糖尿病药物治疗-问题与失误课件

糖尿病药物治疗—问题与失误课件1糖尿病药物治疗—问题与失误课件2血糖是最难控制的代谢异常多种病理生理机制自然病程演变,各种病理生理基础发生变化影响因素多,波动性大,需要反复的反馈血糖是最难控制的代谢异常多种病理生理机制3ASCOT:ReductionsinTotalandLDLCholesterol2460123Atorvastatin10mgPlacebo1234012320015015075125100100(mg/dL)(mg/dL)Totalcholesterol(mmol/L)LDLcholesterol(mmol/L)Years1.3mmol/L1.0mmol/L1.2mmol/L1.0mmol/LSeverPS,DahlöfB,PoulterN,WedelH,etal,fortheASCOTInvestigators.Lancet.2019;361:1149-58ASCOT:ReductionsinTotaland4LIIFE研究---相同的降压疗效061218243036424854研究月份405060708090100110120130140150160170180收缩压舒张压平均动脉压mmHg阿替洛尔145.4mmHg氯沙坦144.1mmHg阿替洛尔80.9mmHg氯沙坦81.3mmHgDahlöfBetalLancet2019;359:995-1003.阿替洛尔102.4mmHg氯沙坦102.2mmHgLIIFE研究---相同的降压疗效06121824303651234…EDICDCCTtoEDIC:Fromexperimenttoreality1234…EDICDCCTtoEDIC:6

06789246810HbA1c(%)Timefromrandomization(years)Upperlimitofnormal=6.2%GlyburideChlorpropamideMetforminInsulin0UKPDS：单一药物治疗的局限性(2019年）AdaptedfromUKPDSGroup.UKPDS34.Lancet2019;352:854–865.*TherapyassignedifFPG>

15mmol/lorsymptomsofhyperglycemiaOverweightpatientsCohort,medianvaluesConventionaltherapy(primarilydietalone*)06789246810HbA1c(%)Timefro7SaydahSHetal.JAMA.2019;291:335-342.Patients(%)HbA1C<7%44.3%NHANESIII;n=1,204NHANES2019-2000; n=37001020304050BP<130/80mmHgTC<200mg/dL29.0%35.8%37.0%Goodcontrol7.3%5.2%33.9%P<.00148.2%RiskFactorControlinAdultsWithDiabetes:NHANESIII(1988-1994)/NHANES2019-2000SaydahSHetal.JAMA.2019;298PercentageofPatientsWithDiabetes

HavingA1C

<7%HarrisMIetal.DiabetesCare.2019;22:403-408KoroCeetal.,DiabetesCare27:17-20,2019020406080100DietaloneOralagentsInsulinNHANESIIIUSAdultsWithDiagnosedDiabetesin1988–9473%38%27%Wholestudypopulation44.5%PercentatgoalTherapyused35.8%NHANES(2019-2000)PercentageofPatientsWithDi9在单药治疗时发现HbA1c>8.0%后仍然维持单药治疗的时间*（2019年） BrownJB,etal.DiabetesCare2019;27:1535–1540.*Mayincludeuptitration0510152025MetforminonlySulfonylureaonlyn=513n=3,39414.5个月20.5

个月月在单药治疗时发现HbA1c>8.0%后仍然维持单药治疗10020406080100%AgeofSubjectsPercentageofSubjectsadvancingwhenHbA1C>8%ClinicalInertia:“Failuretoadvancetherapywhenrequired”Diet66.6%Sulfonylurea35.3%Metformin44.6%Combination18.6%Brownetal.TheBurdenofTreatmentFailureinType2Diabetes.DiabetesCare27:1535-1540,2019AtInsulinInitiation,theaveragepatienthad:5yearswithHbA1C>8%10yearswithHbA1C>7%020406080100%AgeofSubjectsPe11糖尿病药物治疗—问题与失误课件12多种代谢异常控制的重要性微血管病变:高血糖是必要条件,但不是充分条件血压*,血脂#,炎症#大血管病变:高血糖不是必要条件,但可能促进因素#*:流行病学证据;#:临床试验证据多种代谢异常控制的重要性微血管病变:高血糖是必要条件,但13Atightbloodpressurecontrolpolicywhichachievedbloodpressureof144/82mmHggavereducedriskof:24%foranydiabetes-relatedendpointp=0.004632%fordiabetes-relateddeathsp=0.01944%forstrokep=0.01337%formicrovasculardiseasep=0.009256%forheartfailurep=0.0043BloodPressureControl,UKPDS糖尿病药物治疗—问题与失误课件14UKPDS研究显示：

严格降压比强化降糖更重要????

中风任何糖尿病终点糖尿病死亡微血管并发症-50-40-30-20-100相对危险度降低（%）严格血糖控制(目标<6.0mmol/L或108mg/dL)严格血压控制(平均144/82mmHg)32%37%10%32%12%24%5%44%BakrisGL,etal.AmJKidneyDis.

2000;36(3):646-661.*****与严格血糖控制比较，P<0.05UKPDS研究显示：

严格降压比强化降糖更重要????

15糖尿病药物治疗—问题与失误课件16糖尿病药物治疗—问题与失误课件17各种治疗达标的百分率糖化血红蛋白<6.5%胆固醇<4.5mmol/l甘油三酯<1.7mmol/l收缩压<130mmHg舒张压<80mmHg8年后达到治疗目标的患者%p=0.06p<0.0001p=0.19p=0.001p=0.21Steno-2强化组常规组强化组常规组强化组常规组强化组常规组强化组常规组各种治疗达标的百分率糖化血红蛋白<6.5%胆固醇甘油三酯收缩18TargetsforcontrolParameterTargetHbA1c

6.5%(DCCT-alignedassay)BP130/80mmHgTotalcholesterol4.5mmol/L(174mg/dl)LDL-cholesterol2.5mmol/L(97mg/dl)HDL-cholesterol1.0mmol/L(39mg/dl)Triglycerides1.5mmol/L(133mg/dl)Urinaryalbumin:creatinine2.5mg/mmol(22mg/g)–men3.5mgmmol(31mg/g)-womenExercise150minutes/weekTargetsforcontrolParameterTa192型糖尿病患者的药物治疗代谢控制

降糖药：格列酮类；双胍类；－糖苷酶抑制剂；促胰岛素分泌剂GLP-1相关药物

调脂药:它汀类药物抗凝

阿司匹林血压控制

降压药2型糖尿病患者的药物治疗代谢控制20Pancreaticb-cellInsulinResistanceInsulinactionIncreasedlipolysisADIPOSETISSUEIsletb-celldegranulationreducedinsulincontentInsulinResistanceandb-cellDysfunctionProduceHyperglycaemiainType2Diabeteslow-plasmainsulinIncreasedglucoseoutputHYPERGLYCEMIADecreasedglucosetransport&activity(expression)ofGLUT4ElevatedplasmaNEFAElevatedTNFa,Resistin?MUSCLE(TG­)LIVERPANCREASPancreaticb-cellInsulinResis21SitesofActionbyTherapeuticOptionsSonnenberg,etal.CurrOpinNephrolHypertens2019;7(5):551-555.GLUCOSEABSORPTIONMUSCLEPANCREASADIPOSETISSUELIVERINTESTINEHYPERGLYCEMIADECREASEDPERIPHERALGLUCOSEUPTAKEINCREASEDGLUCOSEPRODUCTIONDECREASEDINSULIN

SECRETIONTherapy:Thiazolidinediones(Biguanides)Therapy:InsulinSulfonylureasMetiglinidesTherapy:BiguanidesThiazolidinedionesTherapy:Alpha-glucosidaseinhibitorsSitesofActionbyTherapeutic22正常人血糖的波动RiddleMC.DiabetesCare1990;13:676–6863002001000血浆葡萄糖浓度(mg/dl) 0600 1200 1800 2400 0600时间(小时)餐时血糖峰值空腹正常人血糖的波动RiddleMC.DiabetesCa232型糖尿病高血糖的构成－空腹血糖增高

RiddleMC.DiabetesCare1990;13:676–6863002001000血浆葡萄糖浓度(mg/dl) 0600 1200 1800 2400 0600时间(小时)肝糖输出正常肝糖输出不能被关闭2型糖尿病高血糖的构成－空腹血糖增高

RiddleMC.24RiddleMC.DiabetesCare1990;13:676–6863002001000血浆葡萄糖浓度(mg/dl) 0600 1200 1800 2400 0600时间(小时)餐时血糖峰值肝糖输出正常2型糖尿病高血糖的构成－餐后血糖增高

RiddleMC.DiabetesCare1990;25二甲双胍磺脲类噻唑烷二酮胰岛素二甲双胍磺脲类噻唑烷二酮胰岛素二甲双胍磺脲类噻唑烷二酮胰岛素-糖苷酶抑制剂速效胰岛素格列奈类-糖苷酶抑制剂速效胰岛素格列奈类-糖苷酶抑制剂速效胰岛素格列奈类降糖药物改善总体血糖控制水平(HbA1c)的途径二甲双胍磺脲类噻唑烷二酮胰岛素二甲双胍二甲双胍二甲双胍-糖苷酶抑制剂-糖苷酶抑制剂-26OverweightorobesepersonwithdiabetesWherepossible,defineobesityusingregionalornationalcriteriaOverweightorobesepersonwit27Non-obesepersonwithdiabetesNon-obesepersonwithdiabetes282型糖尿病自然病程050100150200250-10-5051015202530糖尿病病史（年）血糖(mg/dL)相对功能(%)胰岛素抵抗胰岛素水平-细胞衰竭*IFG=impairedfastingglucose50100150200250300350空腹血糖餐后血糖AdaptedfromInternationalDiabetesCenter(IDC)Minneapolis,Minnesota肥胖空腹葡萄糖异常*糖尿病未控制的高血糖

2型糖尿病自然病程050100150200250-10-5029针对2型糖尿病自然病程中不同时期的病理生理变化特点的药物治疗

针对2型糖尿病自然病程中不同时期的病理生理变化特点的药物治疗307698HbA1c(%)10单药治疗Diet口服药联合口服药物＋基础胰岛素传统的非积极的糖尿病治疗模式加量病程口服药物加多次胰岛素7698HbA1c(%)10单药治疗Diet口服药联合口服31口服药加基础胰岛素口服药加多此胰岛素注射Diet口服药物单药治疗（胰岛素)口服药联合治疗

积极治疗糖尿病－早期联合治疗

口服药物加量病程7698HbA1c(%)10口服药加基础胰岛素口服药加多此胰岛素注射Diet口服药物单药32美国糖尿病药物的市场情况NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367美国糖尿病药物的市场情况NATURER33“Combinationtherapyisstandard”Althoughthereareanumberoforaldrugsonthemarkettotreatdiabetes,atpresentnosinglemarketeddrugiscapableofloweringHbA1ctothetargetrangeforasustainedperiodoftimeforthemajorityofpatientswithtype2diabetes.Evenwhenusedincombination,thesemedicationstendtolosemuchoftheirefficacyafter3–4yearsoftreatment.NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367“Combinationthera34口服糖尿病药物联合的策略理性化联合（rationalcombination）：药物之间的作用机制互补，针对糖尿病的多种缺陷积极联合（provativeapproach）：早期联合，发挥药物联合之间最大的治疗潜力以达标为驱动力：用HbA1c作为“金标准”同时减少大、小血管病变的危险性口服糖尿病药物联合的策略35InzucchiSE.JAMA2019;287:360–372.改善血糖控制减少CVD危险性磺脲类促进胰岛素分泌格列酮类强胰岛素增敏作用增加骨骼肌血糖利用改善大血管病变危险因素+格列酮＋磺脲类：不同作用机制间的互补作用改善多重缺陷InzucchiSE.JAMA2019;287:3636InzucchiSE.JAMA2019;287:360–372.改善血糖控制减少CVD危险性二甲双胍弱胰岛素增敏作用减少肝糖输出改善大血管病变临床终点格列酮类强胰岛素增敏作用增加骨骼肌血糖利用改善大血管病变危险因素+格列酮＋二甲双胍：不同作用机制间的互补作用改善多重缺陷InzucchiSE.JAMA2019;287:3637InzucchiSE.JAMA2019;287:360–372.改善血糖控制减少CVD危险性二甲双胍弱胰岛素增敏作用减少肝糖输出改善大血管病变临床终点促分泌剂增加胰岛素分泌+促泌剂＋二甲双胍：不同作用机制间的互补作用改善多重缺陷InzucchiSE.JAMA2019;287:36382型糖尿病口服药物联合治疗思维的改变传统思维：单一药物逐渐加量至推荐最大剂量新思维：在单一药物的半量或次大剂量时联合用药(理性结合）

2型糖尿病口服药物联合治疗思维的改变传统思维：单一药物逐渐加39**–1.0–0.8–0.6–0.4–0.20.0MeanchangeinHbA1c

frombaseline(%)半量二甲双胍＋罗格列酮与二甲双胍加量的比较(EMPIREStudy)–HbA1cBaselineHbA1c(%)n=7.953138.05322MET1g/day

+RSG8mg/dayPatientsweretreatedfor24weeksAllpatientswereinadequatelycontrolledonMET1g/dayalone*Significantvs.baselineMET1g/day+MET1g/dayErrorbars=95%CIRosenstockJ,etal.Diabetes2019;53(Suppl.2):A144–145.–0.63%–0.82%**–1.0–0.8–0.6–0.4–0.20.0Mean40N=635

Patientsweretreatedfor24weeksAllpatientswereinadequatelycontrolledonMET1g/dayalone*P<0.05vs.MET1g/day+MET1g/dayErrorbars=95%CIRosenstockJ,etal.Diabetes2019;53(Suppl.2):A144–145.25.9%0102030405060Patientsachieving

HbA1cgoals(%)AACE/

IDF

goal<

6.5%ADAgoal<7%*MET1g/day+MET1g/dayn=313MET1g/day

+RSG8mg/dayn=32238.5%45%55%半量二甲双胍＋罗格列酮与二甲双胍加量的比较(EMPIREStudy)–达标率N=635

Patientsweretreated41–20Geometricmeanpercent

changefrombaseline

inHOMA-cellfunctionTime(weeks)024527610402040608010099869064875183Errorbars=SESU+RSG(upto8mg/day)SU加量+PBO罗格列酮加磺脲类与磺脲类加量比较(RESULTstudy)-

b-细胞功能SU+PBOn=106SU+RSGn=105n=numberofpatientswithon-therapyvalueatthevisit

ITTwithoutLOCFVinikAI,etal.Diabetes2019;53(Suppl.2):A162.ADA2019,Poster680.–20Geometricmeanpercent

c420.002452Time(weeks)761046.87.07.27.47.67.8SU加量+PBO

n=110MeanHbA1c(%)SU+RSG

n=115Errorbars=SEITTpopulation,olderT2Dpatients(>60years)inwhomglycemiccontrolwasinadequateOn-therapyvaluesRosenstockJ,etal.DiabetesMetab2019;29:4S247–4S248.IDF2019,Poster2278.罗格列酮加磺脲类与磺脲类加量比较(RESULTstudy)-

HbA1c0.002452Time(weeks)761046.87.439%29%0204060HbA1cresponders(%)UptitratedSU+PBOn=106SU+RSG11322%50%AACE/

IDF

goal6.5%ADAgoal<7.0%RosenstockJ,etal.DiabetesMetab2019;29:4S247–4S248.IDF2019,Poster2278.罗格列酮加磺脲类与磺脲类加量比较(RESULTstudy)–

达标率9%29%0204060HbA1cresponders(44加强“内-心”合作，催生“预防血管病学”加强“内-心”合作，催生“预防血管病学”45糖尿病药物治疗—问题与失误课件46糖尿病药物治疗—问题与失误课件47糖尿病药物治疗—问题与失误课件48血糖是最难控制的代谢异常多种病理生理机制自然病程演变,各种病理生理基础发生变化影响因素多,波动性大,需要反复的反馈血糖是最难控制的代谢异常多种病理生理机制49ASCOT:ReductionsinTotalandLDLCholesterol2460123Atorvastatin10mgPlacebo1234012320015015075125100100(mg/dL)(mg/dL)Totalcholesterol(mmol/L)LDLcholesterol(mmol/L)Years1.3mmol/L1.0mmol/L1.2mmol/L1.0mmol/LSeverPS,DahlöfB,PoulterN,WedelH,etal,fortheASCOTInvestigators.Lancet.2019;361:1149-58ASCOT:ReductionsinTotaland50LIIFE研究---相同的降压疗效061218243036424854研究月份405060708090100110120130140150160170180收缩压舒张压平均动脉压mmHg阿替洛尔145.4mmHg氯沙坦144.1mmHg阿替洛尔80.9mmHg氯沙坦81.3mmHgDahlöfBetalLancet2019;359:995-1003.阿替洛尔102.4mmHg氯沙坦102.2mmHgLIIFE研究---相同的降压疗效061218243036511234…EDICDCCTtoEDIC:Fromexperimenttoreality1234…EDICDCCTtoEDIC:52

06789246810HbA1c(%)Timefromrandomization(years)Upperlimitofnormal=6.2%GlyburideChlorpropamideMetforminInsulin0UKPDS：单一药物治疗的局限性(2019年）AdaptedfromUKPDSGroup.UKPDS34.Lancet2019;352:854–865.*TherapyassignedifFPG>

15mmol/lorsymptomsofhyperglycemiaOverweightpatientsCohort,medianvaluesConventionaltherapy(primarilydietalone*)06789246810HbA1c(%)Timefro53SaydahSHetal.JAMA.2019;291:335-342.Patients(%)HbA1C<7%44.3%NHANESIII;n=1,204NHANES2019-2000; n=37001020304050BP<130/80mmHgTC<200mg/dL29.0%35.8%37.0%Goodcontrol7.3%5.2%33.9%P<.00148.2%RiskFactorControlinAdultsWithDiabetes:NHANESIII(1988-1994)/NHANES2019-2000SaydahSHetal.JAMA.2019;2954PercentageofPatientsWithDiabetes

HavingA1C

<7%HarrisMIetal.DiabetesCare.2019;22:403-408KoroCeetal.,DiabetesCare27:17-20,2019020406080100DietaloneOralagentsInsulinNHANESIIIUSAdultsWithDiagnosedDiabetesin1988–9473%38%27%Wholestudypopulation44.5%PercentatgoalTherapyused35.8%NHANES(2019-2000)PercentageofPatientsWithDi55在单药治疗时发现HbA1c>8.0%后仍然维持单药治疗的时间*（2019年） BrownJB,etal.DiabetesCare2019;27:1535–1540.*Mayincludeuptitration0510152025MetforminonlySulfonylureaonlyn=513n=3,39414.5个月20.5

个月月在单药治疗时发现HbA1c>8.0%后仍然维持单药治疗56020406080100%AgeofSubjectsPercentageofSubjectsadvancingwhenHbA1C>8%ClinicalInertia:“Failuretoadvancetherapywhenrequired”Diet66.6%Sulfonylurea35.3%Metformin44.6%Combination18.6%Brownetal.TheBurdenofTreatmentFailureinType2Diabetes.DiabetesCare27:1535-1540,2019AtInsulinInitiation,theaveragepatienthad:5yearswithHbA1C>8%10yearswithHbA1C>7%020406080100%AgeofSubjectsPe57糖尿病药物治疗—问题与失误课件58多种代谢异常控制的重要性微血管病变:高血糖是必要条件,但不是充分条件血压*,血脂#,炎症#大血管病变:高血糖不是必要条件,但可能促进因素#*:流行病学证据;#:临床试验证据多种代谢异常控制的重要性微血管病变:高血糖是必要条件,但59Atightbloodpressurecontrolpolicywhichachievedbloodpressureof144/82mmHggavereducedriskof:24%foranydiabetes-relatedendpointp=0.004632%fordiabetes-relateddeathsp=0.01944%forstrokep=0.01337%formicrovasculardiseasep=0.009256%forheartfailurep=0.0043BloodPressureControl,UKPDS糖尿病药物治疗—问题与失误课件60UKPDS研究显示：

严格降压比强化降糖更重要????

中风任何糖尿病终点糖尿病死亡微血管并发症-50-40-30-20-100相对危险度降低（%）严格血糖控制(目标<6.0mmol/L或108mg/dL)严格血压控制(平均144/82mmHg)32%37%10%32%12%24%5%44%BakrisGL,etal.AmJKidneyDis.

2000;36(3):646-661.*****与严格血糖控制比较，P<0.05UKPDS研究显示：

严格降压比强化降糖更重要????

61糖尿病药物治疗—问题与失误课件62糖尿病药物治疗—问题与失误课件63各种治疗达标的百分率糖化血红蛋白<6.5%胆固醇<4.5mmol/l甘油三酯<1.7mmol/l收缩压<130mmHg舒张压<80mmHg8年后达到治疗目标的患者%p=0.06p<0.0001p=0.19p=0.001p=0.21Steno-2强化组常规组强化组常规组强化组常规组强化组常规组强化组常规组各种治疗达标的百分率糖化血红蛋白<6.5%胆固醇甘油三酯收缩64TargetsforcontrolParameterTargetHbA1c

6.5%(DCCT-alignedassay)BP130/80mmHgTotalcholesterol4.5mmol/L(174mg/dl)LDL-cholesterol2.5mmol/L(97mg/dl)HDL-cholesterol1.0mmol/L(39mg/dl)Triglycerides1.5mmol/L(133mg/dl)Urinaryalbumin:creatinine2.5mg/mmol(22mg/g)–men3.5mgmmol(31mg/g)-womenExercise150minutes/weekTargetsforcontrolParameterTa652型糖尿病患者的药物治疗代谢控制

降糖药：格列酮类；双胍类；－糖苷酶抑制剂；促胰岛素分泌剂GLP-1相关药物

调脂药:它汀类药物抗凝

阿司匹林血压控制

降压药2型糖尿病患者的药物治疗代谢控制66Pancreaticb-cellInsulinResistanceInsulinactionIncreasedlipolysisADIPOSETISSUEIsletb-celldegranulationreducedinsulincontentInsulinResistanceandb-cellDysfunctionProduceHyperglycaemiainType2Diabeteslow-plasmainsulinIncreasedglucoseoutputHYPERGLYCEMIADecreasedglucosetransport&activity(expression)ofGLUT4ElevatedplasmaNEFAElevatedTNFa,Resistin?MUSCLE(TG­)LIVERPANCREASPancreaticb-cellInsulinResis67SitesofActionbyTherapeuticOptionsSonnenberg,etal.CurrOpinNephrolHypertens2019;7(5):551-555.GLUCOSEABSORPTIONMUSCLEPANCREASADIPOSETISSUELIVERINTESTINEHYPERGLYCEMIADECREASEDPERIPHERALGLUCOSEUPTAKEINCREASEDGLUCOSEPRODUCTIONDECREASEDINSULIN

SECRETIONTherapy:Thiazolidinediones(Biguanides)Therapy:InsulinSulfonylureasMetiglinidesTherapy:BiguanidesThiazolidinedionesTherapy:Alpha-glucosidaseinhibitorsSitesofActionbyTherapeutic68正常人血糖的波动RiddleMC.DiabetesCare1990;13:676–6863002001000血浆葡萄糖浓度(mg/dl) 0600 1200 1800 2400 0600时间(小时)餐时血糖峰值空腹正常人血糖的波动RiddleMC.DiabetesCa692型糖尿病高血糖的构成－空腹血糖增高

RiddleMC.DiabetesCare1990;13:676–6863002001000血浆葡萄糖浓度(mg/dl) 0600 1200 1800 2400 0600时间(小时)肝糖输出正常肝糖输出不能被关闭2型糖尿病高血糖的构成－空腹血糖增高

RiddleMC.70RiddleMC.DiabetesCare1990;13:676–6863002001000血浆葡萄糖浓度(mg/dl) 0600 1200 1800 2400 0600时间(小时)餐时血糖峰值肝糖输出正常2型糖尿病高血糖的构成－餐后血糖增高

RiddleMC.DiabetesCare1990;71二甲双胍磺脲类噻唑烷二酮胰岛素二甲双胍磺脲类噻唑烷二酮胰岛素二甲双胍磺脲类噻唑烷二酮胰岛素-糖苷酶抑制剂速效胰岛素格列奈类-糖苷酶抑制剂速效胰岛素格列奈类-糖苷酶抑制剂速效胰岛素格列奈类降糖药物改善总体血糖控制水平(HbA1c)的途径二甲双胍磺脲类噻唑烷二酮胰岛素二甲双胍二甲双胍二甲双胍-糖苷酶抑制剂-糖苷酶抑制剂-72OverweightorobesepersonwithdiabetesWherepossible,defineobesityusingregionalornationalcriteriaOverweightorobesepersonwit73Non-obesepersonwithdiabetesNon-obesepersonwithdiabetes742型糖尿病自然病程050100150200250-10-5051015202530糖尿病病史（年）血糖(mg/dL)相对功能(%)胰岛素抵抗胰岛素水平-细胞衰竭*IFG=impairedfastingglucose50100150200250300350空腹血糖餐后血糖AdaptedfromInternationalDiabetesCenter(IDC)Minneapolis,Minnesota肥胖空腹葡萄糖异常*糖尿病未控制的高血糖

2型糖尿病自然病程050100150200250-10-5075针对2型糖尿病自然病程中不同时期的病理生理变化特点的药物治疗

针对2型糖尿病自然病程中不同时期的病理生理变化特点的药物治疗767698HbA1c(%)10单药治疗Diet口服药联合口服药物＋基础胰岛素传统的非积极的糖尿病治疗模式加量病程口服药物加多次胰岛素7698HbA1c(%)10单药治疗Diet口服药联合口服77口服药加基础胰岛素口服药加多此胰岛素注射Diet口服药物单药治疗（胰岛素)口服药联合治疗

积极治疗糖尿病－早期联合治疗

口服药物加量病程7698HbA1c(%)10口服药加基础胰岛素口服药加多此胰岛素注射Diet口服药物单药78美国糖尿病药物的市场情况NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367美国糖尿病药物的市场情况NATURER79“Combinationtherapyisstandard”Althoughthereareanumberoforaldrugsonthemarkettotreatdiabetes,atpresentnosinglemarketeddrugiscapableofloweringHbA1ctothetargetrangeforasustainedperiodoftimeforthemajorityofpatientswithtype2diabetes.Evenwhenusedincombination,thesemedicationstendtolosemuchoftheirefficacyafter3–4yearsoftreatment.NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367“Combinationthera80口服糖尿病药物联合的策略理性化联合（rationalcombination）：药物之间的作用机制互补，针对糖尿病的多种缺陷积极联合（provativeapproach）：早期联合，发挥药物联合之间最大的治疗潜力以达标为驱动力：用HbA1c作为“金标准”同时减少大、小血管病变的危险性口服糖尿病药物联合的策略81InzucchiSE.JAMA2019;287:360–372.改善血糖控制减少CVD危险性磺脲类促进胰岛素分泌格列酮类强胰岛素增敏作用增加骨骼肌血糖利用改善大血管病变危险因素+格列酮＋磺脲类：不同作用机制间的互补作用改善多重缺陷InzucchiSE.JAMA2019;287:3682InzucchiSE.JAMA2019;287:360–372.改善血糖控制减少CVD危险性二甲双胍弱胰岛素增敏作用减少肝糖输出改善大血管病变临床终点格列酮类强胰岛素增敏作用增加骨骼肌血糖利用改善大血管病变危险因素+格列酮＋二甲双胍：不同作用机制间的互补作用改善多重缺陷InzucchiSE.JAMA2019;287:3683InzucchiSE.JAMA2019;287:360–372.改善血糖控制减少CVD危险性二甲双胍弱胰岛素增敏作用减少肝糖输出改善大血管病变临床终点促分泌剂增加胰岛素分泌+促泌剂＋二甲双胍：不同作用机制间的互补作用改善多重缺陷InzucchiSE.JAMA2019;287:36842型糖尿病口服药物联合治疗思维的改变传统思维：单一药物逐渐加量至推荐最大剂量新思维：在单一药物的半量或次大剂量时联合用药(理性结合）

2型糖尿病口服药物联合治疗思维的改变传统思维：单一药物逐渐加85**–1.0–0.8–0.6–0.4–0.20.0Meanchangein