胰高血糖素样肽_1受体激动剂类药物的临床应用_

[e-mail]·-1朱延华，翁建平DOI10．7504/nk2014090202Ｒ587．1A对肠促胰素在维持葡萄糖稳定作用的认识，促进了对2型糖尿病患者以肠促胰素活性缺乏为靶向的药物研发。胰高血糖素样肽-1(GLP-1)是在营养物质的刺激下由小肠L细胞分泌的一种肽类激素。由于天然GLP-1循环半衰期短，需要开发新型GLP-1受体激动剂以便于临床应用。GLP-1受体激动剂以葡萄糖浓度依赖性刺激胰岛素分泌，还具有抑制胰高血糖素分泌和减慢胃排空，抑制食欲等作用。GLP-1受体激动剂作为治疗糖尿病的新型药物得到广泛应用。新的临床证据表明，GLP-1受体激动剂除了良好的血糖控制作用外还具有较好的安全性和心血管益处。文章综述GLP-1受体激动剂的临床疗效和安全性，剖析此类药物在2型糖尿病治疗中的地位。GLP-1受体激动剂;糖尿病TheclinicalexperienceofGLP-1receptoragonistdrugs．ZHUYan-huaWENGJian-ping．DepartmentofEndocri-nologyandMetbolismtheThirdAffiliatedHospitalSunYat-SenUniveristy[e-mail]standingoftheroleofincretinhormonesinmaintainingglucosehomeostasishasenabledthede-velopmentofpharmacotherapythattargetdeficientincretinactivityintype2diabetesmellitus．Glucagon-likepeptide-1GLP-1isapeptidehormonesecretedfromthesmallintestineinresponsetonutrientingestion．Becauseoftheshortcircu-latinghalf-lifeofthenativeGLP-1novelGLP-1receptorGLP-1Ｒagonistshavebeendevelopedtofacilitateclinicaluse．GLP-1Ｒagonistsstimulateinsulinsecretioninaglucosedependentmanner．GLP-1Ｒagonistscaninhibitglucagonsecretionandgastricemptyingandreduceappetite．AsnewantidiabeticdrugsGLP-1Ｒagonistshavebeenwidelyused．BEmergingevidenceindicatethatGLP-1-basedtherapyaresafeandmayprovidecardiovascular-benefitsbeyondglycemiccontrol．ThisarticlereviewstheclinicalaspectsofefficacyandsafetyofGLP-1Ｒagonistsandelucidatestheirrolesintreatingtype2dia-betesmellitus．KeywordsGLP-1receptoragonistsdiabetes翁建平，主任医师、二级教授、博士生导师。中山大学附属第三医院副院长，国家重点学科和国家临床重点专科(内分泌代谢病)学科带头人，教育部长江学者特聘教授、国家杰出青年基金获得者;兼任中华医学会糖尿病学分会主任委员、亚洲分子糖尿病研究会副主席。2011年获国家科技进步二等奖。先后承担科技部、卫生部、教育部多项课题，在Lancet、NewJMed、Diabetes、Diabe-tesCare、Diabetologia、Endocrinology等杂志发表SCI学术论文70余篇。“”incretin1。GIP1GLP-12GIPGIPBα。GLP-1249ChineseJournalofPracticalInternalMedicineOct．2014Vol．34No．10、。GLP-1DPP-41～2min2GLP-1GLP-1GLP-1DPP-4GLP-1GLP-1。2005。2GLP-1、、、、。1GLP-1LGLP-1。GLP-1AB、、、、、、、GLP-13－4。GLP-1GLP-1GLP-1B、B。2GLP-1。。48、confidence25416230～70HbA1c7%～10%BMI20～351∶1∶1、。BBAIＲ、PI/IDI、。2GLP-1。Jour-nalofInternalMedicine。2.1GLP-1KATPGLP-1。GLP-1α。GLP-1。2HbAlc0.8%。2.2B2BGLP-1BB、B。AMIGO2C1.532.85P＜0.0001B5。B6。LEADHOMA1.8mgB28%～34%B7－8。GLP-1B。GLP-lB。2.3GLP-1、。AMIGO93.1kg。confidence245.0kg。LEAD10－113492014103410。BMI。。LEAD-210－112。、12。BMI2。2.4GLP-1、、13。GLP-1GLP-1DPP-4。DUＲATION-110μg22mg130142。GLP-1。。SBP12226。16Meta152435.24mmHg5.91mmHg。GLP-1。10816。GLP-117。ＲCTEXSCEL、LEADEＲGLP-1GLP-1。2.5GLP-1、、、18。3GLP-1GLP-12。、2。、、。。。2。4GLP-1GLP-112h2～5hGLP-1。GLP-1124h1h。2GLP-1。3GLP-1、GLP-1GLP-1。GLP-119。5GLP-1GLP-1。、、、、、。、。449ChineseJournalofPracticalInternalMedicineOct．2014Vol．34No．105.11GLP-1T1DMT1DM20－21。GLP-1T1DM。GLP-11。5.222。、。5.3GLP-1DPP-4、。GLP-1。。MetaGLP-123。GLP-1GLP-1。ＲCTGLP-124。FDA。。。、TG＞5.0mmol/L、。5.4GLP-1GLP-1。GLP-1。5.5。＜30mL/min。5.6GLP-1、38%69.8%8.6%。。5.7NYHAⅠ～ⅡⅢ～Ⅳ。5.8MTC2MEN2。5.9GLP-1HbA1c。GLP-1Meta。6GLP-12。GLP-l、、。AACE2013GLP-1。GLP-1。54920141034102。、、、。1．1J．20146114－20.2ThorensBWaeberG．Glucagon-likepeptide-Iandthecontrolofin-sulinsecretioninthenormalstateandinNIDDMJ．Diabetes19934291219－1225.3WeiYMojsovS．Tissue-specificexpressionofthehumanreceptorforglucagon-likepeptide-IbrainheartandpancreaticformshavethesamededucedaminoacidsequencesJ．FEBSLett19953583219－224.4YamatoEIkegamiHTakekawaKetal．Tissue-specificandglu-cose-dependentexpressionofreceptorgenesforglucagonandgluca-gon-likepeptide-1GLP-1J．HormMetabＲes199729256－59.5BunckMCDiamantMCornerAetal．One-yeartreatmentwithex-enatideimprovesbeta-cellfunctioncomparedwithinsulinglargineinmetformin-treatedtype2diabeticpatientsarandomizedcon-trolledtrialJ．DiabetesCare2009325762－768.6VilsbollTBrockBPerrildHetal．Liraglutideaonce-dailyhumanGLP-1analogueimprovespancreaticB-cellfunctionandarginine-stimulatedinsulinsecretionduringhyperglycaemiainpatientswithType2diabetesmellitusJ．DiabetMed2008252152－156.7ZinmanBGerichJBuseJBetal．Efficacyandsafetyofthehumanglucagon-likepeptide-1analogliraglutideincombinationwithmet-forminandthiazolidinedioneinpatientswithtype2diabetesLEAD-4Met+TZDJ．DiabetesCare20093271224－1230.8Ｒussell-JonesDVaagASchmitzOetal．Liraglutidevsinsulinglargineandplaceboincombinationwithmetforminandsulfonylureatherapyintype2diabetesmellitusLEAD-5met+SUarandom-isedcontrolledtrialJ．Diabetologia2009.52102046－2055.9DeFronzoＲAＲatnerＲEHanJKimDDFinemanMSBaronAD．Effectsofexenatideexendin-4onglycemiccontrolandweighto-ver30weeksinmetformin-treatedpatientswithtype2diabetes．Dia-betesCare20052851092－1100.10NauckMFridAHermansenKetal．Efficacyandsafetycompari-sonofliraglutideglimepirideandplaceboallincombinationwithmetforminintype2diabetestheLEADliraglutideeffectandac-tionindiabetes-2studyJ．DiabetesCare200932184－90.11GarberAHenryＲＲatnerＲetal．Liraglutideversusglimepiridemonotherapyfortype2diabetesLEAD-3Monoarandomised52-weekphaseⅢdouble-blindparallel-treatmenttrialJ．Lan-cet20093739662473－481.12YangWChenLJiQetal．LiraglutideprovidessimilarglycaemiccontrolasglimepiridebothincombinationwithmetforminandreducesbodyweightandsystolicbloodpressureinAsianpopula-tionwithtype2diabetes