糖尿病藥物治療-問題與失誤課件

糖尿病藥物治療—問題與失誤課件1糖尿病藥物治療—問題與失誤課件2血糖是最難控制的代謝異常多種病理生理機制自然病程演變,各種病理生理基礎發(fā)生變化影響因素多,波動性大,需要反復的反饋血糖是最難控制的代謝異常多種病理生理機制3ASCOT:ReductionsinTotalandLDLCholesterol2460123Atorvastatin10mgPlacebo1234012320015015075125100100(mg/dL)(mg/dL)Totalcholesterol(mmol/L)LDLcholesterol(mmol/L)Years1.3mmol/L1.0mmol/L1.2mmol/L1.0mmol/LSeverPS,Dahl?fB,PoulterN,WedelH,etal,fortheASCOTInvestigators.Lancet.2019;361:1149-58ASCOT:ReductionsinTotaland4LIIFE研究---相同的降壓療效061218243036424854研究月份405060708090100110120130140150160170180收縮壓舒張壓平均動脈壓mmHg阿替洛爾145.4mmHg氯沙坦144.1mmHg阿替洛爾80.9mmHg氯沙坦81.3mmHgDahl?fBetalLancet2019;359:995-1003.阿替洛爾102.4mmHg氯沙坦102.2mmHgLIIFE研究---相同的降壓療效06121824303651234…EDICDCCTtoEDIC:Fromexperimenttoreality1234…EDICDCCTtoEDIC:6

06789246810HbA1c(%)Timefromrandomization(years)Upperlimitofnormal=6.2%GlyburideChlorpropamideMetforminInsulin0UKPDS：單一藥物治療的局限性(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在單藥治療時發(fā)現(xiàn)HbA1c>8.0%后仍然維持單藥治療的時間*（2019年） BrownJB,etal.DiabetesCare2019;27:1535–1540.*Mayincludeuptitration0510152025MetforminonlySulfonylureaonlyn=513n=3,39414.5個月20.5

個月月在單藥治療時發(fā)現(xiàn)HbA1c>8.0%后仍然維持單藥治療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糖尿病藥物治療—問題與失誤課件12多種代謝異常控制的重要性微血管病變:高血糖是必要條件,但不是充分條件血壓*,血脂#,炎癥#大血管病變:高血糖不是必要條件,但可能促進因素#*:流行病學證據(jù);#:臨床試驗證據(jù)多種代謝異?？刂频闹匾晕⒀懿∽?高血糖是必要條件,但13Atightbloodpressurecontrolpolicywhichachievedbloodpressureof144/82mmHggavereducedriskof:24%foranydiabetes-relatedendpointp=0.004632%fordiabetes-relateddeathsp=0.01944%forstrokep=0.01337%formicrovasculardiseasep=0.009256%forheartfailurep=0.0043BloodPressureControl,UKPDS糖尿病藥物治療—問題與失誤課件14UKPDS研究顯示：

嚴格降壓比強化降糖更重要????

中風任何糖尿病終點糖尿病死亡微血管并發(fā)癥-50-40-30-20-100相對危險度降低（%）嚴格血糖控制(目標<6.0mmol/L或108mg/dL)嚴格血壓控制(平均144/82mmHg)32%37%10%32%12%24%5%44%BakrisGL,etal.AmJKidneyDis.

2000;36(3):646-661.*****與嚴格血糖控制比較，P<0.05UKPDS研究顯示：

嚴格降壓比強化降糖更重要????

15糖尿病藥物治療—問題與失誤課件16糖尿病藥物治療—問題與失誤課件17各種治療達標的百分率糖化血紅蛋白<6.5%膽固醇<4.5mmol/l甘油三酯<1.7mmol/l收縮壓<130mmHg舒張壓<80mmHg8年后達到治療目標的患者%p=0.06p<0.0001p=0.19p=0.001p=0.21Steno-2強化組常規(guī)組強化組常規(guī)組強化組常規(guī)組強化組常規(guī)組強化組常規(guī)組各種治療達標的百分率糖化血紅蛋白<6.5%膽固醇甘油三酯收縮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型糖尿病患者的藥物治療代謝控制

降糖藥：格列酮類；雙胍類；－糖苷酶抑制劑；促胰島素分泌劑GLP-1相關藥物

調(diào)脂藥:它汀類藥物抗凝

阿司匹林血壓控制

降壓藥2型糖尿病患者的藥物治療代謝控制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正常人血糖的波動RiddleMC.DiabetesCare1990;13:676–6863002001000血漿葡萄糖濃度(mg/dl) 0600 1200 1800 2400 0600時間(小時)餐時血糖峰值空腹正常人血糖的波動RiddleMC.DiabetesCa232型糖尿病高血糖的構成－空腹血糖增高

RiddleMC.DiabetesCare1990;13:676–6863002001000血漿葡萄糖濃度(mg/dl) 0600 1200 1800 2400 0600時間(小時)肝糖輸出正常肝糖輸出不能被關閉2型糖尿病高血糖的構成－空腹血糖增高

RiddleMC.24RiddleMC.DiabetesCare1990;13:676–6863002001000血漿葡萄糖濃度(mg/dl) 0600 1200 1800 2400 0600時間(小時)餐時血糖峰值肝糖輸出正常2型糖尿病高血糖的構成－餐后血糖增高

RiddleMC.DiabetesCare1990;25二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍磺脲類噻唑烷二酮胰島素-糖苷酶抑制劑速效胰島素格列奈類-糖苷酶抑制劑速效胰島素格列奈類-糖苷酶抑制劑速效胰島素格列奈類降糖藥物改善總體血糖控制水平(HbA1c)的途徑二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍二甲雙胍二甲雙胍-糖苷酶抑制劑-糖苷酶抑制劑-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)相對功能(%)胰島素抵抗胰島素水平-細胞衰竭*IFG=impairedfastingglucose50100150200250300350空腹血糖餐后血糖AdaptedfromInternationalDiabetesCenter(IDC)Minneapolis,Minnesota肥胖空腹葡萄糖異常*糖尿病未控制的高血糖

2型糖尿病自然病程050100150200250-10-5029針對2型糖尿病自然病程中不同時期的病理生理變化特點的藥物治療

針對2型糖尿病自然病程中不同時期的病理生理變化特點的藥物治療307698HbA1c(%)10單藥治療Diet口服藥聯(lián)合口服藥物＋基礎胰島素傳統(tǒng)的非積極的糖尿病治療模式加量病程口服藥物加多次胰島素7698HbA1c(%)10單藥治療Diet口服藥聯(lián)合口服31口服藥加基礎胰島素口服藥加多此胰島素注射Diet口服藥物單藥治療（胰島素)口服藥聯(lián)合治療

積極治療糖尿?。缙诼?lián)合治療

口服藥物加量病程7698HbA1c(%)10口服藥加基礎胰島素口服藥加多此胰島素注射Diet口服藥物單藥32美國糖尿病藥物的市場情況NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367美國糖尿病藥物的市場情況NATURER33“Combinationtherapyisstandard”Althoughthereareanumberoforaldrugsonthemarkettotreatdiabetes,atpresentnosinglemarketeddrugiscapableofloweringHbA1ctothetargetrangeforasustainedperiodoftimeforthemajorityofpatientswithtype2diabetes.Evenwhenusedincombination,thesemedicationstendtolosemuchoftheirefficacyafter3–4yearsoftreatment.NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367“Combinationthera34口服糖尿病藥物聯(lián)合的策略理性化聯(lián)合（rationalcombination）：藥物之間的作用機制互補，針對糖尿病的多種缺陷積極聯(lián)合（provativeapproach）：早期聯(lián)合，發(fā)揮藥物聯(lián)合之間最大的治療潛力以達標為驅(qū)動力：用HbA1c作為“金標準”同時減少大、小血管病變的危險性口服糖尿病藥物聯(lián)合的策略35InzucchiSE.JAMA2019;287:360–372.改善血糖控制減少CVD危險性磺脲類促進胰島素分泌格列酮類強胰島素增敏作用增加骨骼肌血糖利用改善大血管病變危險因素+格列酮＋磺脲類：不同作用機制間的互補作用改善多重缺陷InzucchiSE.JAMA2019;287:3636InzucchiSE.JAMA2019;287:360–372.改善血糖控制減少CVD危險性二甲雙胍弱胰島素增敏作用減少肝糖輸出改善大血管病變臨床終點格列酮類強胰島素增敏作用增加骨骼肌血糖利用改善大血管病變危險因素+格列酮＋二甲雙胍：不同作用機制間的互補作用改善多重缺陷InzucchiSE.JAMA2019;287:3637InzucchiSE.JAMA2019;287:360–372.改善血糖控制減少CVD危險性二甲雙胍弱胰島素增敏作用減少肝糖輸出改善大血管病變臨床終點促分泌劑增加胰島素分泌+促泌劑＋二甲雙胍：不同作用機制間的互補作用改善多重缺陷InzucchiSE.JAMA2019;287:36382型糖尿病口服藥物聯(lián)合治療思維的改變傳統(tǒng)思維：單一藥物逐漸加量至推薦最大劑量新思維：在單一藥物的半量或次大劑量時聯(lián)合用藥(理性結合）

2型糖尿病口服藥物聯(lián)合治療思維的改變傳統(tǒng)思維：單一藥物逐漸加39**–1.0–0.8–0.6–0.4–0.20.0MeanchangeinHbA1c

frombaseline(%)半量二甲雙胍＋羅格列酮與二甲雙胍加量的比較(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%半量二甲雙胍＋羅格列酮與二甲雙胍加量的比較(EMPIREStudy)–達標率N=635

Patientsweretreated41–20Geometricmeanpercent

changefrombaseline

inHOMA-cellfunctionTime(weeks)024527610402040608010099869064875183Errorbars=SESU+RSG(upto8mg/day)SU加量+PBO羅格列酮加磺脲類與磺脲類加量比較(RESULTstudy)-

b-細胞功能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.羅格列酮加磺脲類與磺脲類加量比較(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.羅格列酮加磺脲類與磺脲類加量比較(RESULTstudy)–

達標率9%29%0204060HbA1cresponders(44加強“內(nèi)-心”合作，催生“預防血管病學”加強“內(nèi)-心”合作，催生“預防血管病學”45糖尿病藥物治療—問題與失誤課件46糖尿病藥物治療—問題與失誤課件47糖尿病藥物治療—問題與失誤課件48血糖是最難控制的代謝異常多種病理生理機制自然病程演變,各種病理生理基礎發(fā)生變化影響因素多,波動性大,需要反復的反饋血糖是最難控制的代謝異常多種病理生理機制49ASCOT:ReductionsinTotalandLDLCholesterol2460123Atorvastatin10mgPlacebo1234012320015015075125100100(mg/dL)(mg/dL)Totalcholesterol(mmol/L)LDLcholesterol(mmol/L)Years1.3mmol/L1.0mmol/L1.2mmol/L1.0mmol/LSeverPS,Dahl?fB,PoulterN,WedelH,etal,fortheASCOTInvestigators.Lancet.2019;361:1149-58ASCOT:ReductionsinTotaland50LIIFE研究---相同的降壓療效061218243036424854研究月份405060708090100110120130140150160170180收縮壓舒張壓平均動脈壓mmHg阿替洛爾145.4mmHg氯沙坦144.1mmHg阿替洛爾80.9mmHg氯沙坦81.3mmHgDahl?fBetalLancet2019;359:995-1003.阿替洛爾102.4mmHg氯沙坦102.2mmHgLIIFE研究---相同的降壓療效061218243036511234…EDICDCCTtoEDIC:Fromexperimenttoreality1234…EDICDCCTtoEDIC:52

06789246810HbA1c(%)Timefromrandomization(years)Upperlimitofnormal=6.2%GlyburideChlorpropamideMetforminInsulin0UKPDS：單一藥物治療的局限性(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在單藥治療時發(fā)現(xiàn)HbA1c>8.0%后仍然維持單藥治療的時間*（2019年） BrownJB,etal.DiabetesCare2019;27:1535–1540.*Mayincludeuptitration0510152025MetforminonlySulfonylureaonlyn=513n=3,39414.5個月20.5

個月月在單藥治療時發(fā)現(xiàn)HbA1c>8.0%后仍然維持單藥治療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糖尿病藥物治療—問題與失誤課件58多種代謝異?？刂频闹匾晕⒀懿∽?高血糖是必要條件,但不是充分條件血壓*,血脂#,炎癥#大血管病變:高血糖不是必要條件,但可能促進因素#*:流行病學證據(jù);#:臨床試驗證據(jù)多種代謝異?？刂频闹匾晕⒀懿∽?高血糖是必要條件,但59Atightbloodpressurecontrolpolicywhichachievedbloodpressureof144/82mmHggavereducedriskof:24%foranydiabetes-relatedendpointp=0.004632%fordiabetes-relateddeathsp=0.01944%forstrokep=0.01337%formicrovasculardiseasep=0.009256%forheartfailurep=0.0043BloodPressureControl,UKPDS糖尿病藥物治療—問題與失誤課件60UKPDS研究顯示：

嚴格降壓比強化降糖更重要????

中風任何糖尿病終點糖尿病死亡微血管并發(fā)癥-50-40-30-20-100相對危險度降低（%）嚴格血糖控制(目標<6.0mmol/L或108mg/dL)嚴格血壓控制(平均144/82mmHg)32%37%10%32%12%24%5%44%BakrisGL,etal.AmJKidneyDis.

2000;36(3):646-661.*****與嚴格血糖控制比較，P<0.05UKPDS研究顯示：

嚴格降壓比強化降糖更重要????

61糖尿病藥物治療—問題與失誤課件62糖尿病藥物治療—問題與失誤課件63各種治療達標的百分率糖化血紅蛋白<6.5%膽固醇<4.5mmol/l甘油三酯<1.7mmol/l收縮壓<130mmHg舒張壓<80mmHg8年后達到治療目標的患者%p=0.06p<0.0001p=0.19p=0.001p=0.21Steno-2強化組常規(guī)組強化組常規(guī)組強化組常規(guī)組強化組常規(guī)組強化組常規(guī)組各種治療達標的百分率糖化血紅蛋白<6.5%膽固醇甘油三酯收縮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型糖尿病患者的藥物治療代謝控制

降糖藥：格列酮類；雙胍類；－糖苷酶抑制劑；促胰島素分泌劑GLP-1相關藥物

調(diào)脂藥:它汀類藥物抗凝

阿司匹林血壓控制

降壓藥2型糖尿病患者的藥物治療代謝控制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正常人血糖的波動RiddleMC.DiabetesCare1990;13:676–6863002001000血漿葡萄糖濃度(mg/dl) 0600 1200 1800 2400 0600時間(小時)餐時血糖峰值空腹正常人血糖的波動RiddleMC.DiabetesCa692型糖尿病高血糖的構成－空腹血糖增高

RiddleMC.DiabetesCare1990;13:676–6863002001000血漿葡萄糖濃度(mg/dl) 0600 1200 1800 2400 0600時間(小時)肝糖輸出正常肝糖輸出不能被關閉2型糖尿病高血糖的構成－空腹血糖增高

RiddleMC.70RiddleMC.DiabetesCare1990;13:676–6863002001000血漿葡萄糖濃度(mg/dl) 0600 1200 1800 2400 0600時間(小時)餐時血糖峰值肝糖輸出正常2型糖尿病高血糖的構成－餐后血糖增高

RiddleMC.DiabetesCare1990;71二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍磺脲類噻唑烷二酮胰島素-糖苷酶抑制劑速效胰島素格列奈類-糖苷酶抑制劑速效胰島素格列奈類-糖苷酶抑制劑速效胰島素格列奈類降糖藥物改善總體血糖控制水平(HbA1c)的途徑二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍二甲雙胍二甲雙胍-糖苷酶抑制劑-糖苷酶抑制劑-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)相對功能(%)胰島素抵抗胰島素水平-細胞衰竭*IFG=impairedfastingglucose50100150200250300350空腹血糖餐后血糖AdaptedfromInternationalDiabetesCenter(IDC)Minneapolis,Minnesota肥胖空腹葡萄糖異常*糖尿病未控制的高血糖

2型糖尿病自然病程050100150200250-10-5075針對2型糖尿病自然病程中不同時期的病理生理變化特點的藥物治療

針對2型糖尿病自然病程中不同時期的病理生理變化特點的藥物治療767698HbA1c(%)10單藥治療Diet口服藥聯(lián)合口服藥物＋基礎胰島素傳統(tǒng)的非積極的糖尿病治療模式加量病程口服藥物加多次胰島素7698HbA1c(%)10單藥治療Diet口服藥聯(lián)合口服77口服藥加基礎胰島素口服藥加多此胰島素注射Diet口服藥物單藥治療（胰島素)口服藥聯(lián)合治療

積極治療糖尿病－早期聯(lián)合治療

口服藥物加量病程7698HbA1c(%)10口服藥加基礎胰島素口服藥加多此胰島素注射Diet口服藥物單藥78美國糖尿病藥物的市場情況NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367美國糖尿病藥物的市場情況NATURER79“Combinationtherapyisstandard”Althoughthereareanumberoforaldrugsonthemarkettotreatdiabetes,atpresentnosinglemarketeddrugiscapableofloweringHbA1ctothetargetrangeforasustainedperiodoftimeforthemajorityofpatientswithtype2diabetes.Evenwhenusedincombination,thesemedicationstendtolosemuchoftheirefficacyafter3–4yearsoftreatment.NATUREREVIEWS|DRUGDISCOVERYVOLUME4|MAY2019|367“Combinationthera80口服糖尿病藥物聯(lián)合的策略理性化聯(lián)合（rationalcombination）：藥物之間的作用機制互補，針對糖尿病的多種缺陷積極聯(lián)合（provativeapproach）：早期聯(lián)合，發(fā)揮藥物聯(lián)合之間最大的治療潛力以達標為驅(qū)動力：用HbA1c作為“金標準”同時減少大、小血管病變的危險性口服糖尿病藥物聯(lián)合的策略81InzucchiSE.JAMA2019;287:360–372.改善血糖控制減少CVD危險性磺脲類促進胰島素分泌格列酮類強胰島素增敏作用增加骨骼肌血糖利用改善大血管病變危險因素+格列酮＋磺脲類：不同作用機制間的互補作用改善多重缺陷InzucchiSE.JAMA2019;287:3682InzucchiSE.JAMA2019;287:360–372.改善血糖控制減少CVD危險性二甲雙胍弱胰島素增敏作用減少肝糖輸出改善大血管病變臨床終點格列酮類強胰島素增敏作用增加骨骼肌血糖利用改善大血管病變危險因素+格列酮＋二甲雙胍：不同作用機制間的互補作用改善多重缺陷InzucchiSE.JAMA2019;287:3683InzucchiSE.JAMA2019;287:360–372.改善血糖控制減少CVD危險性二甲雙胍弱胰島素增敏作用減少肝糖輸出改善大血管病變臨床終點促分泌劑增加胰島素分泌+促泌劑＋二甲雙胍：不同作用機制間的互補作用改善多重缺陷InzucchiSE.JAMA2019;287:36842型糖尿病口服藥物聯(lián)合治療思維的改變傳統(tǒng)思維：單一藥物逐漸加量至推薦最大劑量新思維：在單一藥物的半量或次大劑量時聯(lián)合用藥(理性結合）

2型糖尿病口服藥物聯(lián)合治療思維的改變傳統(tǒng)思維：單一藥物逐漸加85**–1.0–0.8–0.6–0.4–0.20.0Meanchangein