DatePresentationtitle人GLP-1类似物
—早期使用，长期获益主要内容2型糖尿病患者的β细胞功能逐渐减退β细胞功能减退是T2DM进展的主要原因2型
糖尿病患者的胰岛结构破坏明显小结：T2DM患者应尽早保护β细胞功能β细胞功能减退是2型糖尿病进展的主要原因UKPDS和ADO
PT研究结果均显示，随着疾病的进展，患者血糖水平逐渐升高，现有药物难以进行良好的控制上述内容提示，应该尽早保护2型糖尿病患者的β
细胞功能，从而延缓疾病的进展主要内容胰高糖素样肽-1(GLP-1)是重要的肠促胰素一种由31个氨基酸组成的肽链1由胃肠道L
-细胞分泌的胰高糖素原水解而成1由进食刺激分泌(直接腔内刺激和间接神经刺激)2GLP-1对胰岛多种细胞发挥作用GLP-1还具
有降低体重和收缩压等降糖外作用小结：GLP-1具有多种重要生理作用GLP-1是一种重要的肠促胰素，能够针对胰岛多种细胞发挥作用
GLP-1不仅能够促进胰岛素合成和分泌，还能够抑制β细胞凋亡，增加β细胞的量。从功能和量两方面保护胰岛β细胞GLP-1还能够对
中枢神经系统、胃肠道和心血管系统发挥作用，给患者带来降低体重和收缩压等额外的益处主要内容诺和力?是每日注射1次的人GLP-1类
似物诺和力?的适应症适应症：用于成人2型糖尿病患者控制血糖适用于单用二甲双胍或磺脲类药物最大可耐受剂量治疗后血糖仍控制不
佳的患者，与二甲双胍或磺脲类药物联合应用诺和力?具有多种重要生理作用单剂量诺和力?可恢复β细胞的葡萄糖敏感性诺和力?葡萄糖浓
度依赖性降糖，低血糖发生少诺和力?可降低体重达3.2kg诺和力?可降低收缩压达6.7mmHg总结：诺和力?早期应用的益处诺
和力?具有改善β细胞功能，增加β细胞量的作用，尽早应用诺和力?具有延缓疾病进展的潜能尽早应用诺和力?可以有效控制患者的血糖，低血
糖发生少尽早应用诺和力?还可以给患者带来降糖外的获益，如减轻体重，降低收缩压谢谢
患者一旦诊断后，我们首先应考虑生活方式干预。但2型糖尿病是一种进展性疾病，很多患者在诊断一段时间以后，饮食控制失败，Belfast
饮食研究中也观察到这一现象，研究中观察胰岛素抵抗与β细胞功能的变化，如右图所示我们发现胰岛素抵抗没有发生明显的变化，胰岛素抵抗从开
始到结束保持一个水平，而左图所示的β细胞功能在进行性发展，导致2型糖尿病进展，导致2型糖尿病继发治疗失败的根本原因是β细胞功能的进
行性减退。Secondaryfailureofplasmaglucosecontrolfollowingini
tialsuccessfulresponsetodiettherapymaybeduetodietaryin
discretion,ortoprogressionoftheintrinsicdiabeticcondition
.Wereporta10-yearprospectivenaturalhistorystudyof432ne
wlydiagnoseddiabeticpatientsaged40-69yearsundertakentoas
sesstheeffectofintensivedietarymanagement,wherepatientsw
eretransferredtoinsulin,ororalhypoglycaemictherapy(tolbut
amide,metformin)bypredeterminedcriteriaofweightandplasma
glucose.Secondaryfailuretodiettherapyoccurredin41patient
sinyears2-4,67patientsinyears5-7,and51patientsinyear
s8-10;173patientsremainedondietaloneuntildeathortheen
dofthestudy.Continuationondietalonewasassociatedwitha
lowerongoingfastingplasmaglucose,greaterbeta-cellfunction
assessedbyanoralglucosetolerancetestat6months,andincre
asingage.Therateofriseoffastingplasmaglucosewasinverse
lyrelatedtothedurationofsuccessfuldietarytherapy,butmea
nweightremainedconstantinallgroupswhileondietalone.The
ongoingfallinbeta-cellfunctionassessedbyHOMAmodellingcl
oselymirroredtheprogressiveriseinfastingplasmaglucose:th
erewasnochangeinmeaninsulinsensitivityinanyofthegroup
s.研究结果证实了2型糖尿病患者无论是否肥胖，其β细胞的凋亡均显著增加。GLP-1:functionalpancrea
ticeffectsGLP-1hasadirectfunctionaleffectonpancreaticce
lls,influencingsecretionsfromalpha-,beta-anddelta-cells.
Oneofitsmostimportanteffectsistoincreaseinsulinsecretio
n.Importantly,however,itsinsulinotropicactionisglucosedep
endent.Consequently,GLP-1hasthecapacitytolowerbloodgluco
sewhileprotectingagainsthypoglycaemia.GLP-1alsoregulates
glucagonsecretion,partlyviaanincreaseinsomatostatinsecre
tion,andpartlyviaadirecteffectonthealpha-cell.Thisredu
ctioninglucagonsecretionservestodecreasehepaticglucoseou
tput.ReferencesDruckeretal.ProcNatlAcadSciUSA1987;84:3
434–3438?rskovetal.Endocrinology1988;123:2009-2013Gluca
gon-likepeptide1inhibitscellapoptosisandimprovesglucoser
esponsivenessoffreshlyisolatedhumanislets.Thepeptidehorm
one,glucagon-likepeptide1(GLP-1),hasbeenshowntoincrease
glucose-dependentinsulinsecretion,enhanceinsulingenetranscr
iption,expandisletcellmass,andinhibitbeta-cellapoptosisi
nanimalmodelsofdiabetes.Theaimofthepresentstudywasto
evaluatewhetherGLP-1couldimprovefunctionandinhibitapoptos
isinfreshlyisolatedhumanislets.Humanisletswereculturedf
or5dinthepresence,orabsence,ofGLP-1(10nm,addedevery
12h)andstudiedforviabilityandexpressionofproapoptotic(c
aspase-3)andantiapoptoticfactors(bcl-2)aswellasglucose-de
pendentinsulinproduction.Weobservedbetter-preservedthree-di
mensionalisletmorphologyintheGLP-1-treatedislets,compared
withcontrols.Nuclearcondensation,afeatureofcellapoptosis,
wasinhibitedbyGLP-1.Thereductioninthenumberofapoptotic
cellsinGLP-1-treatedisletswasparticularlyevidentatd3(6
.1%apoptoticnucleiintreatedculturesvs.15.5%incontrols;P
<0.01)andatd5(8.9vs.18.9%;P<0.01).Theantiapoptotic
effectofGLP-1wasassociatedwiththedown-regulationofactive
caspase-3(P<0.001)andtheup-regulationofbcl-2(P<0.01).
TheeffectofGLP-1ontheintracellularlevelsofbcl-2andcas
pase-3wasobservedatthemRNAandproteinlevels.Intracellular
insulincontentwasmarkedlyenhancedinisletsculturedwithGL
P-1vs.control(P<0.001,atd5),andtherewasaparallelGLP
-1-dependentpotentiationofglucose-dependentinsulinsecretion
(P<0.01atd3;P<0.05atd5).Ourfindingsprovideevidence
thatGLP-1addedtofreshlyisolatedhumanisletspreservesmorp
hologyandfunctionandinhibitscellapoptosis.大鼠与小鼠的在体研究
也证明了利拉鲁肽可以明显增加β细胞量。Liraglutideincreases?-cellmassinanimal
modelsofdiabetesContinued?-cellfailureisafeatureoftype
2diabetes.Ideallytherefore,treatmentsfortype2diabetessho
uldaddressthisissue.Thesetwostudiesshowedthatliraglutide
increases?-cellmassinanimals.Inonestudy,Zuckerdiabetic
fatty(ZDF)rats(thatshowinsulinresistanceand?-celldefects
),receivedsubcutaneousinjectionsof150μg/kgliraglutideorv
ehicletwicedailyfor6weeks.Attheendofthetreatmentperio
d,?-cellmasswassignificantlygreaterintheliraglutidegroup
(leftgraph).Inthesecondstudy,db/db(diabetic)micerecei
vedsubcutaneousinjectionsofvehicleorliraglutidetwicedaily
for2weeks(200μg/kg).Bloodglucosetestsondays1,8and15
demonstratedthatmicetreatedwithliraglutidehadlowerblood
glucose(asmeasuredusing24-hourareaunderthecurve,AUC)rel
ativetothosereceivingvehicle.Furthermore,attheendofthe
trial,?-cellmass(righthandfigure)andproliferationratewer
esignificantlygreaterwithliraglutidetreatment.NB.Thedat
afromtheZDFstudyhavebeenconvertedfrompercentbeta-cellv
olumetobeta-cellmasstosimplifycomparisonwiththedatafrom
thedb/dbmice.ReferencesStudypreclin05.Sturisetal.BrJ
Pharmacol2003;140:123–132Studypreclin04.Rolinetal.AmJP
hysiolEndocrinolMetab2002;283:E745–E752Diseaseprogressioni
ntype2diabetesAsUKPDSdemonstrated,evenwithintensivether
apy,targetglycaemiclevelsarenotmaintainedlong-term.Oneof
themainreasonsforthisisthattype2diabetesisaprogressi
vediseasecharacterisedbycontinued,worseningbeta-cellfailur
e.Indeed,atthetimeofdiagnosis,beta-cellfunctionisalread
ymarkedlycompromised(byapproximately50%),and,astheabove
slideshows,functioncontinuestoworsen.Furthermore,astheex
trapolationonthisslidedemonstrates,beta-cellfunctionmayha
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:1249–58.Asingledoseofliraglutiderestores?-cellglucoses
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sessedusingagradedglucoseinfusionprotocol,duringwhichglu
coseisinfusedtocreategraduallyrisingplasmalevelsfrom5–1
2mmol/L(90–216mg/dL)over3hours.Approximately9hoursbefor
ethegradedglucoseinfusion,patientswithtype2diabetes(n=1
0)receivedasinglesubcutaneousdoseofliraglutide(7.5μg/kg)
orasingledoseofplaceboinadouble-blind,crossoverdesign
(3–6-weekwashoutperiod).Agroupofhealthycontrolswhodidno
treceiveanyinjectionswerealsoincluded.Afteranovernightf
astandpriortoglucoseinfusion,allgroupsreceivedasmalli.
v.bolusofinsulin(0.007–0.014units/kg).Thisbolusreducedbl
oodglucosetoapproximately5mmol/l(90mg/dl)inhealthycontr
ols,and6mmol/L(108mg/dL)intheliraglutideandplacebogrou
ps(thisbolusprobablyexplainsthehorizontallinebetweenthe
firsttwomeasurements).Gradedglucoseinfusionwastheninitiat
edandinsulinsecretionassessed.Inallgroups,insulinsecreti
onincreasedconcomitantlywithincreasesinglucoseconcentratio
n.However,afterliraglutidedosing,theeffectwasmorepronoun
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thatobservedinthenon-diabeticcontrols.Thus,asingledose
ofliraglutideissufficienttoreinstatetheinsulinresponseto
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slidescanbeconsideredquitebrieflyastheysetthescenefor
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addingliraglutideEstimatedmeansareobtainedfromanANCOVAw
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7–63;2.Farillaetal.Endocrinology2002;143:4397–408胃排空与胃酸分
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illaetal.Endocrinology2003;144:5149–58GLP-1对照胰岛素μU/ml/μ
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nology2003;144:5149–58安慰剂GLP-1第1天第3天第5天T2DM的β细胞功能缺陷1
GLP-1对胰岛β细胞的作用2早期应用诺和力?可延缓T2DM进展3Knudsenetal.JMedChem20
00;43:1664–9;Degnetal.Diabetes2004;53:1187–947369LysHis
AlaThrThrSerPheGluGlyAspValSerSerTyrLeuGluGlyAla
AlaGlnLysPheGluIleAlaTrpLeuGlyValGlyArg天然人GLP-1T?
=1.5–2.1分钟被二肽激肽酶（DPP-4）降解?从皮下组织缓慢吸收?不易被DPP-4降解，不从肾脏滤过?
血浆半衰期长达13小时，降糖作用>24小时-97%氨基酸序列与人GLP-1同源通过酰基化与白蛋白结合；自联作用C
-16脂肪酸(棕榈酰)HisAlaThrThrSerPheGluGlyAspValSerSerTy
rLeuGluGlyAlaAlaGlnLysPheGluIleAlaTrpLeuGlyValGly
ArgGluArg7936利拉鲁肽从皮下组织缓慢吸收不易被DPP-4降解血浆半衰期长达13小时，降糖作用>24
小时诺和力?的药代药效学特征吸收：皮下注射后吸收较缓慢，给药后8-12小时达到最大浓度。在1.8mg的剂量水平下，平均稳态
浓度（AUCτ/24）约为34nmol/L分布：与血浆蛋白广泛结合（>98％）代谢：以与大分子蛋白类似的形式代谢，无特定的消除
器官消除：消除半衰期约为13小时。其半衰期延长主要是因为：由于分子结构的改变，诺和力?注射后会在皮下形成7聚体，缓慢释放。诺
和力?从皮下缓慢吸收后，通过酰基化与血中白蛋白结合，使其不易被DPP-4降解，逐步释放游离的活性物质，从而进一步延长作用时间。根
据诺和力?(利拉鲁肽)中文说明书根据诺和力?(利拉鲁肽)中文说明书＊动物实验诺和力?增加糖尿病动物模型的β细胞量β细胞量(
mg/pancreas)ZDF大鼠1每天两次注射，6周研究05101520安慰剂(n=7)利拉鲁肽(n=8
)p<0.05p=0.0019150μg/kgbid02468安慰剂(n=10)利拉鲁肽(n=10)
200μg/kgbid10db/db小鼠2每天两次注射，2周研究1.Sturisetal.BrJPha
rmacol2003;140:123–32.Dataonfile2.Rolinetal.AmJPhysiol
EndocrinolMetab2002;283:E745–52.数据为均数±标准差Type2diabetespa
tientsreceivedasingleliraglutideorplaceboinjection9hbef
ore(crossover)trialInsulinsecretionwasmeasuredLiraglutide
restoredbeta-cellresponsivenesstoelevatedglucosetotheleve
lofhealthyvolunteersT2DM患者在试验前9h接受一次利拉鲁肽或安慰剂注射检测胰岛素分泌情况利拉鲁肽
能够使β细胞对高血糖的反应性恢复至健康人水平Changetal.Diabetes2003;52:1786–91数据为均
数±标准差;2型糖尿病患者(n=10)胰岛素分泌率（pmol/mim/kg)健康对照（n=10）利拉鲁肽7.5μg/k
g安慰剂葡萄糖（mg/dL）诺和力?显著改善患者的β细胞功能Mean(SE)Zinmanetal.Diabe
tesCare2009;32:1224–30(LEAD-4)深色=基线值(%);渐变色=变化值(%)利拉鲁肽1.8
mg利拉鲁肽1.2mg安慰剂利拉鲁肽1.8mg利拉鲁肽1.2mg安慰剂基线胰岛素原:胰岛素比值的变化LEAD-4
加用诺和力?后患者HbA1c下降可达1.6%所有患者HbA1c的变化(LEAD-4,-5,-6,LiravsSita)
;饮食和运动无效时加用(LEAD-3);或者在OAD单药治疗的基础上加用(LEAD-2,-1).p<0.01,p
<0.0001vs.对照.数据来自核心研究Marreetal.DiabetMed2009;26;268–7
8(LEAD-1);Naucketal.DiabetesCare2009;32;84–90(LEAD-2);Ga
rberetal.Lancet2009;373:473–81(LEAD-3);Zinmanetal.Diabet
esCare2009;32:1224–30(LEAD-4);Russell-Jonesetal.Diabetolog
ia2009;52:2046–55(LEAD-5);Buseetal.Lancet2009;374:39–47(L
EAD-6);Pratleyetal.Lancet2010;375:1447–56(liravs.sita)0
.0-0.2-0.4-0.6-0.8-1.0-1.2-1.4联合SULEAD-1?联合MetLEAD-2
?联合Met+TZDLEAD-4联合Met+SULEAD-5-1.6单药LEAD-3?5
1%43%基线A1c%Met和/或SULEAD-6-1.5-1.3-1.5-1.4-1.3
-1.6-1.2-1.5-1.38.38.68.58.78.68.48.88.58.5-1.1
8.2利拉鲁肽1.8mg利拉鲁肽1.2mg格列美脲罗格列酮甘精胰岛素安慰剂艾塞那肽HbA1c变化(%)-0
.9-0.8-1.1-0.58.48.38.78.4-0.88.18.1-1.2不同HbA1c控制水平时
的低血糖发生率LEAD1-6荟萃分析N=3967低血糖事件/患者-年Goughetal.Diabetes2010;
59(Suppl.1):A208(764-P)利拉鲁肽1.8mg利拉鲁肽1.2mg格列美脲26周HbA1c水平体重变
化(kg)0.0-0.5-1.0-1.5-2.051%43%-2.5-3.0-3.52.52.01.5
1.00.5+1.1+1.6+0.6-2.9+1.0+2.1联合SULEAD-1联合MetLEAD
-2联合Met+TZDLEAD-4联合Met+SULEAD-5单药治疗LEAD-3联合Met和/或SULEAD-6安慰剂利拉鲁肽1.8mg利拉鲁肽1.2mg格列美脲罗格列酮甘精艾塞那肽全部患者；与对照相比具有显著差异Marreetal.DiabetMed2009;26;268–78(LEAD-1);Naucketal.DiabetesCare2009;32;84–90(LEAD-2);Garberetal.Lancet2009;373:473–81(LEAD-3);Zinmanetal.DiabetesCare2009;32:1224–30(LEAD-4);Russell-Jonesetal.Diabetologia2009;52:2046–55(LEAD-5);Buseetal.Lancet2009;374:39–47(LEAD-6)-1.8-2.0-2.6-2.1-2.5-1.0-2.8-3.2+0.3-0.2Marreetal.DiabetMed2009;26;268–78(LEAD-1);Naucketal.DiabetesCare2009;32;84–90(LEAD-2);Garberetal.Lancet2009;373:473–81(LEAD-3);Zinmanetal.DiabetesCare2009;32:1224–30(LEAD-4);Russell-Jonesetal.Diabetologia2009;52:2046–55(LEAD-5);Buseetal.Lancet2009;374:39–47(LEAD-6)SBP变化(mmHg)联合SULEAD-1联合MetLEAD-2联合Met+TZDLEAD-4联合Met+SULEAD-5单药治疗LEAD-31-5-6-7-4-3-2-10-0.7-2.80.4-2.6-2.8-6.7-5.6-4.00.5-0.9-2.3-2.1-3.6-2.5-2.0联合Met和/或SULEAD-6-1.1全部患者。p<0.0001p<0.001p<0.05，与基线相比。安慰剂利拉鲁肽1.8mg利拉鲁肽1.2mg格列美脲罗格列酮甘精艾塞那肽 |
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