12.00
2.00
16.00
6.97
.06
322.00
7.02
6.91
16.00
2.00
20.00
6.99
.06
321.00
7.05
6.93
20.00
2.00
24.00
6.99
.06
318.00
7.05
6.93
24.00
2.00
28.00
7.02
.06
316.00
7.08
6.96
28.00
2.00
32.00
6.98
.06
313.00
7.04
6.92
32.00
IDeg
IGlar
HbA1c(%)
IDeg
IGlar
.00
.00
8.00
8.00
12.00
12.00
16.00
16.00
20.00
20.00
24.00
24.00
28.00
28.00
32.00
32.00
7.60
7.57
.06
.06
.06
.06
7.21
7.24
.06
.06
.06
.06
7.14
7.09
.06
.06
.06
.06
7.07
6.97
.06
.06
.06
.06
7.09
6.99
.06
.06
.06
.06
7.09
6.99
.06
.06
.06
.06
7.12
7.02
.07
.07
.06
.06
7.06
6.98
.06
.06
.06
.06
f_nhypo_main_mcf_sas
Chart1
f_nhypo_main_mcf_sas
EVENT_WEEKS
IDEG
IDEG_
IGLAR
IGLAR_
SEQ
X_AXIS_WEEKS
.00
.00
.00
.00
.00
1.00
16.00
.14
1.62E-03
2.00
16.14
.29
4.75E-03
3.24E-03
3.00
16.29
.43
7.92E-03
4.85E-03
4.00
16.43
.57
.01
8.10E-03
5.00
16.57
.71
.01
6.00
16.71
.86
.02
7.00
16.86
1.00
.01
.02
8.00
17.00
1.14
.02
9.00
17.14
1.29
.02
10.00
17.29
1.43
.02
.02
11.00
17.43
1.57
.03
12.00
17.57
1.71
.03
13.00
17.71
1.86
.02
.02
14.00
17.86
2.14
.03
.03
15.00
18.14
2.57
.03
16.00
18.57
2.71
.04
17.00
18.71
2.86
.04
18.00
18.86
3.00
.04
19.00
19.00
3.14
.02
20.00
19.14
3.29
.03
.04
21.00
19.29
3.43
.03
.05
22.00
19.43
3.57
.05
23.00
19.57
3.86
.06
24.00
19.86
4.00
.03
.03
.06
.06
25.00
20.00
4.14
.03
26.00
20.14
4.29
.06
27.00
20.29
4.43
.04
28.00
20.43
4.71
.04
.07
29.00
20.71
4.86
.04
.07
30.00
20.86
5.00
.04
.07
31.00
21.00
5.29
.08
32.00
21.29
5.43
.04
33.00
21.43
5.71
.05
.08
34.00
21.71
5.86
.05
.09
35.00
21.86
6.00
.05
.05
.09
.09
36.00
22.00
6.14
.05
.09
37.00
22.14
6.43
.10
38.00
22.43
6.57
.10
39.00
22.57
6.71
.10
40.00
22.71
6.86
.05
.11
41.00
22.86
7.00
.06
.11
42.00
23.00
7.29
.11
43.00
23.29
7.43
.11
44.00
23.43
7.57
.06
.12
45.00
23.57
7.71
.07
46.00
23.71
7.86
.07
.12
47.00
23.86
8.00
.07
.07
48.00
24.00
8.14
.12
.12
49.00
24.14
8.29
.07
.12
50.00
24.29
8.43
.08
.13
51.00
24.43
8.57
.08
.13
52.00
24.57
8.71
.08
.14
53.00
24.71
8.86
.08
.14
54.00
24.86
9.00
.09
.15
55.00
25.00
9.14
.09
.15
56.00
25.14
9.29
.15
57.00
25.29
9.43
.09
.15
58.00
25.43
9.57
.09
.16
59.00
25.57
9.86
.16
60.00
25.86
10.00
.17
.17
61.00
26.00
10.14
.10
.10
62.00
26.14
10.43
.10
.17
63.00
26.43
10.57
.10
.18
64.00
26.57
10.71
.10
.18
65.00
26.71
10.86
.11
.18
66.00
26.86
11.00
.18
67.00
27.00
11.14
.18
68.00
27.14
11.29
.11
.19
69.00
27.29
11.43
.11
70.00
27.43
11.57
.11
.19
71.00
27.57
11.71
.12
.20
72.00
27.71
11.86
.12
.12
.20
73.00
27.86
12.00
.20
.20
74.00
28.00
12.14
.12
.21
75.00
28.14
12.29
.12
.21
76.00
28.29
12.57
.13
77.00
28.57
12.71
.13
78.00
28.71
12.86
.13
.21
79.00
28.86
13.00
.14
.22
80.00
29.00
13.14
.14
.22
81.00
29.14
13.29
.22
82.00
29.29
13.43
.22
83.00
29.43
13.57
.23
84.00
29.57
13.71
.23
85.00
29.71
13.86
.23
86.00
29.86
14.00
.14
.14
.24
.24
87.00
30.00
14.14
.24
88.00
30.14
14.29
.24
89.00
30.29
14.43
.24
90.00
30.43
14.57
.14
.25
91.00
30.57
14.71
.15
.25
92.00
30.71
14.86
.26
93.00
30.86
15.00
.15
.26
94.00
31.00
15.14
.15
.26
95.00
31.14
15.29
.27
96.00
31.29
15.43
.15
.27
97.00
31.43
15.57
.15
.27
98.00
31.57
15.71
.16
.28
99.00
31.71
15.86
.16
.28
100.00
31.86
16.00
.17
.17
.29
.29
101.00
32.00
IDEG
IGLAR
NocturnalsevereorBGconfirmed
symptomatichypoglycemia
(cumulativeeventsperpatient)
IDEG
IGLAR
16.00
16.00
16.14
16.14
16.29
16.29
16.43
16.43
16.57
16.57
16.71
16.71
16.86
16.86
17.00
17.00
17.14
17.14
17.29
17.29
17.43
17.43
17.57
17.57
17.71
17.71
17.86
17.86
18.14
18.14
18.57
18.57
18.71
18.71
18.86
18.86
19.00
19.00
19.14
19.14
19.29
19.29
19.43
19.43
19.57
19.57
19.86
19.86
20.00
20.00
20.14
20.14
20.29
20.29
20.43
20.43
20.71
20.71
20.86
20.86
21.00
21.00
21.29
21.29
21.43
21.43
21.71
21.71
21.86
21.86
22.00
22.00
22.14
22.14
22.43
22.43
22.57
22.57
22.71
22.71
22.86
22.86
23.00
23.00
23.29
23.29
23.43
23.43
23.57
23.57
23.71
23.71
23.86
23.86
24.00
24.00
24.14
24.14
24.29
24.29
24.43
24.43
24.57
24.57
24.71
24.71
24.86
24.86
25.00
25.00
25.14
25.14
25.29
25.29
25.43
25.43
25.57
25.57
25.86
25.86
26.00
26.00
26.14
26.14
26.43
26.43
26.57
26.57
26.71
26.71
26.86
26.86
27.00
27.00
27.14
27.14
27.29
27.29
27.43
27.43
27.57
27.57
27.71
27.71
27.86
27.86
28.00
28.00
28.14
28.14
28.29
28.29
28.57
28.57
28.71
28.71
28.86
28.86
29.00
29.00
29.14
29.14
29.29
29.29
29.43
29.43
29.57
29.57
29.71
29.71
29.86
29.86
30.00
30.00
30.14
30.14
30.29
30.29
30.43
30.43
30.57
30.57
30.71
30.71
30.86
30.86
31.00
31.00
31.14
31.14
31.29
31.29
31.43
31.43
31.57
31.57
31.71
31.71
31.86
31.86
32.00
32.00
.00
.00
1.62E-03
4.75E-03
3.24E-03
7.92E-03
4.85E-03
.01
8.10E-03
.01
.02
.01
.02
.02
.02
.02
.02
.03
.03
.02
.03
.03
.04
.04
.04
.02
.03
.04
.03
.05
.05
.06
.03
.06
.03
.06
.04
.04
.07
.04
.07
.04
.07
.08
.04
.05
.08
.05
.09
.05
.09
.05
.09
.10
.10
.10
.05
.11
.06
.11
.11
.11
.06
.12
.07
.07
.12
.07
.12
.07
.12
.08
.13
.08
.13
.08
.14
.08
.14
.09
.15
.09
.15
.15
.09
.15
.09
.16
.16
.17
.10
.10
.17
.10
.18
.10
.18
.11
.18
.18
.18
.11
.19
.11
.11
.19
.12
.20
.12
.20
.20
.12
.21
.12
.21
.13
.13
.13
.21
.14
.22
.14
.22
.22
.22
.23
.23
.23
.14
.24
.24
.24
.24
.14
.25
.15
.25
.26
.15
.26
.15
.26
.27
.15
.27
.15
.27
.16
.28
.16
.28
.17
.29
Sheet1
Chart1
X-Values
Y-Values
Column1
1.00
.00
1.00
7.00
.00
7.00
.00
7.00
.00
7.00
1.55
6.00
1.22
6.00
1.96
6.00
1.51
5.00
1.26
5.00
1.81
5.00
2.82
4.00
1.82
4.00
4.36
4.00
1.47
3.00
1.18
3.00
1.84
3.00
1.49
2.00
1.24
2.00
1.78
2.00
2.06
1.00
1.08
1.00
3.93
1.00
Y-Values
Column1
1.00
1.00
1.00
1.00
.00
.00
.00
.00
.00
.00
1.55
1.55
1.22
1.22
1.96
1.96
1.51
1.51
1.26
1.26
1.81
1.81
2.82
2.82
1.82
1.82
4.36
4.36
1.47
1.47
1.18
1.18
1.84
1.84
1.49
1.49
1.24
1.24
1.78
1.78
2.06
2.06
1.08
1.08
3.93
3.93
.00
7.00
7.00
7.00
7.00
6.00
6.00
6.00
5.00
5.00
5.00
4.00
4.00
4.00
3.00
3.00
3.00
2.00
2.00
2.00
1.00
1.00
1.00
|
|
