T.Heise,etal.Diabetes2004(Study1450)Inordertoillustrate
whattheobservedvariability(incombinationwiththemeantrea
tmenteffect)meansforanindividualpatientwecalculatedapre
dictionintervalcontaining95%ofthepredictedvaluesforanav
eragepatient.Thelowerandupperlimitofthispredictioninter
valwerecalculatedforeachinsulinpreparationbysubtractinga
ndaddingtheobservedstandarddeviationmultipliedby1.96.In
thetopbarofthetablethecalculationisdoneforthesameen
dpoint,themeanareaunderthetime-actionprofilesover24h.I
nthebottombarofthetablethecalcuationisdonefortheanot
herendpoint,thevarianceofMaxGIR.Thepredictedclinicalco
nsequencesofthesecalculationsareillustratedhere:Forexamp
le,observeddifferencesinvariabilitycanbeillustratedbycon
sideringapatientinwhichanaverageglucose-loweringeffectov
er24hoursof1mg/(kg/min)wasinducedbyapplicationofagive
nlong-actinginsulinpreparation.Inthispatient,theprobabili
tyofexperiencinganaverageeffectoflessthanhalftheusual
effect(i.e.,<0.5mg/(kg/min)),whichcanresultintheclinical
consequenceofhyperglycaemiais0.5%ifthesubjectusesinsuli
ndetemir,above7%withinsulinglargine,andabove15%withNPH
insulin.AndinnearlyeverycasewherethevariabilityofFBG
hasbeenmeasuredintermsofSD,therehasbeenasignificant
advantageforIDet.Intheonestudywheretherewasnosignific
antdifferenceinthisparameter,therewasasignificantdiffere
nceinpre-dinnerBGvariability.Thisstudywasatypicalasite
mployedatreat-to-targetprotocoladdingIDetorNPHasaninsul
insupplementtoOADsinpoorlycontrolledtype2diabetes.Iti
snoteworthythatvariabilityisinanycaseconsistentlyloweri
nthetype2diabetestrials.Speculatively,thismightreflectt
heabilityofendogenousinsulinsecretiontobufferthevariable
BGloweringactionofexogenousinsulin.不同基础胰岛素对体重的影响是不同的。一般来说
，胰岛素治疗往往在治疗的六个月和三年后引起的体重增加最多，可以达到4.8到7.8公斤，而大部分体重增加会出现在最初应用胰岛素的三个
月。和NPH胰岛素和甘精胰岛素相比，诺和平?是目前唯一具有体重优势的基础胰岛素，短期应用不增加体重，1年后体重增加较甘精胰岛素少，
且体重优势随着BMI的增加而增加的特点。SOLVETM国际研究是一项观察性研究，即在真实临床环境中观察口服药失效的
T2DM患者起始一天一次地特胰岛素治疗的安全性和有效性。在SOLVETM国际研究中由研究者根据经验来决定诺和平?剂量调整，研究
对基线、12周、24周的访视资料收集并进行分析。共纳入了来自10个国家，2817个研究中心的17374名2型糖尿病患者，其中包括
了3272例中国的患者，中国患者居全球第二。临床研究也显示地特胰岛素更加严格的血糖控制目标并没有增加低血糖风险，无论全部低
血糖还是夜间低血糖在两组之间没有统计学差异。METHODS:Inthis20-week,randomized,con
trolled,open-label,multicentre,treat-to-targetstudy,244insu
lin-na?vesubjectswithtype2diabetes,HbA(1c)>or=7.0and.0%onOADtreatment,wererandomized(1:1)tooneoftwotreat
mentarmsusing3.9-5.0or4.4-6.1mmol/lFPGastitrationtarget
s.Once-dailyinsulindetemirdoseswereadjustedusingalgorithm
-guidedpatient-directedtitrationtoachievetargetFPGvalues.
RESULTS:Overall,thecombinedtreatmentgroupsachievedamean
HbA(1c)levelof6.9%attheendofthestudy.Substantialreduct
ionsinHbA(1c)wereseeninbothtreatmentgroups,withthemajo
rityofsubjectsinbothtitrationgroupsattheendofthestudy
achievingtheAmericanDiabetesAssociation(ADA)-recommendedHb
A(1c)levelof<7%.Inthe3.9-5.0mmol/lFPGtargettreatmentgr
oup,HbA(1c)valuesdecreasedfromabaselinemeanof8.0%to6.8
%at20weeks.Inthe4.4-6.1mmol/lFPGtargetgroup,HbA(1c)va
luesdecreasedfrom7.9%atbaselineto7.0%at20weeks(Intenti
ontotreat-lastobservationcarriedforwarddataset).Thesed
ecreasesweresignificantlydifferentbetweenthetwotreatmentg
roups(Leastsquaresmeandifference=-0.271,95%CI-0.441to-
0.101,p=0.0019),favouringtheFPGtargetof3.9-5.0mmol/lvs
.the4.4-6.1mmol/ltarget.Attheendofthestudyperiod,64.3
%ofsubjectsinthe3.9-5.0mmol/ltreatmentgroupachievedHbA(
1c)levels<7%comparedwith54.5%ofsubjectsinthe4.4-6.1mmo
l/lgroup(95%CI1.03-3.37,oddsratio1.86,p=0.04).Insulin
detemirdosingpatternsweresimilarbetweentreatmentgroups,wi
ththe3.9-5.0mmol/lgroupusingslightlygreaterdosesthrougho
utthestudyperiod(0.57U/kgvs.0.51U/kgattheendofthest
udy).Overallratesofhypoglycaemiaepisodeswerelowandwerec
omparablebetweentreatmentgroups(7.73and5.27events/subject/
yearforthe3.9-5.0and4.4-6.1mmol/lgroups,respectively).A
singleeventofmajorhypoglycaemiawasreportedinthe3.9-5.0m
mol/lgroup.Meanweightchangesfrombaselinetotheendofthe
studyweresmallanddidnotdiffersignificantlybetweentreatme
ntgroups.PREDICTIVE?研究是一项大型的国际多中心观察性研究，在接受调查的受试者中，经过一段时间的诺和平?
治疗，68%的受试者体重减少或没有改变。基础胰岛素的理想选择本节内容理想的基础胰岛素所具备的特性基础胰岛素+OADs治
疗方案是空腹状态下的胰岛素分泌，不依赖于进食，血浆胰岛素浓度为5~15μU/ml主要生理作用：抑制肝糖原和糖异生的产生和释放入
血，使人体在基础非进餐状态的血糖维持在正常水平分泌量：约18~32U/24h（0.7~1.3mg）1.陈家伦主编.临床内分泌学
.上海科学技术出版社,2011年8月;1062.2.潘长玉主译.糖尿病学(第14版),北京:人民卫生出版社,2007.5:117
.4:0025507516:0020:0024:004:00胰岛素水平μU/ml8:0012:00
8:00时间基础胰岛素生理性的胰岛素分泌基础胰岛素生理性基础胰岛素分泌传统中/长效胰岛素临床应用的局限性NPH/P
ZI都是混悬液，皮下注射后药物吸收不稳定，出现血药浓度峰值，很难提供相对平稳、接近生理的基础胰岛素水平1NPH作用持续时间不足2
4小时，有明显峰值，低血糖风险较高葡萄糖输注率（mg/kg/min）Scholtz,etal.2005,0.4U/k
g;健康志愿者Plank,etal,2005,0.3U/kg;T1DMLepore,etal.2000,0
.3U/kg;T1DMHeise,etal.2004,0.4U/kg;T1DM时间（小时）1.郭晓蕙主编.中国
糖尿病患者胰岛素使用教育管理规范.天津科学技术出版社,2011年10月;29.NPH,中效人胰岛素；PZI,长效动物胰岛素理想
的基础胰岛素郭晓蕙主编.中国糖尿病患者胰岛素使用教育管理规范.天津科学技术出版社,2011年10月;29.第3代长效胰岛素类似
物更接近模拟生理性基础胰岛素分泌皮下注射后2~3h起效，药物吸收稳定，无明显血药峰值每日一次注射药效维持24h低血糖（特别是
夜间低血糖）发生率明显低于传统中/长效胰岛素1.郭晓蕙主编.中国糖尿病患者胰岛素使用教育管理规范.天津科学技术出版社,2011年
10月;29-30.2.Heiseetal.Diabetes2004;53:1614–20.0246810
12141618202224葡萄糖输注率(mg/kg/min)00.51.01.52.02.50.4
U/kg地特胰岛素NPH1型糖尿病相比NPH，地特胰岛素作用曲线更平稳第3代长效胰岛素类似物具有更少的自身变异T.
Heiseetal.Diabetes2004;53:1614-1620p<0.001forallcomparis
onsofAUCGIR(mg/kg/min)ElapsedTime(hours)NPH甘精地特N
=54T1DM68%48%27%T.Heiseetal.Diabetes2004;53:1614-1620
1小于胰岛素平均作用效果50%以上的风险2大于胰岛素平均作用效果2倍以上的风险自身变异低可使血糖波动更小胰岛素作用的个体
内变异性NPH地特胰岛素高血糖风险157次/每年2次/每年低血糖风险224次/每年0.5次/每年7.6
07.667.778.027.558.307.887.497.636.587.647.737.947.9
37.558.418.117.517.486.46HbA1CT2DM研究地
特胰岛素NPHp<0.05012345VaguePieberHomeRobertsonK?lendor
fRussell-JonesHermansenRa?lováHaakHermansen自我监测FBG/FPG的标准差
(mmol/l)第3代长效胰岛素类似物空腹血糖波动更小对体重的影响评价6个月-3年后体重增加4.8-7.8kg；
胰岛素强化治疗体重增加会更多；50%的体重增加会出现在应用的最初3个月胰岛素NPH若联合口服药晚间单次注射体重增加的会
少一些甘精胰岛素3.3kg/年，短期使用时比NPH体重增加少，但1年后两者体重增加相似诺和平?±短期应用不增加体重，
1年后体重增加较甘精胰岛素少体重优势随着BMI的增加而增加JoannaMitri,etal.ExpertOpin.
DrugSaf.2009,8(5):573-584第3代长效胰岛素类似物-地特胰岛素具有更少的体重增加本节内容
理想的基础胰岛素所具备的特性基础胰岛素+OADs治疗方案基础胰岛素+OADs治疗方案使用方法：继续口服降糖药治疗，联合基础胰
岛素睡前皮下注射基础胰岛素能减少夜间肝糖原产生和降低空腹血糖口服降糖药控制餐后血糖中华医学会糖尿病学分会.中国2型糖尿病防
治指南(2010年版).第24页.4:0025507516:0020:0024:004:00胰岛素水平μU
/ml8:0012:008:00时间基础胰岛素生理性的胰岛素分泌基础胰岛素午餐晚餐口服药口服药早餐口
服药常见基础胰岛素+OADs方案举例基础胰岛素（如NPH、地特胰岛素）二甲双胍+胰岛素促泌剂(如瑞格列奈)α-糖苷
酶抑制剂二甲双胍+胰岛素促泌剂(如瑞格列奈)或或或NPH+OADs治疗方案起始剂量：早餐或睡前0.2U/kg
·d开始剂量调整：根据空腹血糖水平调整胰岛素剂量；3～5天调整1次，每次调整1～4个单
位早餐午餐晚餐胰岛素浓度曲线示意图每日两次注射早餐午餐晚餐每日一次注射诺和灵?N中华医学会糖尿病学分会.中国
2型糖尿病防治指南(2010年版).第24页.长效胰岛素类似物+OADs治疗方案起始剂量：未用过胰岛素治疗者：睡前0.2
U/kg·d正在接受基础胰岛素治疗者：以等剂量原则转换剂量调整：以地特胰岛素为例，3～5天调整1次，直到空腹血糖达标早餐前平
均自测血糖浓度（SMBG）剂量调整（U）＞10.0mmol/L+89.1-10.0mmol/L+68.1-9.0m
mol/L+47.1-8.0mmol/L+26.1-7.0mmol/L+2若其中一次SMBG测量在此区间3.1
-4.0mmol/L－2＜3.1mmol/L－41.中华医学会糖尿病学分会.中国2型糖尿病防治指南(2010年版).第24
页.2.诺和平?说明书早餐午餐晚餐诺和平?胰岛素浓度曲线示意图诺和平?SOLVETM国际研究，
一天一次地特胰岛素显著改善空腹血糖，促进血糖达标14.012.010.08.06.04.02.00.0基线研
究结束9.56.8P<0.0001空腹血糖(mmol/L)8.010.17.1P<0.000114.012.0
10.06.04.02.00.0空腹血糖(mmol/L)基线研究结束N=17374T2DMN=3272T2
DM1.Diabetes,ObesityandMetabolism2012Jul.[Epubaheadofpr
int]2.PanCYetal.CSE2012924PO-263,926PO-262.3.CYPan.
2012ADA.2429-PO;2446-PO血糖达标比例(HbA1c<7%)全球中国TITRATETM研究：
更严格的血糖控制目标未增加地特胰岛素的低血糖风险低血糖（事件/患者-年）全部低血糖夜间低血糖NSNSFPG4.4-
6.1mmol/LFPG3.9-5.0mmol/LBlondeLetal.DiabObesMetab2
009;11:623-31.多中心、随机、开放标签、设定不同治疗目标的20周研究244名口服药失效的T2DM患者起始一天一次地
特胰岛素在达到不同空腹血糖治疗目标的安全性和有效性PREDICTIVE?研究:一天一次地特胰岛素68%患者无体重增加，且体重
优势随BMI增加而增加Dornhorstetal.IntJClinPract2008;62:659-65.BM
I分级(kg/m2)体重变化(Kg)<2525–<2727–<2929–<31≥31BMI0%10%20%
30%40%50%60%70%80%90%100%%患者68%患者体重减少或无改变n=1527体重减
少无变化体重增加国际多中心、前瞻性、非盲、观察性研究，评价一天一次地特胰岛素±OADs治疗的安全性和有效性来自欧洲的队列亚
组分析地特胰岛素平均治疗14.4周的体重变化小结理想的基础胰岛素应该接近模拟生理性基础胰岛素分泌模式：平稳无峰，个体内变异性
低，作用时间持续24h一天一次注射即可有效控制空腹血糖，同时不增加低血糖风险，体重增加少研究证明，第3代长效胰岛素类似物（地特
胰岛素）一天一次注射不但能够提供良好的空腹血糖和HbA1C控制，同时个体内变异性小，更低的降糖目标也不增加低血糖风险，减少体重增加
的优势明显p<0.001forallcomparisonsofAUCThisslidesummarisesn
icelytheimprovementsthathavebeenmadewithLevemir?.Thesli
deshowssomeglucoseinfusionrate(GIR)curvesforindividuals
withtype1diabetes,withtherangeillustratedbasedonfourre
peatedmeasurementsinaclampstudy(Heiseetal.2004).Thebro
wncurvesshowtheprofilesforpatientsgivenfourseparateNPH
injections,eachprecedinga24-hourclamp.Thepinkcurvesshow
equivalentdataforinsulinglargine,andthegreencurvesforLe
vemir?.Firstly,itisstrikingthattheLevemir?curvesarenot
ablylongerandflatterincomparisonwiththeNPHcurvesshowing
amoreprolongedabsorption,withlessofapeakeffect.Sec
ondly,itisstrikingthattheLevemir?curvesaremuchmoreclos
elyspacedforeachpatientsincomparisonwiththoseofNPHand
glargine.Thisshowsthat,underclampconditionsatleast,Levem
ir?producesamuchmorereproducibleeffectfromoneinjectiont
othenextinanindividualpatienthelpingtobettercontrolof
glycaemia.Thefinalpanelshowsthecalculatedvaluesforthec
oefficientofvariation(CV)forGIRAUC(0–24h),whichisameasu
reofthevariabilityinthetotalglucose-loweringeffectover2
4hours.Levemir?wassignificantlylessvariableinthisparamet
erthaneitherNPHorglargine(p<0.001,bothcomparisons).This
wasalsotruefortheCVofGIRmax(23vs.46vs.36%),whichis
ameasureofvariabilityinthemaximalglucose-loweringeffect.
Thus,thisstudyshowedthataswellasprovidingabettermean
profilethanolderbasalinsulins(longdurationofactionwithl
owpeakeffect).Levemir?providesgreaterreproducibilityinthe
sedesiredaspectsofitsprofilethaneitherNPHorglargine.
SolubleatneutralpH:avoidsvariabilityproblemsassociatedwi
th:Resuspensionofpre-formedcrystals(NPH)Precipitation&red
issolutionofformulationsdesignedforsubcutaneousprecipitatio
n(bothNPH:precipitate&Glargine:micro-precipitate)p<0.001
forallcomparisonsofAUCThisslidesummarisesnicelytheimp
rovementsthathavebeenmadewithLevemir?.Theslideshowssome
glucoseinfusionrate(GIR)curvesforindividualswithtype1d
iabetes,withtherangeillustratedbasedonfourrepeatedmeasur
ementsinaclampstudy(Heiseetal.2004).Thebrowncurvessho
wtheprofilesforpatientsgivenfourseparateNPHinjections,e
achprecedinga24-hourclamp.Thepinkcurvesshowequivalentda
taforinsulinglargine,andthegreencurvesforLevemir?.Firs
tly,itisstrikingthattheLevemir?curvesarenotablylongera
ndflatterincomparisonwiththeNPHcurvesshowingamoreprolo
ngedabsorption,withlessofapeakeffect.Secondly,itis
strikingthattheLevemir?curvesaremuchmorecloselyspacedfo
reachpatientsincomparisonwiththoseofNPHandglargine.Thi
sshowsthat,underclampconditionsatleast,Levemir?produces
amuchmorereproducibleeffectfromoneinjectiontothenextin
anindividualpatienthelpingtobettercontrolofglycaemia.T
hefinalpanelshowsthecalculatedvaluesforthecoefficientof
variation(CV)forGIRAUC(0–24h),whichisameasureofthevar
iabilityinthetotalglucose-loweringeffectover24hours.Leve
mir?wassignificantlylessvariableinthisparameterthaneithe
rNPHorglargine(p<0.001,bothcomparisons).Thiswasalsotrue
fortheCVofGIRmax(23vs.46vs.36%),whichisameasureof
variabilityinthemaximalglucose-loweringeffect.Thus,thiss
tudyshowedthataswellasprovidingabettermeanprofilethan
olderbasalinsulins(longdurationofactionwithlowpeakeffec
t).Levemir?providesgreaterreproducibilityinthesedesiredas
pectsofitsprofilethaneitherNPHorglargine.Solubleatn
eutralpH:avoidsvariabilityproblemsassociatedwith:Resuspens
ionofpre-formedcrystals(NPH)Precipitation&redissolutionof
formulationsdesignedforsubcutaneousprecipitation(bothNPH:
precipitate&Glargine:micro-precipitate)T.Heise,etal.D
iabetes2004(Study1450)Inordertoillustratewhattheobser
vedvariability(incombinationwiththemeantreatmenteffect)m
eansforanindividualpatientwecalculatedapredictioninterva
lcontaining95%ofthepredictedvaluesforanaveragepatient.
Thelowerandupperlimitofthispredictionintervalwerecalcul
atedforeachinsulinpreparationbysubtractingandaddingtheo
bservedstandarddeviationmultipliedby1.96.Inthetopbarof
thetablethecalculationisdoneforthesameendpoint,themea
nareaunderthetime-actionprofilesover24h.Inthebottomba
rofthetablethecalcuationisdonefortheanotherendpoint,t
hevarianceofMaxGIR.Thepredictedclinicalconsequencesoft
hesecalculationsareillustratedhere:Forexample,observeddi
fferencesinvariabilitycanbeillustratedbyconsideringapati
entinwhichanaverageglucose-loweringeffectover24hoursof
1mg/(kg/min)wasinducedbyapplicationofagivenlong-actingi
nsulinpreparation.Inthispatient,theprobabilityofexperienc
inganaverageeffectoflessthanhalftheusualeffect(i.e.,<
0.5mg/(kg/min)),whichcanresultintheclinicalconsequenceof
hyperglycaemiais0.5%ifthesubjectusesinsulindetemir,abov
e7%withinsulinglargine,andabove15%withNPHinsulin.And
innearlyeverycasewherethevariabilityofFBGhasbeenmeasu
redintermsofSD,therehasbeenasignificantadvantageforI
Det.Intheonestudywheretherewasnosignificantdifference
inthisparameter,therewasasignificantdifferenceinpre-dinn
erBGvariability.Thisstudywasatypicalasitemployedatreat
-to-targetprotocoladdingIDetorNPHasaninsulinsupplementt
oOADsinpoorlycontrolledtype2diabetes.Itisnoteworthyth
atvariabilityisinanycaseconsistentlylowerinthetype2di
abetestrials.Speculatively,thismightreflecttheabilityofe
ndogenousinsulinsecretiontobufferthevariableBGloweringac
tionofexogenousinsulin.不同基础胰岛素对体重的影响是不同的。一般来说，胰岛素治疗往往在治疗的六个月
和三年后引起的体重增加最多，可以达到4.8到7.8公斤，而大部分体重增加会出现在最初应用胰岛素的三个月。和NPH胰岛素和甘精胰岛素
相比，诺和平?是目前唯一具有体重优势的基础胰岛素，短期应用不增加体重，1年后体重增加较甘精胰岛素少，且体重优势随着BMI的增加而增
加的特点。SOLVETM国际研究是一项观察性研究，即在真实临床环境中观察口服药失效的T2DM患者起始一天一次地特胰
岛素治疗的安全性和有效性。在SOLVETM国际研究中由研究者根据经验来决定诺和平?剂量调整，研究对基线、12周、24周的访视资
料收集并进行分析。共纳入了来自10个国家，2817个研究中心的17374名2型糖尿病患者，其中包括了3272例中国的患者，中国患
者居全球第二。临床研究也显示地特胰岛素更加严格的血糖控制目标并没有增加低血糖风险，无论全部低血糖还是夜间低血糖在两组之间没
有统计学差异。METHODS:Inthis20-week,randomized,controlled,open-l
abel,multicentre,treat-to-targetstudy,244insulin-na?vesubje
ctswithtype2diabetes,HbA(1c)>or=7.0andtment,wererandomized(1:1)tooneoftwotreatmentarmsusing
3.9-5.0or4.4-6.1mmol/lFPGastitrationtargets.Once-dailyi
nsulindetemirdoseswereadjustedusingalgorithm-guidedpatient
-directedtitrationtoachievetargetFPGvalues.RESULTS:Overa
ll,thecombinedtreatmentgroupsachievedameanHbA(1c)levelo
f6.9%attheendofthestudy.SubstantialreductionsinHbA(1c)
wereseeninbothtreatmentgroups,withthemajorityofsubject
sinbothtitrationgroupsattheendofthestudyachievingthe
AmericanDiabetesAssociation(ADA)-recommendedHbA(1c)levelof
<7%.Inthe3.9-5.0mmol/lFPGtargettreatmentgroup,HbA(1c)va
luesdecreasedfromabaselinemeanof8.0%to6.8%at20weeks.
Inthe4.4-6.1mmol/lFPGtargetgroup,HbA(1c)valuesdecreased
from7.9%atbaselineto7.0%at20weeks(Intentiontotreat-l
astobservationcarriedforwarddataset).Thesedecreasesweresignificantlydifferentbetweenthetwotreatmentgroups(Leastsquaresmeandifference=-0.271,95%CI-0.441to-0.101,p=0.0019),favouringtheFPGtargetof3.9-5.0mmol/lvs.the4.4-6.1mmol/ltarget.Attheendofthestudyperiod,64.3%ofsubjectsinthe3.9-5.0mmol/ltreatmentgroupachievedHbA(1c)levels<7%comparedwith54.5%ofsubjectsinthe4.4-6.1mmol/lgroup(95%CI1.03-3.37,oddsratio1.86,p=0.04).Insulindetemirdosingpatternsweresimilarbetweentreatmentgroups,withthe3.9-5.0mmol/lgroupusingslightlygreaterdosesthroughoutthestudyperiod(0.57U/kgvs.0.51U/kgattheendofthestudy).Overallratesofhypoglycaemiaepisodeswerelowandwerecomparablebetweentreatmentgroups(7.73and5.27events/subject/yearforthe3.9-5.0and4.4-6.1mmol/lgroups,respectively).Asingleeventofmajorhypoglycaemiawasreportedinthe3.9-5.0mmol/lgroup.Meanweightchangesfrombaselinetotheendofthestudyweresmallanddidnotdiffersignificantlybetweentreatmentgroups.PREDICTIVE?研究是一项大型的国际多中心观察性研究，在接受调查的受试者中，经过一段时间的诺和平?治疗，68%的受试者体重减少或没有改变。 |
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