糖尿病治療之新趨勢王朝弘醫(yī)師內(nèi)分泌暨新陳代謝科馬偕醫(yī)院92-11-2507:30~08:20糖尿病治療之新趨勢王朝弘醫(yī)師1

一、Introduction二、PathophysiologyofDiabetesMellitus三、Treatmentstrategies四、ClinicalTrials五、DrugsforTreatment六、TheFuture七、Questions&AnswersA)CurrentmedicationsB)InsulinsensitizersC)InsulintherapyinT2DMD)Drugsinteraction一、IntroductionA)Currentmedi2第一型糖尿病的疾病生理發(fā)展階段第一階段 基因體質(zhì)第二階段 環(huán)境觸發(fā)第三階段 自家免疫啟動第四階段 貝它細(xì)胞逐漸失能第五階段 糖尿病顯現(xiàn)第一型糖尿病的疾病生理發(fā)展階段3IMPAIREDGLUCOSETOLERANCEDYSLIPIDAEMIATYPE2DIABETESHYPERTENSIONFIBRINOLYSISURICACIDSYSTEMICINFLAMMATIONLEPTINATHEROSCLEROSISENDOTHELIALDYSFUNCTIONCENTRALOBESITYINSULINRESISTANCEIMPAIREDDYSLIPIDAEMIATYPE2DI4LossofEarly-phaseInsulinRelease

inType2DiabetesWardWKetal.DiabetesCare1984;7:491–502NormalType2diabetes120100806040200 –30 0 30 60 90 120Time(minutes) –30 0 30 60 90 120Time(minutes)Plasmainsulin(μU/ml)12010080604020020gglucose20g

glucosePlasmainsulin(μU/ml)Patternofinsulinreleaseisalteredearlyintype2diabetesLossofEarly-phaseInsulinRe5GeneticPredispositionEnvironmentalfactorsObesityAgeLifestyleInsulinResistanceInsulinSecretionCVDHTNStrokeLipiddisordersManyotherdiseasesIFG,IGT,T2DM+β-celldefectMetabolic(InsulinResistance)SyndromeGeneticEnvironmentalfactorsIn6-12-10-6-202610140255075100IGTPostprandialHyperglycemiaType2DiabetesPhaseIType2DiabetesPhaseIIType2DiabetesPhaseIIIYearsFromDiagnosisBetaCellFunction(%)StagesofType2Diabetes-12-10-6-2026101407DiabetesTreatmentGoalsPlasmaGlucose(mg/dL) Preprandial PostprandialA1C(%)Normal<110<140?<6.0ADA90~130<180<7.0ACE/AACE<110<140?<6.5*ACEE=AmericanAssociationofClinicalEndocrinology;ACE=AmericanCollegeofEndocrinology; ADA=AmericanDiabetesAssociation.?Two-hourpostprandialDiabetesTreatmentGoalsPlasma8CorrelationbetweenA1C&

meanplasmaglucoselevelA1C(%)6789101112Meanplasmaglucose(mg/dl)

135 170

205 240

275 310

345ADA2003CorrelationbetweenA1C&

mea9NormalPhysiologyofGlucoseHomeostasisGlucoseuptake,hepaticglucoseproduction&storageofglycogenInsulin-stimulatedglucoseuptakeRegulationoflipolysis

Adipose

tissueCarbohydrateBloodGlucoseDigestiveenzymesGutPancreasMuscleLiverInsulinNormalPhysiologyofGlucoseH10SteppedManagementofType2DiabetesSteppedManagementofType2D11TreatmentStrategiesFPG(mg/dl)A1C(%)140~1607.0~8.0>160>8.0or+1OHA+Insulin

Insulinsensitizer

-glucosidase

monotherapy

Combinationtherapy(2OHAs)<1406.5~7.0TreatmentStrategiesFPG(mg/dl12FinnishDiabetesPreventionStudy

meandurationof3.2years

Interventiongr. Controlgr.

n=265 n=257

Specificdietaryinstructionoralorwritteninformationatbaseline(diet&exercise)

Moderateexercise≧30min/dnospecificindividualized program

DMdevelopedn=27 n=59

DMdeveloped3%/yr 6%/yr

RiskofT2DMreducedby58%FinnishDiabetesPreventionSt13DiabetesPreventionProgram

3yearsofobservationIntensetherapeuticlifestylechange．Metformin．Placebowtloss>7% ．850mgb.i.d.．IGT→T2DMExercise>150min/wk 11%/yr

N=1073 ．N=1082 ．N=1079Riskreduction58%．riskreduction31%DiabetesPreventionProgram

314UKPDSForeach1%reductioninA1COvera6-yearperiod,~53%ofpt’streatedwith sulfonylureasneededadditionalinsulin therapyA21%decreaseinanyendpointrelatedtodiabetes&in diabetes-relateddeathA14%decreaseinall-causemortality&MIA43%decreaseinamputationordeathfromPVDA37%decreasedriskformicrovascularcomplicationsUKPDSForeach1%reductionin15

非藥物生活型態(tài)之改變飲食、營養(yǎng)之控制規(guī)律之運動非藥物生活型態(tài)之改變16OralAntihyperglycemicAgentsAgentSulfonylureasNateglinideRepaglinideMetforminPioglitazoneRosiglitazoneAcarboseMiglitolClassSulfonylureaNonsulfonylureainsulinsecretagogueNonsulfonylureainsulinsecretagogueBiguanideThiazolidinedioneThiazolidinedione-Glucosidaseinhibitor-GlucosidaseinhibitorMajormechanismofactioninsulinsecretionprandialinsulinsecretionprandialinsulinsecretioninsulinresistance(hepatic)insulinresistance(peripheral)insulinresistance(peripheral)DelaysCHOabsorptionfromG-ItractDelaysCHOabsorptionfromG-ItractOralAntihyperglycemicAgentsA17a)MetforminPharmacologicalAgents(1.0)Action:Insulinresistance(plasmainsulinconc.)byInsulin-mediatedmuscleglucoseuptake

Insulin-mediatedhepaticgluconeogenesis

Translocationofglucosereceptorstoplasma membranea)MetforminPharmacologicalA18ContraindicationsandPrecautions

MetforminHepaticdisease,CHF(drugstreated)HxoflacticacidosisRenalimpartment—GFRs(<60ml/min)or Srcr(men:>1.5mg/dl,women:>1.4mg/dl)AlcoholingestionShockSurgeryAging(80years)ContraindicationsandPrecauti19c)Alpha-glucosidaseinhibitors(AGIs)

differentmodeofactionfromotherdrugsAction:Inhibitstarchdigestioninsmallintestine, &delayingglucoseabsorptionAdvantages:

wt

postprandialglycemia

noriskofhypoglycaemia

flatulence&bloatingDisadvantages:

diarrheaPharmacologicalAgents(2.0)c)Alpha-glucosidaseinhibito20InsulinSecretion1st-phaseNoYes2nd-phaseexaggeratedNoBiologicalhalf-lifeVeryshortStarlixShortTolbutamideNovoNormIntermediateGlipizide,Diamicron,AmaryllongEuglucon,DiabenaseHypoglycemicrisk

SulfonylureasNon-sulfonylureasInsulinSecretagoguesInsulinSecretionSulfo21d)Sulphonylureas

powerfulhypoglycemiceffectAction:IncreaseinsulinsecretionbyclosingKatp channelsinpancreaticβcellAdvantages:

lowcost

noGIintolerance

weightgainDisadvantages:

secondaryfailurecommon

riskofhypoglycaemiaPharmacologicalAgents(3.0)d)Sulphonylureaspowerfulhy22NovoNorm(4.3)ShortactingDifferentbindingsiteatSURreceptorRapidlyabsorbed(peak~45’)Actionwithin30’0.5~4.0mgacwithin30’Stimulateearly-phaseinsulinsecretion,subside~4hMeanA1C~1.7%MeanFPG~61mg/dlLivermetabolism~100%

Lesshypoglycemia&wtgainòòvs.PlaceboNovoNorm(4.3)Shortactingòòv23Starlix:

使糖立釋膜衣錠60毫克(5.0)成分名：Nateglinide商品名：Starlix?適應(yīng)癥：第2型糖尿病(非胰島素依賴型糖尿病)最新一類藥物：D-phenylalanine氨基酸衍生物，被 FDA證明可分泌早期胰島素的抗糖尿病藥物作用機(jī)轉(zhuǎn)：可藉由高度選擇性地阻斷鉀離子管道(Katp channel)，恢復(fù)人體本能胰島素分泌的能力(mimicphysical insulinrelease)臨床療效：明顯降低飯後血糖(2hr-PPG)，糖化血色素 (A1C)與空腹血糖(FPG)，而不刺激胰臟β-細(xì)胞分泌過 度的胰島素Starlix:使糖立釋膜衣錠60毫克(5.0)成24快速生效(Fast-on)；快速恢復(fù)(Fast-off)的作用(5.1)‘Fast-on’:(快速生效)作用，可重建糖尿病患喪失的 「早期胰島素」分泌功能?！瓼ast-off’:(快速恢復(fù))作用，可避免因高胰島素延緩 而導(dǎo)致的低血糖危險Starlix?對血中葡萄糖濃度感受性非常明顯；當(dāng)血糖 高時，作用明顯；反之血糖低時，則作用減低。 不易造成高胰島素或低血糖之副作用。快速生效(Fast-on)；快速恢復(fù)(Fast-off)的作25Starlix(5.2)

Rapidlyabsorbed&actingSignificantselectivityon-cells&cardiaccellsNoaccumulationortissueretentionwith

repeatedadministrationRelativelylowpotentialfordrag-druginteractionsRestoringearly-phaseinsulinsecretionNospecialdoseadjustments(elderly,renalimpairment)60~180mgtaken1’~30’beforemealHypoglycemia&wtgain─lowpotentialMonotherapy&combinationtherapyStarlix(5.2)Rapidlyabsorbed26

NovoNorm(1mg/#)Starlix(60mg/#)

rapidlyabsorbed

Peakplasmalevelwithin1°within45minBioavailability65%70%plasmat1/2~1h0.5~1.9hKatp-channelbindingfaster-affinitylowerMetabolismliverintoinactiveliver(85-95%)

substancesto3~6lesspotentproductsExcretionbile(major)urine(75%)

urine6%feces(~10%)

Maximaldose16mg/d540mg/d

NovoNorm27ContraindicationsandPrecautions

SulphonylureasT1DMPregnancyorbreast-feedingDocumentedhypersensitivitySeverehepaticorrenaldysfunctionSevere,acuteillness(e.g.,infection,MI),surgery, stressContraindicationsandPrecauti28b)Thiazolidinediones

powerfulhypoglycemiceffectAction:ReduceinsulinresistancebyactingasPPAR

g

agonists

lowriskofsecondaryfailureAdvantages:

lipids

plasmainsulin

noriskofhypoglycaemia

fluidretentionDisadvantages:

weightgain

?Hepaticdysfunction

dilutionalanemia

highcostPharmacologicalAgents(6.0)b)Thiazolidinedionespowerfu29ContraindicationsandPrecautions

ThiazolidinedionesT1DMPre-existinghepaticdisease

*ALT>2.5UNL

*d/c,ifALT>3UNL,risingserumbilirubin

*HepatitisSx(malaise,fatigue,nausea,

vomiting,darkurine,abdominalpain,……)SevereCHF(NYHAclassesⅢ&Ⅳ)Premenopausalanovulatorywoman—unwantedpregnancyHxofhypersensitivitytoTZDsDrugsmetabolizedbyCYP3A4ContraindicationsandPrecauti30DrugsInteraction

Sulphonylurea

Effect

*AntacidsGastricpHEnhancedEugluconabsorption*CimetidineTolbutamidehepaticmetabolism*FluconazolePlasmaconc.*GemfibrozilProteindisplacement,needtodoseofSU*SulfinpyrazoneTolbutamidehepaticmetabolism&t1/2 2~3

Effect*AlcoholTolbutamidehepaticmetabolism2*RifampinEugluconmetabolismt1/2&plasmadrug conc.OralAnti-diabetesAgents(1)

DrugsInteractionSulphonylure31DrugsInteractionMetformin*AlcoholEffectsofmetforminonlactatemetabolism*CimetidinePeakmetforminplasmaconc.*ErythromycinSeverecholestatichepatitisreported (withchlorpropamide)*I-contrastdyeARF,lacticacidosis-GlucosidaseInhibitors*DigestiveenzymepreparationsAcarboseeffect*DigoxinSerumdigoxinconc.therapeuticeffects*InderalBioavailabilityofpropranolol~40%*RanitidineBioavailabilityofRanitidine~60%(Miglitol)OralAnti-diabetesAgents(2)DrugsInteractionMetforminOral32DrugsInteractionThiazolidinediones*KetoconazoneInhibitthemetabolismofActos*OralpillsPlasmaconc.(~30%)ofethinyl estradiol&norethindorne(Actos), watchforforflushes(estrogendef)*TerfenadinePlasmaconc.(~50~70%)of Terfenadine(Troglitazone)

OralAnti-diabetesAgents(3)DrugsInteractionThiazolidined33ComparisonofHumanInsulins

andInsulinAnaloguesLispro/aspartHumanregularHumanNPH?/Lente?HumanUltralenteGlargine5~15min30~60min1~2h2-4h1-2h1~22~44~8UnpredictableFlat4~68~1010~2016~20About24InsulinpreparationOnsetofactionPeak(h)Durationofaction(h)*Thetimecourseofactionofanyinsulinmayvaryindifferentindividualsoratdifferenttimesinthesameindividual.Becauseofthisvariation,timeframesshouldbeconsideredgeneralguidelinesonly.?Humaninsulinisophanesuspension(orneutralprotamineHagedorn).?Humaninsulinzincsuspension.ComparisonofHumanInsulins

34PremixedInsulinCombinationsCombinationNovologMix70/30 (70%insulinaspartprotamine&30%insulinaspart)Novolin70/30 (70%insulinNPH&30%insulinregular)HumalogMix75/25 (75%insulinlisproprotamine&25%insulinlispro)Humulin70/30 (70%insulinNPH&30%insulinregular)Intervalbetweendosing&mealinitiation(min)10~20301530~60Timeofpeakactivity(hafterdosing)2.2+0.804.2+0.932.6(1.0~6.5)4.4(1.5~16)PremixedInsulinCombinationsC35RoleforInsulinTherapyinT2DMAdiseaseofinsulindeficiency–continuingdeterioration inβ-cellfunctionNotgoodatdiagnosingdiabetesAlltype2diabetesisnottype2diabetesEffectsofOHAsarelimitedNaturalHxofT2DMisOHAfailureGuidelinesforoptimalglucosecontrolaregoinglowerPotentialforglucoseloweringwithinsulinisunlimited

RoleforInsulinTherapyinT236EstablishingStarting

BasalandBolusDoses50%BasalPre-PumpDosePumpStartingDose(70-75%ofPre-PumpDose)50%BolusEstablishingStarting

Basalan37TheMajorityoftheDayisSpendin

aPost-prandial&Post-absorptiveStateBreakfastLunchDinner0:00am4:00amBreakfastPost-prandialPost-absorptiveFastingMonnierL.EurJClinInvest2000;30(Suppl.2):3–11TheMajorityoftheDayisSpe38AcuteinPGfreeradical,PAI-I hypercoagulabilityatherosclersis.ChronicPPGactivationofproteinkinaseCinthe endotheliumendothelialdysfunction.SignificancesofHyperglycemiaAcuteinPGfreeradical39FPG=fastingplasmaglucose;PPG=postprandialplasmaglucoseHbA1CPPGFPG+=AdaptedfromSDelPrato,2002PostprandialGlucoseSpikesSignificantlyAffectA1CHbA1CPPGFPG+=AdaptedfromSDe40CombinationTherapyCombopill

Glucovance(Glyburide+Metformin)1.25mg/250mg;2.5mg/500mg;5mg/500mg

Metaglip(Glipizide+Metformin)2.5mg/250mg,2.5mg/500mg,5mg/500mg

Avandamet(Avandia+MetforminHCl)1mg/500mg;2mg/500mg;4mg/500mg

SUMetforminAcarboseTZDs(Starlix,NovoNorm)InsulinCombinationTherapy41TrendinTreatmentforDiabetesEarlierdetectionPrevention,focusonthe metabolicriskfactorsAggressivetreatmentEarlieruseofinsulinTotaltreatmentPoly-pharmacyandcombopillOptimaltreatmentgoalIndividualized (co-morbidity&complications)TrendinTreatmentforDiabete42糖尿病治療之新趨勢王朝弘醫(yī)師內(nèi)分泌暨新陳代謝科馬偕醫(yī)院92-11-2507:30~08:20糖尿病治療之新趨勢王朝弘醫(yī)師43

一、Introduction二、PathophysiologyofDiabetesMellitus三、Treatmentstrategies四、ClinicalTrials五、DrugsforTreatment六、TheFuture七、Questions&AnswersA)CurrentmedicationsB)InsulinsensitizersC)InsulintherapyinT2DMD)Drugsinteraction一、IntroductionA)Currentmedi44第一型糖尿病的疾病生理發(fā)展階段第一階段 基因體質(zhì)第二階段 環(huán)境觸發(fā)第三階段 自家免疫啟動第四階段 貝它細(xì)胞逐漸失能第五階段 糖尿病顯現(xiàn)第一型糖尿病的疾病生理發(fā)展階段45IMPAIREDGLUCOSETOLERANCEDYSLIPIDAEMIATYPE2DIABETESHYPERTENSIONFIBRINOLYSISURICACIDSYSTEMICINFLAMMATIONLEPTINATHEROSCLEROSISENDOTHELIALDYSFUNCTIONCENTRALOBESITYINSULINRESISTANCEIMPAIREDDYSLIPIDAEMIATYPE2DI46LossofEarly-phaseInsulinRelease

inType2DiabetesWardWKetal.DiabetesCare1984;7:491–502NormalType2diabetes120100806040200 –30 0 30 60 90 120Time(minutes) –30 0 30 60 90 120Time(minutes)Plasmainsulin(μU/ml)12010080604020020gglucose20g

glucosePlasmainsulin(μU/ml)Patternofinsulinreleaseisalteredearlyintype2diabetesLossofEarly-phaseInsulinRe47GeneticPredispositionEnvironmentalfactorsObesityAgeLifestyleInsulinResistanceInsulinSecretionCVDHTNStrokeLipiddisordersManyotherdiseasesIFG,IGT,T2DM+β-celldefectMetabolic(InsulinResistance)SyndromeGeneticEnvironmentalfactorsIn48-12-10-6-202610140255075100IGTPostprandialHyperglycemiaType2DiabetesPhaseIType2DiabetesPhaseIIType2DiabetesPhaseIIIYearsFromDiagnosisBetaCellFunction(%)StagesofType2Diabetes-12-10-6-20261014049DiabetesTreatmentGoalsPlasmaGlucose(mg/dL) Preprandial PostprandialA1C(%)Normal<110<140?<6.0ADA90~130<180<7.0ACE/AACE<110<140?<6.5*ACEE=AmericanAssociationofClinicalEndocrinology;ACE=AmericanCollegeofEndocrinology; ADA=AmericanDiabetesAssociation.?Two-hourpostprandialDiabetesTreatmentGoalsPlasma50CorrelationbetweenA1C&

meanplasmaglucoselevelA1C(%)6789101112Meanplasmaglucose(mg/dl)

135 170

205 240

275 310

345ADA2003CorrelationbetweenA1C&

mea51NormalPhysiologyofGlucoseHomeostasisGlucoseuptake,hepaticglucoseproduction&storageofglycogenInsulin-stimulatedglucoseuptakeRegulationoflipolysis

Adipose

tissueCarbohydrateBloodGlucoseDigestiveenzymesGutPancreasMuscleLiverInsulinNormalPhysiologyofGlucoseH52SteppedManagementofType2DiabetesSteppedManagementofType2D53TreatmentStrategiesFPG(mg/dl)A1C(%)140~1607.0~8.0>160>8.0or+1OHA+Insulin

Insulinsensitizer

-glucosidase

monotherapy

Combinationtherapy(2OHAs)<1406.5~7.0TreatmentStrategiesFPG(mg/dl54FinnishDiabetesPreventionStudy

meandurationof3.2years

Interventiongr. Controlgr.

n=265 n=257

Specificdietaryinstructionoralorwritteninformationatbaseline(diet&exercise)

Moderateexercise≧30min/dnospecificindividualized program

DMdevelopedn=27 n=59

DMdeveloped3%/yr 6%/yr

RiskofT2DMreducedby58%FinnishDiabetesPreventionSt55DiabetesPreventionProgram

3yearsofobservationIntensetherapeuticlifestylechange．Metformin．Placebowtloss>7% ．850mgb.i.d.．IGT→T2DMExercise>150min/wk 11%/yr

N=1073 ．N=1082 ．N=1079Riskreduction58%．riskreduction31%DiabetesPreventionProgram

356UKPDSForeach1%reductioninA1COvera6-yearperiod,~53%ofpt’streatedwith sulfonylureasneededadditionalinsulin therapyA21%decreaseinanyendpointrelatedtodiabetes&in diabetes-relateddeathA14%decreaseinall-causemortality&MIA43%decreaseinamputationordeathfromPVDA37%decreasedriskformicrovascularcomplicationsUKPDSForeach1%reductionin57

非藥物生活型態(tài)之改變飲食、營養(yǎng)之控制規(guī)律之運動非藥物生活型態(tài)之改變58OralAntihyperglycemicAgentsAgentSulfonylureasNateglinideRepaglinideMetforminPioglitazoneRosiglitazoneAcarboseMiglitolClassSulfonylureaNonsulfonylureainsulinsecretagogueNonsulfonylureainsulinsecretagogueBiguanideThiazolidinedioneThiazolidinedione-Glucosidaseinhibitor-GlucosidaseinhibitorMajormechanismofactioninsulinsecretionprandialinsulinsecretionprandialinsulinsecretioninsulinresistance(hepatic)insulinresistance(peripheral)insulinresistance(peripheral)DelaysCHOabsorptionfromG-ItractDelaysCHOabsorptionfromG-ItractOralAntihyperglycemicAgentsA59a)MetforminPharmacologicalAgents(1.0)Action:Insulinresistance(plasmainsulinconc.)byInsulin-mediatedmuscleglucoseuptake

Insulin-mediatedhepaticgluconeogenesis

Translocationofglucosereceptorstoplasma membranea)MetforminPharmacologicalA60ContraindicationsandPrecautions

MetforminHepaticdisease,CHF(drugstreated)HxoflacticacidosisRenalimpartment—GFRs(<60ml/min)or Srcr(men:>1.5mg/dl,women:>1.4mg/dl)AlcoholingestionShockSurgeryAging(80years)ContraindicationsandPrecauti61c)Alpha-glucosidaseinhibitors(AGIs)

differentmodeofactionfromotherdrugsAction:Inhibitstarchdigestioninsmallintestine, &delayingglucoseabsorptionAdvantages:

wt

postprandialglycemia

noriskofhypoglycaemia

flatulence&bloatingDisadvantages:

diarrheaPharmacologicalAgents(2.0)c)Alpha-glucosidaseinhibito62InsulinSecretion1st-phaseNoYes2nd-phaseexaggeratedNoBiologicalhalf-lifeVeryshortStarlixShortTolbutamideNovoNormIntermediateGlipizide,Diamicron,AmaryllongEuglucon,DiabenaseHypoglycemicrisk

SulfonylureasNon-sulfonylureasInsulinSecretagoguesInsulinSecretionSulfo63d)Sulphonylureas

powerfulhypoglycemiceffectAction:IncreaseinsulinsecretionbyclosingKatp channelsinpancreaticβcellAdvantages:

lowcost

noGIintolerance

weightgainDisadvantages:

secondaryfailurecommon

riskofhypoglycaemiaPharmacologicalAgents(3.0)d)Sulphonylureaspowerfulhy64NovoNorm(4.3)ShortactingDifferentbindingsiteatSURreceptorRapidlyabsorbed(peak~45’)Actionwithin30’0.5~4.0mgacwithin30’Stimulateearly-phaseinsulinsecretion,subside~4hMeanA1C~1.7%MeanFPG~61mg/dlLivermetabolism~100%

Lesshypoglycemia&wtgainòòvs.PlaceboNovoNorm(4.3)Shortactingòòv65Starlix:

使糖立釋膜衣錠60毫克(5.0)成分名：Nateglinide商品名：Starlix?適應(yīng)癥：第2型糖尿病(非胰島素依賴型糖尿病)最新一類藥物：D-phenylalanine氨基酸衍生物，被 FDA證明可分泌早期胰島素的抗糖尿病藥物作用機(jī)轉(zhuǎn)：可藉由高度選擇性地阻斷鉀離子管道(Katp channel)，恢復(fù)人體本能胰島素分泌的能力(mimicphysical insulinrelease)臨床療效：明顯降低飯後血糖(2hr-PPG)，糖化血色素 (A1C)與空腹血糖(FPG)，而不刺激胰臟β-細(xì)胞分泌過 度的胰島素Starlix:使糖立釋膜衣錠60毫克(5.0)成66快速生效(Fast-on)；快速恢復(fù)(Fast-off)的作用(5.1)‘Fast-on’:(快速生效)作用，可重建糖尿病患喪失的 「早期胰島素」分泌功能?！瓼ast-off’:(快速恢復(fù))作用，可避免因高胰島素延緩 而導(dǎo)致的低血糖危險Starlix?對血中葡萄糖濃度感受性非常明顯；當(dāng)血糖 高時，作用明顯；反之血糖低時，則作用減低。 不易造成高胰島素或低血糖之副作用?？焖偕?Fast-on)；快速恢復(fù)(Fast-off)的作67Starlix(5.2)

Rapidlyabsorbed&actingSignificantselectivityon-cells&cardiaccellsNoaccumulationortissueretentionwith

repeatedadministrationRelativelylowpotentialfordrag-druginteractionsRestoringearly-phaseinsulinsecretionNospecialdoseadjustments(elderly,renalimpairment)60~180mgtaken1’~30’beforemealHypoglycemia&wtgain─lowpotentialMonotherapy&combinationtherapyStarlix(5.2)Rapidlyabsorbed68

NovoNorm(1mg/#)Starlix(60mg/#)

rapidlyabsorbed

Peakplasmalevelwithin1°within45minBioavailability65%70%plasmat1/2~1h0.5~1.9hKatp-channelbindingfaster-affinitylowerMetabolismliverintoinactiveliver(85-95%)

substancesto3~6lesspotentproductsExcretionbile(major)urine(75%)

urine6%feces(~10%)

Maximaldose16mg/d540mg/d

NovoNorm69ContraindicationsandPrecautions

SulphonylureasT1DMPregnancyorbreast-feedingDocumentedhypersensitivitySeverehepaticorrenaldysfunctionSevere,acuteillness(e.g.,infection,MI),surgery, stressContraindicationsandPrecauti70b)Thiazolidinediones

powerfulhypoglycemiceffectAction:ReduceinsulinresistancebyactingasPPAR

g

agonists

lowriskofsecondaryfailureAdvantages:

lipids

plasmainsulin

noriskofhypoglycaemia

fluidretentionDisadvantages:

weightgain

?Hepaticdysfunction

dilutionalanemia

highcostPharmacologicalAgents(6.0)b)Thiazolidinedionespowerfu71ContraindicationsandPrecautions

ThiazolidinedionesT1DMPre-existinghepaticdisease

*ALT>2.5UNL

*d/c,ifALT>3UNL,risingserumbilirubin

*HepatitisSx(malaise,fatigue,nausea,

vomiting,darkurine,abdominalpain,……)SevereCHF(NYHAclassesⅢ&Ⅳ)Premenopausalanovulatorywoman—unwantedpregnancyHxofhypersensitivitytoTZDsDrugsmetabolizedbyCYP3A4ContraindicationsandPrecauti72DrugsInteraction

Sulphonylurea

Effect

*AntacidsGastricpHEnhancedEugluconabsorption*CimetidineTolbutamidehepaticmetabolism*FluconazolePlasmaconc.*GemfibrozilProteindisplacement,needtodoseofSU*SulfinpyrazoneTolbutamidehepaticmetabolism&t1/2 2~3

Effect*AlcoholTolbutamidehepaticmetabolism2*RifampinEugluconmetabolismt1/2&plasmadrug conc.OralAnti-diabetesAgents(1)

DrugsInteractionSulphonylure73DrugsInteractionMetformin*AlcoholEffectsofmetforminonlactatemetabolism*CimetidinePeakmetforminplasmaconc.*ErythromycinSeverecholestatichepatitisreported (withchlorpropamide)*I-contrastdyeARF,lacticacidosis-GlucosidaseInhibitors*DigestiveenzymepreparationsAcarboseeffect*DigoxinSerumdigoxinconc.therapeuticeffects*InderalBioavailabilityofpropranolol~40%*RanitidineBioavailabilityofRanitidine~60%(Miglitol)OralAnti-diabetesAgents(2)DrugsInteractionMetforminOral74DrugsInteractionThiazolidinediones*KetoconazoneInhibitthemetabolismofActos*OralpillsPlasmaconc.(~30%)ofethinyl estradiol&norethindorne(Actos), watchforforflushes(estrogendef)*TerfenadinePlasmaconc.(~50~70%)of Terfenadine(Troglitazone)

OralAnti-diabetesAgents(3)DrugsInteractionThiazolidined75ComparisonofHumanInsulins

andInsulinAnaloguesLispro/aspartHumanr