心血管疾病中降糖藥物治療的選擇

AntihyperglycemicAgents:

MajorSitesofActionSulfonylureasMeglitinidesInjected

InsulinLiverPlasmaglucoseGlitazonesGItract

-Glucosidase

Inhibitors+PancreasMetforminMuscle/Fat–(–)(+)(+)(–)(+)CarbohydrateAbsorptionHepaticgluconeogenesisInsulinSecretionGlucoseUptakeInsulinSecretiona-Glucosidaseinhibitor作用機(jī)制：只作用于小腸。作用機(jī)理具有生物學(xué)基礎(chǔ)。穩(wěn)定和降低血糖水平，促進(jìn)食物正常運(yùn)行。較好的耐受性可與其他藥物同時使用?；颊邎?jiān)持規(guī)定的飲食，通常不會有任何問題。胃小腸胃小腸沒有拜唐蘋，碳水化合物的消化和吸收只發(fā)生在小腸的上段。a-葡萄糖苷酶無活性的a-葡萄

糖苷酶拜唐蘋碳水化合物拜唐蘋減慢碳水化合物的消化，從而減慢葡萄糖的攝取。a-葡萄糖苷酶無活性的a-葡萄

糖苷酶拜唐蘋碳水化合物AntihyperglycemicAgents:

MajorSitesofActionSulfonylureasMeglitinidesInjected

InsulinLiverPlasmaglucoseGlitazonesGItract

-Glucosidase

Inhibitors+PancreasMetforminMuscle/Fat–(–)(+)(+)(–)(+)CarbohydrateAbsorptionHepaticgluconeogenesisInsulinSecretionGlucoseUptakeInsulinSecretionPPAR

的激活PPAR

激動劑視黃酸PPAR

RXR基因轉(zhuǎn)錄蛋白合成mRNA增加對胰島素的反應(yīng)

–增加葡萄糖攝取–減少脂肪酸釋放AdaptedfromArnerP.DiabetesObesMetab2001;3(Suppl1):S11–S19.PPAR

激活增加胰島素的活性Youngetal.Diabetes1995;44:1087–1092.葡萄糖進(jìn)入細(xì)胞激活劑+PPAR

加快GLUT-4向細(xì)胞膜的轉(zhuǎn)運(yùn)增加GLUT-4的蛋白合成胰島素激活前脂肪細(xì)胞和脂肪細(xì)胞中的PPAR

前脂肪細(xì)胞分化激活劑特定脂肪基因的表達(dá)增強(qiáng)如aP2,LPL,FAS,PEPCK特定基因的表達(dá)增強(qiáng)

如GLUTs脂肪細(xì)胞葡萄糖

葡萄糖

葡萄糖

PPAR

胰島素刺激正常個體脂肪萎縮性糖尿病糖尿病伴肥胖糖尿病伴肥胖+PPAR

激動劑N

Freefattyacids↑Freefattyacids↓Freefattyacids“Fattyacidsteal”↓VLDLNVLDLN

Bloodglucose↑VLDL↑BloodglucoseInsulinresistance↓BloodglucoseInsulinsensitizingNormalinsulinsensitivityLiverLiverMuscleLiverFatcelldifferentiationSubcutaneous>VisceralMuscleMuscleLipotoxicdisease:RogersUnger,Annu.Rev.Med2002.53:319-36PPAR

激活促進(jìn)脂肪細(xì)胞分化PPAR

激活的其他效應(yīng)減少炎性因子-C反應(yīng)蛋白減少PAI-1(纖溶酶原激活劑的抑制劑-1)其他潛在的抗動脈粥樣硬化特性：改善血管彈性MCP-1(單核細(xì)胞化學(xué)誘導(dǎo)物蛋白-1)

;MMP-9(基質(zhì)金屬蛋白酶-9)

;ROS(活性氧簇)減少減少平滑肌細(xì)胞的增殖AntihyperglycemicAgents:

MajorSitesofActionSulfonylureasMeglitinidesInjected

InsulinLiverPlasmaglucoseGlitazonesGItract

-Glucosidase

Inhibitors+PancreasMetforminMuscle/Fat–(–)(+)(+)(–)(+)CarbohydrateAbsorptionHepaticgluconeogenesisInsulinSecretionGlucoseUptakeInsulinSecretionStructureofSulfonylureaTolbutamide(Rastinon)Glibenclamide(Daonil,Glycomin)Glipizide(Minidiab)Glimepiride(Amaryl)CIOOOOOOSOOOSOOOSOOOSOONNHNHNHNHNHNHNHNHNHNHNHNSUmoietyD-phenylalanine

D-苯丙氨酸NateglinideH2NHOOHOOHNORepaglinideOHOOHNNHNOOHOMeglitinide氯茴苯酸HNOSOOOHNHNOCIGlyburide(Glibenclamide)StructureofSulfonylureaandMeglitinideSUMoiety達(dá)美康Tolbutamide優(yōu)降糖格列美嬲促胰島素分泌劑的化學(xué)結(jié)構(gòu)瑞格列奈分子磺脲/列奈類藥物作用機(jī)理K+caChannelGlucose

Insulin細(xì)胞核glucoseATP細(xì)胞膜電位蛋白質(zhì)合成Ca2+insulinCa2+ChannelK+ATPChannelH+

ChannelNa+

Channel磺脲類藥物Glut-2列奈類Ca2+Kir6.2SUR1SUR1Kir6.2Kir6.2SUR1SUR1Kir6.2磺脲類受體孔形成單位SUR1在胰腺

-細(xì)胞,大腦SUR2A在心臟和骨骼肌SUR2B在平滑肌、大腦bKir6.2磺脲類受體亞型結(jié)構(gòu)GribbleFMDiabetes1998化學(xué)結(jié)構(gòu)與功能的關(guān)系磺脲類基團(tuán)（達(dá)美康）SSK+SUR1SKir6.2SUR2Kir6.2AshcroftFMDiabetologia1999磺脲基團(tuán)和苯氨酸基團(tuán)（如優(yōu)降糖和格列美脲）SUR1BBSSSKir6.2BBSUR2BKir6.2BSUR1Kir6.2SUR2Kir6.2缺血、缺氧基礎(chǔ)狀態(tài)基礎(chǔ)狀態(tài)KATP通道的作用及分布胰腺

-細(xì)胞心肌血管平滑肌生理刺激在2型糖尿病

關(guān)閉通道在心肌缺血患者

開放通道在心肌缺血患者開放通道神經(jīng)遞質(zhì)治療目的組織反應(yīng)肌肉松弛

擴(kuò)血管作用胰島素分泌缺氧缺氧高血糖縮短反應(yīng)預(yù)期

心臟作功缺血預(yù)適應(yīng)心律失常30s1nA10μM格列齊特

10μM格列齊特Kir6.2/SUR1

-細(xì)胞型Kir6.2/SUR2A心肌細(xì)胞型GribbleFMDiabetes1998G/Gc8700.20.40.60.816低親和性G/Gc8700.20.40.60.816-log10{[格列齊特](M)}-log10{[格列齊特](M)}高親和性治療濃度范圍達(dá)美康

對克隆

-細(xì)胞及心肌通道的不同作用不同促分泌劑在不同組織磺脲類受體結(jié)合的可逆性差異Kir6.2/SUR2AKir6.2/SUR110Mgliclazidem10Mgliclazidem100nMglibenclamide100nMglibenclamide10Mmeglitinidem10Mmeglitinidem1nAAshcroftFMDiabetologia1999Or1uMglimepirideOr1uMglimepiride格列美脲選擇率達(dá)美康優(yōu)降糖瑞格列奈1600072<1不同促分泌劑的選擇性差異不同藥物對心血管KATP通道的抑制藥物胰島B細(xì)胞（大鼠）冠脈平滑肌細(xì)胞（豬）主動脈平滑肌細(xì)胞（大鼠）心肌細(xì)胞（大鼠）那格列奈63%15%*13%*39%格列本脲62%44%47%35%瑞格列奈62%25%*20%*66%在對B細(xì)胞KATP通道等效抑制時，不同藥物對心血管KATP通道的抑制百分比*與B細(xì)胞相比，P<0.05英國劍橋大學(xué)完成尼可地爾為鉀通道激活劑，心絞痛治療新藥，國際上應(yīng)用日趨廣泛研究發(fā)現(xiàn)格列美脲和優(yōu)降糖明顯抑制尼可地爾活性達(dá)美康對心臟無作用心絞痛患者服用尼可地爾時，建議選擇達(dá)美康FrankReimann，Diabetes，Vol。50，October2001抗心絞痛的鉀通道開放劑—

尼可地爾(Nicorandil)和磺脲類藥物的交互影響0243165通道開放通道關(guān)閉格列美脲優(yōu)降糖達(dá)美康NS磺脲類與尼可地爾在心臟KATP通道的交互作用FrankReimann，Diabetes，Vol。50，October2001+++尼可地爾尼可地爾尼可地爾“b-細(xì)胞選擇性的磺脲類藥物代表著糖尿病合并有缺血性心臟病的藥物治療的新策略"BradyPJACC1998選擇性研究的結(jié)論提示--保證有效降低血糖的同時，尋求更好的心臟或其他器官保護(hù)作用達(dá)美康對血液生化的影響使血小板功能正?；寡鼙诘睦w溶蛋白溶酶活性正?；宄杂苫謴?fù)前列腺素的平衡保護(hù)內(nèi)皮功能達(dá)美康使血小板功能正?；“迥?%)405060708090100P<0.0103P=0.00603個月優(yōu)降糖達(dá)美康JenningsPEetal.Metabolism.1992;41:36-39.NS個月達(dá)美康清除自由基血漿脂類過氧化物優(yōu)降糖0MDA-LM(

ol/L)P=0.009達(dá)美康1234567897.28.8RBC*超氧歧化酶優(yōu)降糖0紅細(xì)胞SOD(

g/mL)P=0.003達(dá)美康20406080100120140160158117JenningsPEetal.Metabolism.1992;41(suppl1):36-39.*紅細(xì)胞達(dá)美康恢復(fù)前列腺素的平衡微血栓素TXB2(ng/L)15020025030003個月前列環(huán)素6-KetoPGF1a(ng/L)6070809003個月100***P<0.001FuZZetal.Metabolism.1992;90:33-35.O’BrienRJDiabetComps200040608010012053.6113.653.153.654.0未治療LDLLDL+達(dá)美康LDL+格列吡嗪LDL+優(yōu)降糖LDL+D860P<0.001LDL+G格列美脲53.5P<0.001延遲LDL氧化時間延遲LDL氧化時間*P<0,05vscontrol#P<0,05vsGHHb7.817.317.337.567.7278controlGHHbGHHb+0.1μM達(dá)美康#**pD2

(Log-1EC50bradykinin)GHHb+1μM達(dá)美康GHHb+10μM達(dá)美康*VallejoSDiabetologia2000評價對內(nèi)皮功能影響PD2：GHHb抑制緩激肽舒血管反應(yīng)，

產(chǎn)生一半最大效應(yīng)所需劑量的負(fù)對數(shù)值GHHb：糖基化的氧合血紅蛋白7.46.936.976.57.5對照GHHbGHHb+

10μM優(yōu)降糖pD2

(Log-1EC50bradykinin)OmiHJDiabetesComplications2001對照p<0.01達(dá)美康p<0.01葡萄糖格列美脲

優(yōu)降糖

那格列奈

二甲雙胍051015202530Neutrophiladhesion(%)對內(nèi)皮功能的保護(hù)作用脂質(zhì)過氧化物（

mol/l）對照組格列本脲組 達(dá)美康組*與正常人相比P=0.0001，**與格列本脲治療組相比P=0.0001。****G.DeMattia,DiabetesUK,DiabeticMedicine,19,752-757脂質(zhì)過氧化物酶(∪mol/L)達(dá)美康增強(qiáng)2型糖尿病人的抗氧化能力和一氧化氮介導(dǎo)的舒血管作用（治療12周）PPAR

激活的其他效應(yīng)減少炎性因子-C反應(yīng)蛋白減少PAI-1(纖溶酶原激活劑的抑制劑-1)其他潛在的抗動脈粥樣硬化特性：改善血管彈性MCP-1(單核細(xì)胞化學(xué)誘導(dǎo)物蛋白-1)

;MMP-9(基質(zhì)金屬蛋白酶-9)

;ROS(活性氧簇)減少減少平滑肌細(xì)胞的增殖心血管疾病中降糖藥物的選擇病人評價一般情況心臟病變糖尿病狀態(tài)肝腎功能藥物選擇作用機(jī)制副作用對心臟病變的影響降糖外作用治療后監(jiān)測血糖副作用程度肝、腎功能病人評價一般情況：年齡：<45歲、＜60歲、≥60歲BMI：＜25、≥25腰圍：男＞90、女＞85腰圍/身高比值：≥0.5病人評價病情評價：心臟病變：高血壓、高血脂、心律失常、冠心病、心臟手術(shù)后、導(dǎo)管術(shù)后、安裝起博器后、心功能治療藥物：

B-阻滯劑、利尿劑糖尿病評價：血糖水平、胰島功能、GAD抗體腎臟情況：血肌酐、BUN、尿蛋白水平、尿酸肝臟情況：轉(zhuǎn)氨酶、脂肪肝基本原則年齡<45歲BMI<25DM、IGT、IFG年齡≥45歲BMI≥25DM、IGT、IFGGAD（+）正常IROGTT葡萄糖鉗夾GAD-Ab測定OGTTGAD（-）抵抗、高InsIns雙胍類GLITAZONES糖苷酶抑制劑磺脲類/列奈類糖苷酶抑制劑雙胍類Glitazones糖苷酶抑制劑每年必要時GAD-Ab血清谷氨酸脫羧酶抗體是一型糖尿病早期診斷的一個關(guān)鍵的自身抗原，GAD正常為陰性，＞50為陽性。胰島細(xì)胞抗體(ICA)、胰島素自身抗體(IAA)谷氨酸脫羧酶抗體（GAD）綜合診斷一型糖尿病的依據(jù)檢測是否為胰島素敏感還是抵抗型：有高胰島素-正常血糖鉗夾和高葡萄糖變量鉗夾兩種方法藥物選擇主要問題降低體重，減輕胰島素抵抗，避免副作用藥物肝腎功能正常肝功能正常、腎功能輕度異常腎功能正常、肝功能輕度異常肝腎功能中度以上異常一線二甲雙胍文迪雅糖苷酶抑制劑文迪雅糖苷酶抑制劑二甲雙胍糖苷酶抑制劑胰島素糖苷酶抑制劑二線（根據(jù)血糖水平）磺脲類（達(dá)美康）列奈類磺脲類（糖適平）列奈類磺脲類（達(dá)美康）列奈類—三線（根據(jù)血糖水平）胰島素胰島素胰島素—高血壓、高血脂、心功能正?！逝炙幬镞x擇主要問題降低體重，減輕胰島素抵抗，避免低血糖??！藥物肝腎功能正常肝功能正常、腎功能輕度異常腎功能正常、肝功能輕度異常肝腎功能中度以上異常一線二甲雙胍文迪雅糖苷酶抑制劑文迪雅糖苷酶抑制劑二甲雙胍糖苷酶抑制劑胰島素糖苷酶抑制劑二線（根據(jù)血糖水平）列奈類短效磺脲類磺脲類（糖適平）列奈類列奈類短效磺脲類—三線**（根據(jù)血糖水平）胰島素胰島素胰島素—心絞痛、心梗后、冠脈術(shù)后穩(wěn)定期、心律失常、心功能正常—肥胖**小劑量長效胰島素為基礎(chǔ)的多中心研究進(jìn)行中注意：腎功能異常者不用二甲雙胍肝功能異常者不用文迪雅（羅格列酮）腎功能異常者可用糖適平（格列奎酮）藥物選擇主要問題測定GAD抗體、OGTT，明確胰島功能和診斷，避免副作用藥物肝腎功能正常肝功能正常、腎功能輕、中度異常腎功能正常、肝功能輕、中度異常肝腎功能中度以上異常一線磺脲類（達(dá)美康）列奈類糖苷酶抑制劑磺脲類（糖適平）列奈類糖苷酶抑制劑磺脲類（達(dá)美康）列奈類糖苷酶抑制劑胰島素糖苷酶抑制劑二線（根據(jù)血糖水平）二甲雙胍文迪雅文迪雅二甲雙胍—三線（根據(jù)血糖水平）胰島素胰島素胰島素—高血壓、高血脂、心功能正?！莘逝终呤走x胰島素增敏劑，而代謝綜合癥的消瘦者注意一型糖尿病，首選促泌劑，根據(jù)肝腎功能選擇具體種類。伴心血管疾病的消瘦者首選增敏劑，注意磺脲類易致低血糖。藥物選擇主要問題測定GAD抗體、OGTT，明確胰島功能和診斷，避免低血糖！！藥物肝腎功能正常肝功能正常、腎功能輕度異常腎功能正常、肝功能輕度異常肝腎功能中度以上異常一線二甲雙胍文迪雅糖苷酶抑制劑文迪雅糖苷酶抑制劑二甲雙胍糖苷酶抑制劑胰島素糖苷酶抑制劑二線（根據(jù)血糖水平）列奈類短效磺脲類糖適平列奈類列奈類短效磺脲類—三線**（根據(jù)血糖水平）胰島素胰島素胰島素—心絞痛、心梗后、冠脈術(shù)后、心律失常穩(wěn)定期、心功能正?！?*小劑量長效胰島素為基礎(chǔ)的多中心研究進(jìn)行中藥物選擇心絞痛、心梗后、心律失常非穩(wěn)定期冠脈術(shù)后早期心功能異常、反復(fù)心衰胰島素治療禁任何口服降糖藥藥物選擇

GAD-Ab（+）或≥60雙胍類GLITAZONES糖苷酶抑制劑胰島素ClinicalEfficacyofOralHypoglycemicAgentsClassofhypoglycemicagentsReductioninHbA1c(%)ReductioninFPG(mgperdl)SulfonylureasMeglitinidesBiguanidesThiazolidinedionesa-Glucosidaseinhibitor0.8to2.00.5to2.01.5to2.00.5to1.50.7to1.060to7065to7550to7025to5035to40OptionsformonotherapySulfonylureasMeglitinidesBiguanidesThiazolidinedionesα-glucosidaseinhibitorsRecenttype2DMdiagnosisType2DM<5yrs’durationRecenttype2DMdiagnosisElevatedPPGOverweight/obeseInsulinresistantInsulinresistantOverweight/obeseDietcontrolElevatedPPGContraindicationstootheragentsAdvantagesSulfonylureasMeglitinidesBiguanidesThiazolidinedionesα-glucosidaseinhibitorsRapidFPGreductionLowcostSomeantioxidative…↓RiskofhypoglycemiaShort-actingMeal-adjusteddosingSafeandeffectiveinrenaldysfunction

(Metabolisedintheliver,biliaryexcretion,Metabolitesareinactive)Noweightgain↓Riskofhypoglycemia↓Amountofinsulin↓RiskhypoglycemiaNoGIsideeffectNodruginteractionNoadjustdoseinRF↓RiskofhypoglycemiaNonsystemicaction↓PPGInsulinsensitizersNostimulationofinsulinsecretionBeneficiallipidprofile

DisadvantagesSulfonylureasMeglitinidesBiguanidesThiazolidinedionesα-glucosidaseinhibitorsWeightgain↑RiskofhypoglycemiaHighcostsFrequentdosingGIsideeffectsRarelacticacidosisHighcostWeightgainSlowonsetofactionIssueoflivertoxicityColonicpolypsEdema（Na,H2Oretention)HeartfailureHighcostGIsideeffectsLimitedefficacyPART1KENMonotherapyPearlsAlldrugsexceptAGIsandnateglinideequallyreduceHbA1cMetforminusuallybestforobese-noweightgainNon-SUsecretagoguesmaybeusefulforirregularmealsMetforminandTZDsavoidhypoglycemiaOptionsforcombinationtherapySulfonylureas+BiguanideOrThiazolidinedioneOra-glucosidaseinhibitorBiguanide+meglitinideBiguanides+ThiazolidinedionesBiguanide+a-glucosidaseinhibitorTriplecombinationtherapySulfonylurea+biguanide+ThiazolidinedioneorSulfonylurea+biguanide+a-glucosidaseinhibitorIftherapeuticgoalsarenotmetusingtheabovecombinations;switchtoinsulin+/-oralagentCombinationTherapyinType2Diabetes:

DecisionConsiderationsHbA1cefficacyReductionsfrombaselineReachingtargetSynergyofmechanismsofactionSideeffectsandtoxicityprofileFrequencyandseverityofhypoglycemiaEffectonweightgainAvoidingpolypharmacyandcomplexregimensComplianceandconvenienceCost5-1aMANAGEMENTGUIDELINES

InitialTreatmentRecommendationsFBG126-140mg/dLMetformin

-GlucosidaseInhibitorsSulfonylureasMetforminMeglitinides

-GlucosidaseInhibitorsSulfonylureasMetforminNosymptoms:SulfonylureasSymptoms:InsulinsFBG140-200mg/dL200-240mg/dLEarlycombinationtherapyIfFPG>140mg/dLorHbA1c>8%>240mg/dLFBG>126mg/dLDiet+exerciseGlitazoneGlitazone4-33GlycemicgoalsnotachievedModifiedfromAmericanDiabetesAssociation.DiabetesCare.1995;18:1510-1518.NonpharmacologicTherapy

Diet

ExerciseMonotherapySulfonylureasBiguanidesa-GlucosidaseInhibitorsGlitazonesMeglitinidesInsulinCombinationTherapy

FrequentlyusedorwellstudiedSulfonylurea+MetforminSulfonylurea+RosiglitazoneSulfonylurea+PioglitazoneSulfonylurea+AcarboseRepaglinide+MetforminRosiglitazone+MetforminPioglitazone+MetforminSulfonylurea+InsulinMetformin+InsulinPioglitazone+InsulinRosiglitazone+InsulinAcarbose+InsulinInfrequentlyusedand/or

lesswellstudiedSulfonylurea+Metformin+GlitazoneSulfonylurea+Metformin+InsulinGlitazone+Metformin+InsulinInsulinIntermediateBIDIntermediate+RegularBIDMultiple(3ormore)injectionsGlycemicgoalsnotachievedGlycemicgoalsnotachievedVerysymptomaticSeverehyperglycemiaKetosisUnrecognizedIDDMPregnancyADA“Consensus”onType2DiabetesTherapy5-1DeFronzo,etal.NEnglJMed.1995;333:541-549;Horton,etal.DiabetesCare.1998;21:1462-1469;Coniff,etal.DiabetesCare.

1995;18:817-824;Moses,etal.DiabetesCare.1999;22:119-124;Schneider,etal.Diabetes.1999;48(suppl1):A106;Egan,etal.Diabetes.1999;48(suppl1):A117;Fonseca,etal.Diabetes.1999:48(suppl1):A100.Regimen

HbA1c

FBG

Sulfonylurea+metformin ~1.7% ~65mg/dL Sulfonylurea+rosiglitazone ~1.4% ~60mg/dL Sulfonylurea+pioglitazone ~1.2% ~50mg/dL Sulfonylurea+acarbose ~1.3% ~40mg/dL

Repaglinide+metformin ~1.4% ~40mg/dL Pioglitazone+metformin ~0.7% ~40mg/dL Rosiglitazone+metformin ~0.8% ~50mg/dL Insulin+oralagents OpentoTarget OpentoTargetCOMBINATIONTHERAPY

EstimatedImprovementsinGlycemicControl5-1bMANAGEMENTGUIDELINES

CombinationsofOralAgents:

Sulfonylurea-BasedRegimensStartwith Long-actingsulfonylureaoncedaily

(glimepirideorextended-releaseglipizide)Add Metformin

(preferredorder)

or

Glitazone

(ifintoleranceorcontraindicationformetforminpresent)

or

-Glucosidaseinhibitor

(ifintoleranceorcontraindicationforboth

metforminandglitazonepresent)5-8PRACTICALGUIDELINES

StartingBasalInsulinContinueoralagent(s)atsamedosage(eventuallyreduce)Addsingle,eveninginsulindose(around10U)NPH(bedtime)（中效胰島素）70/30(eveningmeal)（短效胰島素）Glargine(bedtimeoranytime)（來得時長效）AdjustdosebyfastingSMBG（空腹自測血糖）IncreaseinsulindoseweeklyasneededIncrease4UifFBG>140mg/dL（相當(dāng)于7.8mmol/L)Increase2UifFBG=120-140mg/dL(相當(dāng)于6.7-7.8mmol/L）Treattotarget(usually<120mg/dL)5-18PracticalManagementofType2DiabetesMellitusFBG>126mg/dL（7mmol/L）DietandExercise126-140mg/dL140-200mg/dL200-240mg/dL240-300