从研发到应用德谷门冬双胰岛素的启航之路技术创新引领胰岛素的研发历程德谷门冬双胰岛素门冬胰岛素30门冬胰岛素地特胰岛素德谷胰岛素双时相胰岛素类
似物速效胰岛素类似物新型胰岛素类似物长效胰岛素类似物动物胰岛素重组人胰岛素19221950s19551960s19771980s1
990s2000s2010s胰岛素分离技术(Banting&Best)实现外源DNA在原核细胞中的表达基因重组技术不断发展明确
胰岛素分子结构(F.Sanger)IDegAsp,德谷门冬双胰岛素兼顾FPG和PPG，是理想的胰岛素制剂的设计初衷生理胰岛素分
泌模式:基础胰岛素组分进餐相关的胰岛素分泌峰速效胰岛素与中效/长效胰岛素联用，可以模拟生理胰岛素分泌将速效胰岛素与中/长效胰岛素混
合起来，就能够一针同时补充基础和餐时胰岛素需求Garberetal.DiabetesObesMetab2007;9:6
30–9.;Polonsky,K.S.etal.NEnglJMed.1996;334(12):777-8
3.双时相胰岛素类似物由单一活性成分的游离态及其与精蛋白的结合态组成门冬胰岛素单六聚体血管注射后，门冬胰岛素进入皮下门冬胰岛素单
体迅速释放入血精蛋白在皮下缓慢解离注射后，精蛋白门冬胰岛素进入皮下制剂中释放出门冬胰岛素单六聚体门冬胰岛素单体释放入血IAsp单
六聚体IAsp+精蛋白Biochim.Biophys.Acta,214(1970)I41-I47.；HokkaidoI
gakuZasshi.1992Jan;67(1):81-8.德谷门冬双胰岛素由基础胰岛素类似物和速效胰岛素类似物混合而成[
Phenol;Zn2+]IDeg双六聚体IAsp单六聚体注射后，进入皮下储库苯酚迅速弥散，德谷胰岛素由双六聚体链接为
多六聚体长链锌离子缓慢弥散，德谷胰岛素多六聚体缓慢解离，其单体缓慢释放入血制剂中皮下门冬胰岛素单体迅速释放入血Jonassene
tal.PharmRes2012;29:2104–14不是所有基础胰岛素类似物都能与速效胰岛素类似物混合地特胰岛素门冬胰岛
素混合六聚体地特胰岛素速效胰岛素类似物溶于pH7.4制剂在常规制剂的条件下，地特胰岛素与速效胰岛素类似物混合，会形成混合六聚体
，导致两种胰岛素的药代动力学发生变化2IGlarU100溶于pH4制剂pH0.07.014.0甘精胰岛素甘精胰岛素U10
0在pH4制剂可溶，在皮下组织的中性环境（pH7.4）成微沉淀物，但目前的速效胰岛素类似物均需储存在pH7.4的制剂中1
1.Lantus?USPrescribingInformation.SanofiApril2010;2.Jon
assenetal.PharmRes2012;29:2104–14.在制剂中和体内，德谷胰岛素和门冬胰岛素各自独立作用
在制剂中在皮下储库德谷门冬双胰岛素(IDegAsp)+=70%德谷胰岛素(IDeg)30%门冬胰岛素(IAsp)ID
eg双六聚体两种胰岛素各自独立存在于制剂中IDegIAsp皮下缓慢解离迅速解离IAsp单六聚体毛细血管Havelundet
al.PharmRes2015;32:2250–8尺寸排除色谱法提示,无论是制剂中或皮下注射后德谷胰岛素组分和门冬胰岛素组分
均独立存在制剂中（预充笔）皮下组织1.001.000.900.90Insulindegludec:IAsp0.800
.80Insulindegludec:IAsp0.700.70Insulindegludecdihexamer0.600.6
0AbsorbanceunitsAbsorbanceunits0.500.500.40Insulindegludecmul
tihexamer0.40IAspmonomer0.300.30IAsphexamer0.200.200.100.100.00
0.0045678910111213144567891011121314MinutesMinutesSize-exclusion
chromatographyofIDegAspinconditionssimulatingthepharmaceut
icalformulationIAsp,insulinaspartHavelundetal.PharmRes.20
15;32:2250–8德谷门冬双胰岛素的餐时和基础组份各自发挥独立的降糖作用在T1DM的患者中，IDegAsp达稳态时的葡萄糖输
注率IDegAsp0.6U/kg(n=22)餐时胰岛素组分基础胰岛素组分GIR(mg/kg/min)时间（小时）GIR：葡
萄糖输注率Heiseetal.DiabetesTher2014;5:255–65相同日剂量，德谷门冬双胰岛素BID注射
能够带来与QD注射同样平稳的基础胰岛素覆盖，同时给予患者两次餐时胰岛素覆盖稳态下IDegAspQD注射的GIR稳态下ID
egAspBID注射的GIRIDegAsp0.3U/kgBIDIDegAsp0.6U/kg88664GIR(mg
/kg/min)4GIR(mg/kg/min)2200048121620204812160全天剂量相同时，德谷门冬双胰岛素QD注
射和BID注射，基础组分的降糖作用相当BID注射的餐时组分单峰曲线下面积为QD注射时餐时组分曲线下面积的一半Timesince
injection(hours)Timesinceinjection(hours)BID,twicedaily;GI
R,glucoseinfusionrate;IDegAsp,insulindegludec/insulinaspar
t;OD,oncedaily;T1D,type1diabetesHeiseetal.DiabetesTher
2014;5:255–65在既往未接受过胰岛素治疗的患者中，无论QD或BID，7:3均是兼顾有效性和安全性的基础-餐时比例
HbA1c降幅(%)低血糖事件发生（事件/患者年）P=NSP=NSQD1确证性低血糖夜间确证性低血糖P=NSIGlar替代制剂ID
egAspP<0.05P=NSBID2P=NS确证性低血糖夜间确证性低血糖QD研究：178例患者随机接受甘精胰岛素（IGlar）Q
D、德谷门冬双胰岛素（IDegAsp）QD或由55%德谷胰岛素和45%门冬胰岛素组成的替代制剂（AF）。BID研究：182例患者随
机接受包括IDegAspBID或AFBID在内的治疗。各组均与二甲双胍联用。研究均持续16周。1.HeiseT,etal
.DiabetesCare.2011Mar;34(3):669-74.;2.NiskanenL,etal.Eu
rJEndocrinol.2012Aug;167(2):287-94.临床研究证实，在基础胰岛素控制不佳的患者中，使用B-
B方案进行强化治疗38周后，基础-餐时比例接近7:3基础-餐时比例(%)IGlar+1~3IAspStepbySt
ep试验是一项为期38周、国际、开放标签、随机、治疗达标试验，共纳入来自7个国家的532例患者，观察比较了在既往使用基础胰岛素联用
或不联用口服降糖药血糖控制不佳，需要胰岛素强化治疗的T2DM患者中，使用IDegAspQD/BID与甘精胰岛素U100加用1至3
针门冬胰岛素的疗效与安全性。Philis-TsimikasAetal.DiabetesResClinPract.2
019Jan;147:157-165.小结德谷门冬双胰岛素由基础胰岛素类似物和速效胰岛素类似物混合而成德谷门冬双胰岛素的基础组分
德谷胰岛素和餐时组份门冬胰岛素在制剂中及注射后均独立存在，并协同发挥降糖作用德谷门冬双胰岛素采用的基础-餐时7:3比例能够同
时兼顾有效性和安全性德谷门冬双胰岛素注射液于2019年5月24日获得国家药品监督管理局（NMPA）的上市批准，用于治疗成人2型糖尿
病德谷门冬双胰岛素已经在中国获批德谷门冬双胰岛素注射液说明书-中国2019年5月24日，国家药品监督管理局批准了诺和诺德公司研发生
产的德谷门冬双胰岛素注射液在中国的上市申请，用于治疗成人2型糖尿病。德谷门冬双胰岛素注射液的获批上市将为中国2型糖尿病患者的血糖管
理带来更多获益！药品基本信息德谷门冬双胰岛素注射液通用名称：制作工艺1ml溶液含100单位活性成分的配比及含量分子量分子结构活性成
分德谷胰岛素重组DNA技术，利用酿酒酵母制成70%(相当于2.56mg)6103.97门冬胰岛素30%(相当于1.05mg)5
825.63辅料甘油、间甲酚、苯酚、氯化钠、醋酸锌、盐酸（用于调节pH值）、氢氧化钠（用于调节pH值）、注射用水可溶性胰岛素。无色
液体，无浑浊，基本不含微粒物质性状成分德谷门冬双胰岛素注射液说明书适应症及适用人群用于治疗成人2型糖尿病，包括老年、肝肾功能损
害的2型糖尿病患者治疗成人、青少年及2岁以上儿童糖尿病，包括老年、肝肾功能损害的2型糖尿病患者和1型糖尿病患者需要胰岛素治疗的糖
尿病，包括成人、1岁及以上儿童和青少年糖尿病患者、老年糖尿病患者、肝肾功能损害的糖尿病患者和1型糖尿病患者1岁及以上糖尿病患者，包
括老年糖尿病患者和1型糖尿病患者中国欧洲美国日本德谷门冬双胰岛素注射液说明书给药方案德谷门冬双胰岛素可随主餐每日一次或每日两次给药
本品可单独给药，也可与口服抗糖尿病药物联合使用，或与餐时胰岛素联合使用每日总起始剂量为10单位，餐时给药，随后进行个体化剂量调整注
：主餐在美国和欧洲说明书中定义为main/largestmeal德谷门冬双胰岛素注射液说明书给药方案给药时间剂量调整可灵活变动，
只要随主餐给药即可主要根据空腹血糖水平调整剂量若忘记给药，建议在当天下一次主餐时补充漏掉的剂量，此后恢复平时的给药方案体力活动增多
，常规饮食改变或伴随其他疾病时，需调整剂量不得为了弥补遗漏剂量而进行额外给药注：本品仅供皮下注射使用德谷门冬双胰岛素注射液说明书给
药方案–从其他胰岛素方案转换转换前方案转换方案每日1次基础或预混胰岛素等剂量转换为QD，总剂量不变＞每日1次基础或预混胰岛素等
剂量转换为BID，总剂量不变基础/餐时胰岛素治疗基于个体需要进行。通常以相同单位数量的基础胰岛素剂量开始治疗改用本品期间及后续数周
内建议密切监测血糖。可能需要调整联合使用的速效或短效胰岛素药品或其他伴随的抗糖尿病治疗药物的剂量和给药时间。德谷门冬双胰岛素注射液
说明书T1DM&特殊人群中国欧洲日本美国老年患者≥65岁应强化血糖监测，并进行个体化的胰岛素剂量调整≥65岁同中国应特别小心低
血糖，关注剂量，加强血糖监测＞75岁初始、增加及维持剂量均应保守治疗，避免低血糖肝/肾功能损伤患者应强化血糖监测，并进行个体化的胰
岛素剂量调整同中国——同中国儿童——2岁以上儿童1岁以上儿童1岁以上儿童T1DM——与短效/速效胰岛素联合使用与短效/速效胰岛素
联合使用与短效/速效胰岛素联合使用德谷门冬双胰岛素注射液说明书总结德谷门冬双胰岛素的组分独立存在，并协同发挥降糖作用德谷门冬双胰岛
素7:3的基础-餐时比例兼顾了有效性和安全性德谷门冬双胰岛素在中国主要用于治疗成人2型糖尿病，可随主餐每日一次或每日两次给药T
hankYouIDegAsp:FromdrugdiscoverytoclinicalpracticeSinceth
eisolationofinsulinin1922byBantingandBest,therehavebe
enseveralsignificantinnovationsinthefieldofinsulindevelo
pment,culminatingintherecentlydevelopednewgenerationanalo
gues.Inordertoincreasethedurationofactionofbasalinsulin
s,sothattheymorecloselymimicthephysiologicalreleaseofi
nsulin,severaldifferentformulationsandproteinmodifications
havebeenutilisedtherebyimprovingthephysiologicaleffectof
combinationinsulinproducts.Now,wehaveanewgenerationofin
sulinanalogue,theInsulinDegludecandInsulinAspartInjection
. Aphysiologicalinsulinprofilecanbecharacterisedbylowba
salsecretionduringmealsandmeal-relatedpeaksofinsulin.In
peoplewithdiabetes,thisphysiologicalsecretionpatterncanbe
partlymimickedeitherbytheuseofarapid-actinginsulinanal
oguetogetherwithabasalinsulinanalogueorbytheuseofapr
emixedinsulinanalogue.德谷胰岛素在制剂中呈双六聚体，两端为苯酚分子封闭了形成多六聚体的可能。注射入皮下后
，苯酚分子迅速弥散，德谷胰岛素六聚体两端打开，相互链接成多六聚体。Thekineticpropertiesofbasal
insulinshavethepotentialtobeimprovedusingacetylationbyf
attyacids.Thisenablessoluble,highmolecularweightcomplexes
toformpost-injection.Jonassenetal(2012)examinedaseries
ofinsulins,acetylatedatB29withfattyacidsviaglutamicacid
spacers,todeducethestructuralrequirements.Theyfoundthat
withdepletionofphenolinsulin,degludecformedhighmolecular
massfilament-likecomplexes,whichdisintegratedwithdepletion
ofzinc.Circulardichroismspectroscopy(CDS)showedtheseanalo
guesadoptingstableT3R3conformationinpresenceofphenoland
zinc,changingtoT6withdepletionofphenol.Thesefindingssug
gestinsulindegludecisdihexamericinpharmaceuticalformulatio
n,becomingmultihexamericafterinjection.Theanaloguesshowed
weakdimericassociation,indicatingrapidreleaseofmonomersfo
llowinghexamerdisassembly.Theauthorsconcludedthatinsulins
canbeengineeredthatremainsolublebutbecomehighlyself-asso
ciatedafterinjection,slowlyreleasingmonomers;thisiscritic
allydependentontheacylationmoiety.Onesuchanalogue,insuli
ndegludec,hastherapeuticpotential.Apotentiallyimportantcon
sequenceofthepropertyofIDegformingverystableT3R3dihexam
ersinapharmaceuticalformulation(andmultihexamersatthesit
eofinjection)isthatotherinsulins(e.g.rapid-actinginsulin
s)canbeco-formulatedwithouttheriskofinter-exchangeofmon
omerstoformhybridhexamerseitherinthecartridgeorinjectio
ndepot.Thiscouldenablethedevelopmentofcombinationproduct
swithdiscretepreservationofthePKprofilesofthecomponent
insulinsIDegAspcomposedof70%IDegand30%IAsp.Thetwoinsuli
nsexistseparatelyinthepen(IDegasdihexamersandIAspashe
xamers).UponinjectionintothesubcutaneousspacetheIAsphexa
mersrapidlydissociateandenterthebloodstream,whileIDegfo
rmsmultihexamerchainsthatslowlydissociateSize-ExclusionChro
matographySize-exclusionchromatography(SEC)wasperformedtoch
aracterizetheassociationstatesfortheindividualbasalandra
pid-actinginsulins,andforthecombinations.ThreeSECmethods
wereusedasinvitromodelstosimulateconditionsinthepharma
ceuticalformulation(athighconcentrationofphenolandroomte
mperature),theconditioninthesubcutaneousdepotafterinjecti
on(withoutphenolandatbodytemperature)and,finally,toeval
uateaserialdecreaseinconcentrationofphenolandm-cresol,a
sexpectedtooccurfollowingsubcutaneousinjection.Furthermore
,fractionsofhighandlowmolarmasswerecollectedfromtheSE
Celuents,andreverse-phasechromatographywasusedtomeasuret
heconcentrationsoftheindividualinsulinwithinthem.SECmetho
d1wasdesignedtosimulateconditionsinthepharmaceuticalfor
mulation(withthesamephenolconcentration),andwasusedtome
asurethepercentageofoligomersofdihexamer,dihexamers,hexam
ers,andmonomerswitheluentof16?mMphenol,140?mMsodiumchlo
ride,10?mMtris(hydroxymethyl)aminomethane(tris)pH?7.3,and
0.01%sodiumazideat23°C.Thesize-exclusioncolumnusedwasAC
QUITYUPLC?BEH200(1504.6?mm,d=?1.7?μm)fromWatersCorporati
on,Milford,MA,USA.Ultravioletdetectionwavelengthswereat2
86,276and290?nmformethods1–3,respectively.Injectionvolum
ewas20?μLandflowwas0.15?mL/min.SECmethod2wasdesignedto
simulateconditionsinthesubcutaneousdepot(inwhichphenolq
uicklydissipates),andwasusedtomeasurethepercentageofmul
tihexamerversusthehexamer–monomerfractionwithaphenol-free
eluentof140?mMsodiumchloride,10?mMtrispH?7.3,0.01%sodium
azide,and5%2-propanolat37°C.Theconcentrationsoftheindi
vidualinsulinanalogsinthemultihexamerfractionandthehexam
er–monomerfractionweredeterminedbyreverse-phasechromatograp
hy.ASymmetryShieldRP18(3.920?mm,d?=?3.5?μm)columnfromWat
ersCorporation(Milford,MA,USA)waselutedwithA:10%(vol)ac
etonitrile0.2?Msodiumsulfate,40?mMo-phosphoricacidadjusted
topH?3.6withsodiumhydroxideandB:70%(vol)acetonitrileat
agradientof20–54%at1.4–5?minat30°C,1?mL/min,anddetectio
nat276?nm.Toavoidadsorption,70?ppmpolysorbate20wasadded
tothefractionvials.Forcomparison,insulindetemirwascombin
edwithinsulinaspartinthesameproportions(volume70:30)and
storedfor4?weeksat25°C.SECmethod2wasmodifiedfortheco
mbinationofinsulindetemirandinsulinaspartbydividingfract
ioncollectionbetweenhexameranddimer(sinceinsulindetemira
chievesitsprotractedabsorptionlargelythroughreversiblealbu
minbindingratherthanmultihexamerformation).SECmethod1was
notemployedforaninsulindetemirandinsulinaspartcombinatio
n.ThisisbecauseinthephenolicSECeluent(similartothepha
rmaceuticalformulation),insulindetemirelutesasahexamer[11
,15],asdoesinsulinaspart,sothetwoinsulinanalogs(andan
yhybridassociations)wouldthereforebeindistinguishableusing
thismethod.SECmethod3wasdesignedtosimulateserialconditi
onsatdecreasingconcentrationsofthepreservativesphenoland
m-cresol,aswilloccurimmediatelyaftersubcutaneousinjection.
ThesetestsweremadebymixingA:16?mMphenolandm-cresol,20
?mMsodiumchloride,3?mMsodiumdihydrogenphosphatepH?7.3,and
0.01%sodiumazide,withB:140?mMsodiumchloride,3?mMsodiumd
ihydrogenphosphatepH?7.3,and0.01%sodiumazideat37°C.Transf
ormationofinsulindegludecdihexamerstomultihexamers,andof
insulinasparthexamerstomonomers,wascomparedwithhumaninsu
lin.AbstractPURPOSE:Tostudytheself-associationstatesofinsu
lindegludecandinsulinaspartaloneandcombinedinpharmaceuti
calformulationandunderconditionssimulatingthesubcutaneous
depot.METHODS:Formulationsweremadeof0.6mMdegludecat3and
5Zn/6insulinmonomers,and0.6mMaspart(2Zn/6insulinmonom
ers).Self-associationwasassessedusingsize-exclusionchromato
graphy(SEC)monitoredbyUVandorthogonalreverse-phasechromat
ography.RESULTS:Simulatingpharmaceuticalformulation,degludec
elutedasdihexamers,whereasaspartelutedashexamersandmonom
ers.Combiningdegludecatlowzincwithaspartincreaseddihexam
ercontent,indicatinghybridhexamerformation.Athighzinccon
centration,however,therewasnoevidenceofthis.Simulatingth
esubcutaneousdepotbyremovingpreservative,degludecelutedas
multihexamersandaspartasmonomers.Aspartwasincorporatedin
tothemultihexamerstructureswhencombinedwithdegludecatlow
zinc,buttherewasnosuchinteractionwithhigh-zincdegludec.
SECusingprogressivelydilutedconcentrationsofphenolandm-c
resolshowedthatdissociationofaspartintomonomersoccursbef
oretheformationofdegludecmultihexamers.CONCLUSION:Insulins
degludecandaspartcanbecombinedwithoutforminghybridhexame
rs,butthiscombinabilityisdependentonzincandpreservative
concentration,andrequiresthatdegludecisfullydihexamericbe
foreadditionofaspart.Themeanglucoseinfusionrate(GIR)prof
ileshowedarapidonsetofactionandadistinctpeakfollowedb
yaflatbasalaction.Thereisaclearanddistinctseparationo
ftheindividualeffectsoftherapid-actingandbasalcomponents
.TheblueshadedarearepresentsIDeg0.4U/kgdatafromthe1993
study.AUCGIR,tau,SS(mg/kg) Geometricmean(CV) 3859.1(32.
8)Min;Max 1452.1;6115.895%CI 3261.9;4565.6GIRmax,SS(mg/
[kg?min])N 22Geometricmean(CV) 7.0(34.6)Min;Max 2.8;12.09
5%CI 5.9;8.3tGIRmax,SS(h)N 22Median(CV) 2.5(29.9)Min;
Max 1.8;4.895%CI 2.1;3.1CV,coefficientofvariationin%C
I,confidenceintervalTheconfidenceintervalforthemeanwasca
lculatedusingat-distributionandlog-transformationoftheend
point.FortGIRmax,Hodges–Lehmann95%CIsarepresentedABSTRACTI
ntroduction/aim:Insulindegludec/insulinaspart(IDegAsp)isas
olubleco-formulationoflong-actingandshort-actinginsulinana
logs.Theprimaryobjectiveofthisstudywastoinvestigatethe
pharmacodynamicresponseofonce-dailyIDegAspdosinginpatients
withtype1diabetes.Pharmacokineticresponse,aswellassafet
yandtolerability,wereassessedassecondaryobjectives.Methodo
logy:Thiswasasingle-center,open-label,single-armstudy.Twe
nty-twosubjectsreceivedonce-dailyinsulindegludec(IDeg)(0.4
2U/kg)forfiveconsecutivedays[withseparatebolusinsulinas
part(IAsp)asneededforsafetyandglycemiccontrol],toachiev
eclinicalsteadystateofthebasalcomponent.OnDay6,theyre
ceivedasingleinjectionofIDegAsp(0.6U/kg,comprising0.42U
/kgIDegand0.18U/kgIAsp).Pharmacodynamicresponsewasassess
edusinga30-heuglycaemicglucoseclamp,withbloodglucosesta
bilizedatatargetof5.5mmol/L.Results:Theglucoseinfusionr
ateprofileshowedarapidonsetofactionandadistinctpeakdu
etoIAsp,followedbyaseparate,flatandstablebasalglucose-
loweringeffectduetotheIDegcomponent.Modelingdatasuggeste
dthatthepharmacodynamicprofileofIDegAspwasretainedwitht
wice-dailydosing(allowingforcoverageoftwomainmealsdaily)
.IDegAspwaswelltoleratedandnosafetyissueswereidentified
inthistrial.Conclusions:Inconclusion,theIAspcomponentof
IDegAsphasafastonsetofappearanceandapeakcoveringthepr
andialphase,whiletheIDegcomponenthasaflatandanevenlyd
istributedpharmacokineticprofileover24h.IDegAspisthefirs
tco-formulationofabasalinsulinanalogwithanultra-longdur
ationofactionandamealtimeinsulinanaloginasinglesoluble
injection.Thesepropertiestranslateintoclinicallyrelevantb
enefits,includingimprovedglycemiccontrolandreductioninhyp
oglycemia.Themeanglucoseinfusionrate(GIR)profileshowedar
apidonsetofactionandadistinctpeakfollowedbyaflatbasal
action.Thereisaclearanddistinctseparationoftheindividu
aleffectsoftherapid-actingandbasalcomponents.Theblueshad
edarearepresentsinsulindegludec0.4U/kgdatafromthe1993s
tudy.AUCGIR,tau,SS(mg/kg) Geometricmean(CV) 3859.1(32.8)
Min;Max 1452.1;6115.895%CI 3261.9;4565.6GIRmax,SS(mg/[k
g?min])N 22Geometricmean(CV) 7.0(34.6)Min;Max 2.8;12.095%
CI 5.9;8.3tGIRmax,SS(h)N 22Median(CV) 2.5(29.9)Min;Ma
x 1.8;4.895%CI 2.1;3.1CV,coefficientofvariationin%CI,
confidenceintervalTheconfidenceintervalforthemeanwascalc
ulatedusingat-distributionandlog-transformationoftheendpo
int.FortGIRmax,Hodges–Lehmann95%CIsarepresentedABSTRACTInt
roduction/aim:Insulindegludec/insulinaspart(IDegAsp)isasol
ubleco-formulationoflong-actingandshort-actinginsulinanalo
gs.Theprimaryobjectiveofthisstudywastoinvestigatetheph
armacodynamicresponseofonce-dailyIDegAspdosinginpatientsw
ithtype1diabetes.Pharmacokineticresponse,aswellassafety
andtolerability,wereassessedassecondaryobjectives.Methodolo
gy:Thiswasasingle-center,open-label,single-armstudy.Twent
y-twosubjectsreceivedonce-dailyinsulindegludec(0.42U/kg)
forfiveconsecutivedays[withseparatebolusinsulinaspart(IA
sp)asneededforsafetyandglycemiccontrol],toachieveclinic
alsteadystateofthebasalcomponent.OnDay6,theyreceiveda
singleinjectionofIDegAsp(0.6U/kg,comprising0.42U/kginsu
lindegludecand0.18U/kgIAsp).Pharmacodynamicresponsewasas
sessedusinga30-heuglycaemicglucoseclamp,withbloodglucose
stabilizedatatargetof5.5mmol/L.Results:Theglucoseinfusi
onrateprofileshowedarapidonsetofactionandadistinctpea
kduetoIAsp,followedbyaseparate,flatandstablebasalgluc
ose-loweringeffectduetotheinsulindegludeccomponent.Modeli
ngdatasuggestedthatthepharmacodynamicprofileofIDegAspwas
retainedwithtwice-dailydosing(allowingforcoverageoftwom
ainmealsdaily).IDegAspwaswelltoleratedandnosafetyissues
wereidentifiedinthistrial.Conclusions:Inconclusion,theIA
spcomponentofIDegAsphasafastonsetofappearanceandapeak
coveringtheprandialphase,whiletheinsulindegludeccomponen
thasaflatandanevenlydistributedpharmacokineticprofileov
er24h.IDegAspisthefirstco-formulationofabasalinsulina
nalogwithanultra-longdurationofactionandamealtimeinsuli
nanaloginasinglesolubleinjection.Thesepropertiestranslat
eintoclinicallyrelevantbenefits,includingimprovedglycemic
controlandreductioninhypoglycaemia.22例1型糖尿病患者，接受德谷胰岛素（0.42U/k
g）+门冬胰岛素（按需给予）治疗5天达稳态。稳态下给予德谷门冬双胰岛素0.6U/kgQD注射，使用30h正常血糖钳夹法检测得GI
R曲线。使用PK/PD模型模拟0.3U/kgBID注射时的GIR曲线。两项II期临床研究，均纳入既往未使用过胰岛素治疗或研究开
始前3个月内使用胰岛素不超过14天，使用1-2种口服药、达到最大剂量的一半、剂量稳定至少2个月且血糖控制不佳的成人2型糖尿病患者。
随机前停用所有口服药，转换为二甲双胍，经过2周的二甲双胍滴定至最大日剂量（2000mg）或能耐受最大日剂量（1500mg）后能够维持剂量稳定1周，且随机前3天早餐前自测血糖不低于7.5mmol/L者纳入研究。A38-week,randomised,open-label,treat-to-targettrialinadultswithtype2diabetesmellitusisgoingtocompareefficacyandsafetyofIDegAsponcedaily(OD)versusinsulinglargine(IGlar)+insulinaspart(IAsp)OD.AtWeek38,thepercentageoftotalbasaldoseswere72.5%,thebolusdoseswere27.5%.Thatmeanstheradiobetweenthemwascloseto7:3.药品名称：德谷门冬双胰岛素注射液成分：活性成分：德谷胰岛素和门冬胰岛素（采用重组DNA技术，利用酿酒酵母制成）。1ml溶液含有100单位德谷胰岛素和门冬胰岛素，其比值为70/30（相当于2.56mg德谷胰岛素和1.05mg门冬胰岛素）。每支预填充注射笔装有3ml溶液，含有300单位德谷胰岛素和门冬胰岛素。辅料：甘油、间甲酚、苯酚、氯化钠、醋酸锌、盐酸（用于调节pH值）、氢氧化钠（用于调节pH值）、注射用水。性状：无色液体，无浑浊，基本不含微粒物质。和锐30、门冬胰岛素的辅料大致相同，只是后两者都多了一个二水合磷酸氢二钠，起锌络合剂的作用。德谷胰岛素的辅料相同。不推荐用于治疗糖尿病酮症酸中毒。不建议儿童患者需要少于5个单位本品可单独给药，也可与口服抗糖尿病药物联合使用，或与餐时胰岛素联合使用给药时间：德谷门冬双胰岛素可灵活变动胰岛素的给药时间，只要随主餐给药即可。如果忘记给药，建议在当天下一次主餐时补充漏掉的剂量，此后恢复平时的给药方案。患者不得为了弥补遗漏剂量而进行额外给药。给药剂量及调整：德谷门冬双胰岛素应根据患者的个体需要给药。建议主要根据空腹血糖水平调整剂量。如果患者的体力活动增多、常规饮食改变或伴随其他疾病，则需调整剂量。给药时间：德谷门冬双胰岛素可灵活变动胰岛素的给药时间，只要随主餐给药即可。如果忘记给药，建议在当天下一次主餐时补充漏掉的剂量，此后恢复平时的给药方案。患者不得为了弥补遗漏剂量而进行额外给药。给药剂量及调整：德谷门冬双胰岛素应根据患者的个体需要给药。建议主要根据空腹血糖水平调整剂量。如果患者的体力活动增多、常规饮食改变或伴随其他疾病，则需调整剂量。本品可单独给药，也可与口服抗糖尿病药物联合使用，或与餐时胰岛素联合使用给药时间：德谷门冬双胰岛素可灵活变动胰岛素的给药时间，只要随主餐给药即可。如果忘记给药，建议在当天下一次主餐时补充漏掉的剂量，此后恢复平时的给药方案。患者不得为了弥补遗漏剂量而进行额外给药。给药剂量及调整：德谷门冬双胰岛素应根据患者的个体需要给药。建议主要根据空腹血糖水平调整剂量。如果患者的体力活动增多、常规饮食改变或伴随其他疾病，则需调整剂量。本品与短效/速效胰岛素在剩余餐时联合使用感谢您的聆听。 |
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