-1糖尿病治療的新希望PPT課件2

GLP-1糖尿病患者的新希望1糖尿病為進(jìn)展性疾病，特征表現(xiàn)為：β細(xì)胞功能下降血糖控制惡化微血管并發(fā)癥大血管并發(fā)癥風(fēng)險(xiǎn)增加在控制血糖的治療中，醫(yī)生、患者將面臨著：低血糖風(fēng)險(xiǎn)增加體重增加復(fù)雜的治療方案自我監(jiān)測(cè)的需求增加

2型糖尿病治療面臨的挑戰(zhàn)2023/4/172隨著時(shí)間的延長(zhǎng)，血糖控制逐漸惡化6.2%–upperlimitofnormalrangeMedianHbA1c(%)Conventional*GlibenclamideMetforminInsulinUKPDS6789Yearsfromrandomisation2468100Recommendedtreatment

target<7.0%?867.576.5Time(years)023451ADOPTMetforminGlibenclamideRosiglitazone*Dietinitiallythensulphonylureas,insulinand/ormetforminifFPG>15mmol/L;?ADAclinicalpracticerecommendations.UKPDS34,n=1704UKPDS34.Lancet1998:352:854–65;Kahnetal(ADOPT).NEJM2006;355(23):2427–432023/4/173體重增加Glibenclamide(n=277)YearsfromrandomisationInsulin(n=409)Metformin(n=342)

Conventionaltreatment(n=411);

dietinitiallythensulphonylureas,insulinand/ormetforminifFPG>15mmol/LUKPDS:upto8kgin12yearsADOPT:upto4.8kgin5yearsWeight(kg)

Rosiglitazone,0.7(0.6to0.8)Metformin,-0.3(-0.4to-0.2)**Glibenclamide,-0.2(-0.3to0.0)**Changeinweight(kg)015036912876432Years0123459692880100UKPDS34.Lancet1998:352:854–65.n=atbaseline;Kahnetal(ADOPT).NEJM2006;355(23):2427–432023/4/174低血糖p<0.05glibenclamide

vs.rosiglitazonePatientswithhypoglycaemia**(%)1039051015202530354045RosiglitazoneMetforminGlibenclamide12Hypoglycaemia,events/patient/year*051020GlargineNPH*Allsymptomatichypoglycaemicevents15Riddleetal.DiabetesCare2003;26:3080;Kahnetal(ADOPT).NEJM2006;355:2427–432023/4/1752型糖尿病的進(jìn)展過(guò)程:HbA1c,FPG和PPG惡化治療加強(qiáng)伴隨著體重增加及低血糖Beta細(xì)胞功能下降Incretin的治療會(huì)改變這些狀況嗎？2型糖尿病的自然進(jìn)展病史導(dǎo)致的結(jié)果是：逐步升級(jí)的治療方法2023/4/176人體的GLP-1具有多重生理作用大腦

胰島素分泌

(葡萄糖依賴)胰高血糖素分泌胰島素合成細(xì)胞量胰腺

肝臟

肝糖輸出

能量攝取胃腸道減少動(dòng)力2023/4/177SlideNo8與人類GLP-1的氨基酸有97%

同源與人類GLP-1的氨基酸有53%同源Studyduration:Liraglutide26weeks;exenatide30weeks.

1LEAD1,2,3,4,5meta-analysisofantibodyformation;Dataonfile;2DeFronzoetal.DiabetesCare2005;28:1092人類GLP-1LiraglutideExenatideLiraglutide:與人類GLP-1高度同源患者使用后抗體增加的比例Liraglutide1

020406080100Exenatide+

metformin243%8.6%

liraglutide抗體對(duì)療效沒(méi)有影響2023/4/178Butleretal.Diabetes2003Meieretal.Diabetologia20052型糖尿病β細(xì)胞凋亡增加2023/4/179RitzelRAetal.DiabetesCare2006;29:717β細(xì)胞量與FPG之間的關(guān)系正常IFG2型糖尿病2023/4/17102型糖尿病1相分泌消失M.A.Pfeiferetal.AmJMed1981;70:579-588對(duì)照2型糖尿病~85%2023/4/1711HolstJJ,etal.physiologicalreviews87：1409-1439，2007DoyleME,EganJM.Pharmacolther2007增加細(xì)胞內(nèi)的鈣濃度可能加強(qiáng)胰島素基因轉(zhuǎn)錄GLP-1增加胰島素mRNA

水平通過(guò)調(diào)節(jié)胰島素轉(zhuǎn)錄通過(guò)穩(wěn)定胰島素mRNA增加PDX-1mRNA及蛋白

水平快速作用慢速作用GLP-1對(duì)β細(xì)胞的作用與受體結(jié)合后激活腺苷酸環(huán)化酶形成cAMP對(duì)細(xì)胞KATP通道的作用（關(guān)閉通道，提高細(xì)胞膜勢(shì)，增加對(duì)葡萄糖的敏感性）釋放細(xì)胞內(nèi)儲(chǔ)存的Ca2+增加可釋放的胰島素分泌囊泡數(shù)量2023/4/1712Farillaetal.Endocrinology2003,

Bulottaetal.JMolEndocrinol2002,

Holzetal.Nature1993;

Druckeretal.ProcNatlAcadSciUSA1987X肥大凋亡新生增殖紅色箭頭代表GLP-1的作用

GLP-1對(duì)β細(xì)胞的調(diào)節(jié)

刺激再生，增加細(xì)胞量（動(dòng)物模型）2023/4/17SlideNo13liraglutide治療后增加β細(xì)胞量（糖尿病動(dòng)物模型）b-cellmass

(mg/pancreas)ZDFrats16-weekstudy1.Sturisetal.BrJPharmacol2003;140:123–132.

2.Rolinetal.AmJPhysiolEndocrinolMetab2002;283:E745–E75205101520Vehicle

(n=7)Liraglutidep<0.05p=0.0019150μg/kgbid(n=8)02468Vehicle

(n=10)Liraglutide200μg/kgbid

(n=10)10db/dbmice22-weekstudy2023/4/1714VehicleGLP-1Farillaetal.Endocrinology2003;144:5149-58Day1Day3Day5在孤立的人胰島GLP-1治療抑制β細(xì)胞凋亡2023/4/17SlideNo15快速輸入GLP-1可恢復(fù)一相胰島素分泌（T2DM）FehseFetal.JClinEndocrinolMetab2005;90(11):5991-5997Healthysubjects,PlaceboType2diabetes,PlaceboType2diabetes,ExenatideExenatidevsHealthyExenatidevsPlaceboP=0.0002P=0.0002P=0.0029Time(min)Insulinsecretion(pmol/kg/min)Mean(SE);N=25.2023/4/17SlideNo16Insulin(pmol/L)(n=7)(n=7)Hyperglycaemicclamp(20mmol/L)plusarginineArginineVisb?lletal.DiabeticMedicine2008;25;152-6.胰島素分泌能力增加到正常人的~50%2023/4/17SlideNo17liraglutide改善?細(xì)胞功能（單藥治療）Vilsb?llTetal.DiabetesCare2007;30(6):1608-1610改善HOMAbetap<0.0001p<0.0001(n=40)ChangeinHOMAbeta-cellfunction(%)versusbaseline-4004080120160(n=42)(n=41)改善胰島素原/胰島素Medianchangeinpro-insulin:insulinratioversusbaselinep<0.02(n=11)-0.3-0.2-0.100.1(n=21)(n=21)p<0.012023/4/17SlideNo18Zanderetal.Lancet2002;359:824-830mgGlucoseperkgleanbodyweightperpmol/lInsulinWeek0Week6在肥胖的T2DM20例患者中進(jìn)行高胰島素正糖嵌夾試驗(yàn)GLP-1治療提高胰島素敏感性2023/4/17SlideNo19GLP-1對(duì)?細(xì)胞作用小結(jié)T2DM表現(xiàn)為胰島素1相分泌消失?細(xì)胞胰島素量減少?細(xì)胞凋亡增加在體外試驗(yàn)，動(dòng)物模型及人類的研究中，均發(fā)現(xiàn)GLP-1對(duì)?細(xì)胞具有多重陽(yáng)性的有益作用GLP-1受體激動(dòng)劑在臨床單藥使用及聯(lián)合治療中改善HOMA?細(xì)胞功能減少胰島素原/胰島素改善1相及最大胰島素分泌恢復(fù)?細(xì)胞的敏感性2023/4/17SlideNo20SlideNo21Mean±2SEGarberetal.Diabetes2008;57(Suppl.1):LB3(LEAD3)Liraglutide迅速高效持久地降低HbA1c

（單純飲食控制者，單藥治療）2023/4/17SlideNo21SlideNo22加用liraglutide后

血糖達(dá)到ADA標(biāo)準(zhǔn)的患者比例高Liraglutide1.8mgLiraglutide1.2mg%reachingADAtargetSUcombinationLEAD1

Metformincombination

LEAD2

Met+TZDcombination

LEAD4

Met+SUcombinationLEAD5

MonotherapyLEAD3***p<0.0001**p<0.001parator;PatientsreachingHbA1cADAtargetsforoverallpopulation(LEAD4,5)add-ontodietandexercisefailureoruptohalfofmaximumdoseof1OAD(LEAD3);oradd-ontomonotherapy(LEAD2,1).

GlimepirideRosiglitazoneGlargineDataoriginallypresentedasMarreetal.Diabetes2008;57(Suppl.1):A4(LEAD1);Naucketal.

Diabetes2008;57(Suppl.1):A150(LEAD2);Garberetal.Diabetes2008;57(Suppl.1):LB3(LEAD3);

Russell-Jonesetal.Diabetes2008;57(Suppl.1):A159(LEAD5);26-weekstudies(LEAD3=52weeks).70605040302010-051%43%54%52%58%57%66%53%62%58%31%56%56%36%44%28%*************************Placebo2023/4/17SlideNo22GLP-1可良好控制血糖、減輕體重體重變化(kg)p=0.013absolutevaluesp=0.16changeinweight–3.0–2.5–2.0–1.5–1.0–0.50.0GLP-1

Saline

8h血糖

(GLP-1組)體重持續(xù)皮下輸注GLP-1或鹽水6周血糖(mmol/L)0510152025012345678注射后（小時(shí)）0周1周GLP-16周GLP-1900180270血糖(mg/dL)360450

Zanderetal.Lancet2002;359:824–30T2DM(n=20)觀察6周2023/4/17SlideNo23SlideNo24體重的降低得益于腹部及皮下脂肪的減少(所有試驗(yàn)組均加用二甲雙胍)體脂變化DEXAscan-4-3-2-10123Changeinbodyfat,kg(%)86%ofweightlosswasfattissue(liraglutide1.8mg)Liraglutide1.2mg+metGlimepiride+met-1.6*(-1.1%*)-2.4*(-1.2%*)+1.1kg(+0.4%)Liraglutide1.8mg+met腹部vs.皮下脂肪CTscan-25-20-1550510-10腹部皮下Changeinpercentagefat(%)-17.1-16.4-4.8-7.8*-8.5*+3.4

Dataaremean±SEM;*p<0.05vs.glim+met;n=160.LEAD2substudy,originallypresentedasJendleetal.Diabetes2008;57(Suppl.1):A32.2023/4/17SlideNo24Liraglutide血糖依賴性調(diào)節(jié)

胰島素和胰高血糖素分泌Naucketal.Diabetes2003;52(Suppl1):A128.Dataaremean±SEM11名2型糖尿病患者Liraglutide或安慰劑注射后給予階梯式低糖鉗夾實(shí)驗(yàn)鉗夾血糖水平mmol/l(mg/dl)Liraglutide(7.5μg/kg體重)(n=11)Placebo(n=11)240胰島素分泌(pmol/kg/min)Minutes10060120180c