40、(2)糖尿病药物治疗11 23

糖尿病药物治疗张国超中山大学附属第三医院内分泌科中国T2DM理想的治疗模式HbA1c纠正胰岛素作用障碍改善β细胞功能L.F.VanGaal,etal.Diabetologia(2004)46:M44–M50针对发病机制，联合治疗方案应兼顾“胰岛素分泌障碍”和“作用障碍”↓HbA1c•↓大血管病变风险•↓微循环病变风险增加胰岛素敏感性•↑胰岛素敏感性•↓肝脏葡萄糖产生↓空腹血糖改善胰岛分泌功能↓餐后血糖•恢复早相胰岛素分泌SomehistoricalpharmacologicalmilestonesinthetreatmentofdiabetesmellitusBiguanides1957Sulphonylureas1957PrandialglucoseregulatorsMetiglinide(1997),Nateglinide(2000)α-Glucosidaseinhibitors1990Thiazolidinediones1997Classicoralhypoglycemicagents(YEAR)Sulfonylureas(SUs)Mechanismofaction:IncreasedinsulinsecretionAdvantages:Wellestablished,decreasesmicrovascularrisk,convenientdailydosing,monotherapyandcombination.Disadvantages:Hypoglycemia,weightgain,hyperinsulinemia(roleuncertain).Biguanides(Metformin)Mechanismofaction:Decreasedhepaticglucoseproduction,increasedinsulinsensitivityinperipheraltissuesAdvantages:Wellestablished,weightloss,nohypoglycemia,decreasesmicro-andmacrovascularrisk,convenientdailydosing,monotherapyandcombinationDisadvantages:Adversegastrointestinaleffects,manycontraindications(e.g.Lacticacidosisextremelyrareifnormalkidneyfunction)GalegaofficinalisMetformin:pleiotropiceffectsSnakebitesLactationDysuriaSanVitodanceInsulinresistancePlagueα-GlucosidaseInhibitorsMechanismofaction:DecreasedgutcarbohydrateabsorbtionAdvantages:Targetspostprandialglycemia,nohypoglycemia,essentiallynon-systemic,maybeusedasmonotherapyorincombinationDisadvantages:Adversegastrointestinaleffects,morecomplexdosingschedule,possiblylessefficientthaneg.SUs,nolong-termdataThiazolidinedionesMechanismofaction:IncreasedperipheralglucosedisposalAdvantages:Nohypoglycemia,reversesoneprimedefectoftype2diabetes,possiblebeta-cellpreservation,beneficialeffectsonlipidmetabolism,improvedendothelialfunction,convenientdailydosing,monotherapyandcombinationwithSUandmetformin.Disadvantages:Weightgain,edema(nottobeprescribedtopeoplewithNYHAIII-IV,slightdecreaseinhemoglobin,slow-onsetofaction,increasefrequencyofheartfailure各种降糖药物对造成高血糖各成份的影响噻唑脘二酮二甲双胍促胰岛素分泌剂胰岛素噻唑脘二酮二甲双胍促胰岛素分泌剂胰岛素噻唑脘二酮二甲双胍促胰岛素分泌剂胰岛素α－糖苷酶抑制剂α－糖苷酶抑制剂α－糖苷酶抑制剂早餐中餐晚餐各种降糖药对高血糖的影响：二甲双胍、磺脲类、胰岛素：降低肝糖输出增加所造成的高血糖和餐后高血糖α－糖苷酶抑制剂：降低餐后高血糖AntidiabeticOralAgentMonotherapyandReductioninHbA1c(RandomizedControlledClinicalTrials)Sulfonylureas0.9-2.5%Metformin0.8-3.0%α-GlucosidaseInhibitors0.4-1.3%Thiazolidinediones1.1-1.6%Non-SUSecretagogues(Repaglinide)1.7-1.9%(Nateglinide)0.6-1.0%单一药物治疗无法良好地控制HbA1c－UKPDSUKPDSGroup.UKPDS34.Lancet1998;352:854–865.*当FPG15mmol/Ｌ或出现高血糖症状即更换治疗格列苯脲氯磺丙脲二甲双胍胰岛素随机化后时间(年)06789HbA1C(%)正常上限=6.2%2468100传统治疗（主要是单纯饮食控制＊）单纯增加OHA剂量将面临安全性、耐受性障碍安全性和耐受性严重肾功能不全禁用2体重增加3,4,6胃肠道副作用3乳酸性酸中毒3水肿5α-糖苷酶抑制剂TZDs胰岛素增敏剂1.KristensenJSetal.Diabetologia1999.2.S.Schumacheretal.EurJClinPharmacol(2001)57:147-1523.DeFronzoRA.AnnInternMed1999;131:281–303.4.UKPDS.Lancet1998;352:837–853.5.NestoRW,etal.Circulation2003;108:2941–2948.6.RLandgrafetal.InternationalJournalofObesity2000;24(Suppl3):S38-S44.磺脲类促泌剂二甲双胍诺和龙低血糖1=单一治疗罕见或不发生=单一治疗极少见=单一治疗多见OHA联合方案应该兼顾FPG/PPG改善胰岛素分泌缺陷(早相胰岛素分泌)抑制空腹、餐后肝糖输出减轻胰岛素抵抗是加用磺脲类药物诊断生活方式干预+二甲双胍HbA1c≥7.0％否是加用基础胰岛素加用磺脲类药物加用格列酮类药物HbA1c≥7.0％HbA1c≥7.0％HbA1c≥7.0％否是否是否强化胰岛素治疗加用格列酮类药物加用基础胰岛素HbA1c≥7.0％HbA1c≥7.0％否是否是加用基础或强化胰岛素治疗强化胰岛素治疗+二甲双胍+/-格列酮类药物2006年ADA/EASD共识2型糖尿病的治疗程序新诊断的2型糖尿病患者饮食控制、运动治疗2－3个月超重/肥胖非肥胖二甲双胍或格列酮类或α-糖苷酶抑制剂磺脲类或格列奈类或双胍类或α-糖苷酶抑制剂以上两种药物之间的联合磺脲类或格列奈类+α-糖苷酶抑制剂或双胍类或磺脲类/格列奈类+格列酮类*血糖控制不满意血糖控制不满意血糖控制不满意非药物治疗口服单药治疗口服药间联合治疗2004年中国糖尿病指南2型糖尿病的治疗程序（续）口服药联合治疗以上两种药物之间的联合磺脲类或格列奈类+α-糖苷酶抑制剂或双胍类或磺脲类/格列奈类+格列酮类*血糖控制不满意磺脲类或格列奈类+双胍类或格列酮类或磺脲类/格列奈类+α-糖苷酶抑制剂血糖控制不满意血糖控制不满意一种口服药**和胰岛素（中效或长效制剂每日1-2次）间的联合血糖控制不满意多次胰岛素***胰岛素补充治疗胰岛素替代治疗注：*有代谢综合征表现者可优先考虑；**肥胖、超重者可优先考虑使用二甲双胍或格列酮类；***如胰岛素用量较大，可加用非胰岛素促分泌剂2004年中国糖尿病指南新型降糖药物及其机理EffectsofGlucagon-LikePeptide1Stimulatesinsulinsecretioninaglucose-dependentmannerSuppressesglucagonsecretionDelaysgastricemptyingIsasatietyfactorLeadstoincreasedbeta-cellmass?Otherextrapancreaticeffects,e.g.theheart,CNS?Strategiestoby-passtherapiddegradationofnativeGLP-1LongactingGLP-1analogues(e.g.NN2211(liraglutide)),CJC-1131SyntheticExendin-4(exenatide,Bayetta)Di-Peptidyl-PeptidaseIVinhibitors,(e.g,Galvus)810121416182022242468Plasmaglucose(mmol/l)46810121416Hourofday810121416182022242468Seruminsulin(pmol/l)0100200300400500600Hourofday810121416182022242468Plasmaglucagon(pg/ml)80100120140=liraglutide=placebo=meal24-hprofilesofglucose,insulinandglucagoninT2DMDegnetal,Diabetes2004;53:1786-1791LiraglutidesignificantlyloweredHbA1cEstimatesareobtainedfromanANOVAwithpretreatmentandtreatmentasfixedeffectsandbaselineasacovariate[95%CI]HbA1c(%)-2.0-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.00.2Forallactivedoselevelsp0.0001-2.2Liraglutide0.65mg/dayLiraglutide1.25mg/dayLiraglutide1.90mg/dayN=283;Mean(±SE);P0.05.HenryR,etal.Diabetes2006;55:A116.ExenatideSustainedA1CReduction2-YearCompleters01020304050607080901001106.57.07.58.08.5Time(wk)Placebo-ControlledOpen-LabelExtensionsBaselineA1C8.3%-1.10.1%A1C(%)Nodietandexerciseregimenwasprovided.N=283;Mean(±SE);P0.05.HenryR,etal.Diabetes2006;55:A116.ExenatideContinuedtoReduceWeight2-YearCompleters0102030405060708090100110-7-6-5