PresentTherapiesofType2DiabetesMellitusEdwardS.Horton,MD

ProfessorofMedicine

HarvardMedicalSchool

DirectorofClinicalResearch

JoslinDiabetesCenterACPAnnualSessionMTP057&058SanFrancisco,CAApril15-16,2019?2019.AmericanCollegeofPhysicians.AllRightsReserved.PresentTherapiesofType2DMTP057DisclosureofRelationshipswithCommercialCompaniesEdwardS.Horton,MD,FACPResearchGrants/Contracts:Takeda,Lilly,MannKind,SankyoHonoraria:Merck,Pfizer,Novartis,Takeda,NovoNordiskConsultantship:Novartis?2019.AmericanCollegeofPhysicians.AllRightsReserved.MTP057DisclosureofRelationsMainTopicsforDiscussionTheDiabetesEpidemicTheRoleofGenesvs.Environment:Obesity,MetabolicSyndromeandLifestyleChangesThePathogenesis/PathophysiologyofDM2anditsComplicationsStrategiesforPreventionDrugsforTreatment:OldandNewTheGlobalApproachtoTreatmentofDM2andCVDRiskFactorsTheNeedto“TreattoTarget”?2019.AmericanCollegeofPhysicians.AllRightsReserved.MainTopicsforDiscussionThe23.0M36.2M↑57.0%14.2M26.2M↑85%48.4M58.6M↑21%

43.0M

75.8M

↑79%

7.1M15.0M↑111%

39.3M

81.6M

↑108%M=million,AFR=Africa,NA=NorthAmerica,EUR=Europe,SACA=SouthandCentralAmerica,EMME=EasternMediterraneanandMiddleEast,SEA=South-EastAsia,WP=WesternPacificDiabetesAtlasCommittee.DiabetesAtlas2ndEdition:IDF2019.GlobalProjectionsfortheDiabetesEpidemic:2019-2025World2019=194M2025=333M↑72%AFRNASACAEURSEAWP19.2M39.4M↑105%EMME20192025?2019.AmericanCollegeofPhysicians.AllRightsReserved.23.0M14.2M48.4M 43.0M7.1MTheDualEpidemic:

ObesityandDiabetes65%ofadultAmericansareoverweight(BMI>25)and21%areobese(BMI>30).24%havetheMetabolicSyndrome.Therearenowanestimated18millionpeoplewithDMintheUSAandevenmorewithIGT.ThelifetimeriskofdevelopingDMforpeoplebornin2000is33%formenand39%forwomen.ForHispanicwomenitis50%.InthispopulationCVDisthemajorcauseofmortality.?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheDualEpidemic:

ObesityandThePrevalenceofOverweightandDiabetesover10YearsMokdadetal.DiabetesCare.2000;23(9):1278-83.Mokdadetal.JAMA.2000;286(10):1195-200.

OverweightBMI>25Kg/m2Diabetes&GestationalDiabetes49%increase25%increase?2019.AmericanCollegeofPhysicians.AllRightsReserved.ThePrevalenceofOverweighta

CHANGESINOURLIFESTYLE!WHATISDRIVINGTHEDUALEPIDEMIC??2019.AmericanCollegeofPhysicians.AllRightsReserved.CHANGESINOURLIFESTYLE!WHATTodiabetesMetabolicSyndrome?DiabetesR.HeineMD?2019.AmericanCollegeofPhysicians.AllRightsReserved.TodiabetesMetabolicDiabetesR.?2019.AmericanCollegeofPhysicians.AllRightsReserved.?2019.AmericanCollegeofPh?2019.AmericanCollegeofPhysicians.AllRightsReserved.?2019.AmericanCollegeofPh?2019.AmericanCollegeofPhysicians.AllRightsReserved.?2019.AmericanCollegeofPhTheRoleofGenesvs.theEnvironment?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheRoleof?2019.AmericanCoObesity(esp.AbdominalObesity)GeneticVariationInCVDRiskFactorRegulationElevatedBloodPressureAtherogenicDyslipidemiaInsulinResistancePro-thromboticStatePro-inflammatoryStatePhysicalInactivityAgingHyperglycemiaTheInsulinResistanceSyndromeModifiedfromS.GrundyMD?2019.AmericanCollegeofPhysicians.AllRightsReserved.ObesityGeneticVariationElevaObesity(esp.AbdominalObesity)GeneticVariationInCVDRiskFactorRegulationElevatedBPBP>130/85mmHgAtherogenicDyslipidemiaInsulinResistancePro-thromboticStatePro-inflammatoryStateWaistCircumferenceMen:>102cm(40in)Women:>88cm(35in)TG>150mg/dLHDL-C<40mg/dL(M)<50mg/dL(F)FastingGlucose

>110mg/dL*MetabolicSyndromeATPIII(3of5)?2019.AmericanCollegeofPhysicians.AllRightsReserved.ObesityGeneticVariationEleva

NationalHealthandNutritionExaminationSurveyIII,1988-1994

PrevalenceoftheMetabolicSyndromeAmongUSAdultsUsingtheATPIIICriteriaAge-AdjustedPrevalenceis23.7%n=8814

Fordetal.JAMA2019;278:356-359?2019.AmericanCollegeofPhysicians.AllRightsReserved.

NationalHealthandNutritioTheMetabolicSyndromeinPeoplewithIGTorDiabetes33%ofpeople50yrs.andolderwithIGThaveMScomparedto35-40%inthegeneralpopulation(NHANESIII)(AlexanderCMetalDiabetes2019;52:1210-1214)OnlylimiteddataonprevalenceofMSinDM2(approximately60-65%inType2DM)TheincreasedriskofCVDinIGTandDM2iswellestablished,buttheroleofhyperglycemiavs.otherCVDriskfactorsisnotwellunderstood.HowmuchdoesMScontribute?NoprospectivestudiesofthedevelopmentofMSinpeoplewithIGTorDM2?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheMetabolicSyndromeinPeop

DIABETESANDCARDIOVASCULARDISEASE?2019.AmericanCollegeofPhysicians.AllRightsReserved.

DIABETESANDCARDIOVASCULARCHDMortality

(incidence/1,000)EschwegeEetal.HormMetabRes.2019;17(suppl):41-46.G<140mg/dL543210IGTG3200mg/dL(newlydiagnosed

diabetes)KnownDiabetesP<0.001(6055)(690)(158)(135)IGTProgressivelyIncreasesRiskof

CHDMortality:ParisProspectiveStudy

(10-yearfollow-up)?2019.AmericanCollegeofPhysicians.AllRightsReserved.CHDMortality

(incidence/1,000DECODE:MortalityRateIncreasesWithIncreasing2-HourGlucose 20151050Mortality

(%)Fastingglucose: <6.1 <7.0(NotDM) <7.0(NotDM) 37.0(DM)2-hglucose: <7.8 7.8–11.0(IGT) 311.1(DM) 311.1(DM)(mmol/L) 612DECODE=DiabetesEpidemiology:CollaborativeAnalysisofDiagnosticCriteriainEurope.AdaptedfromDECODEStudyGroup.Lancet.2019;354:617-621.(1172/18,252)(325/2766)15(63/432)16(146/909)?2019.AmericanCollegeofPhysicians.AllRightsReserved.DECODE:MortalityRateIncreas051015202530354045507-YearIncidence

ofMI(%)

NopreviousMI* PreviousMI NopreviousMI* PreviousMI NoDiabetes Diabetes (n=1373) (n=1059)P<0.001P<0.0014%19%20%45%Seven-YearIncidenceofFatal/NonfatalMIinFinland*Atbaseline.HaffnerSMetal.NEnglJMed.2019;339:229-234.?2019.AmericanCollegeofPhysicians.AllRightsReserved.051015202530354045507-YearIncGlycemiainRelationtoMicrovascularDiseaseandMIUKPDS35.BMJ2000;321:405–12MIMicrovasculardiseaseUpdatedmeanHbA1C(%)Incidenceper

1,000patient-years806040200 0 5 6 7 8 9 10 11?2019.AmericanCollegeofPhysicians.AllRightsReserved.GlycemiainRelationtoMicrovEndothelialDysfunctionisanEarlyAbnormalityinObesityandPre-diabetes?2019.AmericanCollegeofPhysicians.AllRightsReserved.EndothelialDysfunctionisanMethacholinechlorideinfusionrate(g/min)ModifiedfromSteinbergHJClinInvest2019;97:2601-2610%changeinlegbloodflowabovebaselineLegBloodFlowChangesDuringMethacholineInfusion?2019.AmericanCollegeofPhysicians.AllRightsReserved.Methacholinechlorideinfusion8.49.810.513.7*0481216ControlsRelativesIGTDiabetes%IncreaseOverBaselineFlowMediatedDilationBrachialArtery*P<0.001Controlsvs.relatives,IGTanddiabetesCaballeroAEetal.Diabetes2019;48:1856-62?2019.AmericanCollegeofPhysicians.AllRightsReserved.8.49.810.513.7*0481216ControlsEndothelialActivation

Controls Relatives IGT DiabetesvWF(%) 11049 10341 12145

13551*

ET-1(pg/mL) 4.82.9

9.48.7* 10.710.5* 10.910.8*ICAM(ng/mL) 22257 25189

26456* 301106*VCAM(ng/mL) 661176

747171*

759254

831257*vWF=vonWillebrandfactor;Mean±SD*P<0.05CaballeroAEetal.Diabetes2019;48:1856-62?2019.AmericanCollegeofPhysicians.AllRightsReserved.EndothelialActivation ControlTHUS…Amajorgoaloftreatmentofpre-diabetesanddiabetesistopreventboththemicro-andmacrovascularcomplications!?2019.AmericanCollegeofPhysicians.AllRightsReserved.THUS…?2019.AmericanCollegePathogenesis/PathophysiologyType2DiabetesMellitusisaProgressiveDisease?2019.AmericanCollegeofPhysicians.AllRightsReserved.Pathogenesis/Pathophysiology?ProgressiontoType2DiabetesFFA=freefattyacid.KruszynskaY,OlefskyJM.JInvestMed.2019;44:413-428.GeneticsInsulinresistanceHyperinsulinemiaCompensatedinsulinresistance

NormalglucosetoleranceImpairedglucosetoleranceType2diabetes↑Insulinresistance↑Hepaticglucoseoutput↓Insulinsecretion-cell"failure"GeneticsAcquiredGlucotoxicity↑FFAlevelsOtherAcquiredObesitySedentarylifestyleAging?2019.AmericanCollegeofPhysicians.AllRightsReserved.ProgressiontoType2DiabetesInsulinSecretion

AIR(μU/mL)

IGTNGTNGTNGTNGTDIA5004003002001000InsulinSensitivity

M-low(mg/kgEMBSperminute)ProgressorsNon-ProgressorsEarlyInsulinSecretionIncreases

WithDecreasingInsulinActionWeyerC,etal.JClinInvest.2019;104:787–794.12345?2019.AmericanCollegeofPhysicians.AllRightsReserved.InsulinSecretion

AIR(μU/mL)

NaturalHistoryofType2

DiabetesinPimaIndiansWeyerC,etal.JClinInvest.2019;104:787–794.AcuteInsulinResponse(μU/mL)NGTProgressors(n=17)Non-Progressors(n=31)NGTNGTTimeNGTIGTDiabetes050150200300***Time*P<0.05;**P<0.01100250050150200300100250?2019.AmericanCollegeofPhysicians.AllRightsReserved.NaturalHistoryofType2

DiabUKPDS:ProgressiveDeterioration

inGlycemicControlOverTimeCUKPDSGroup.Lancet.2019;352:837-853.AllpatientsassignedtoregimenIntensiveConventionalPatientsfollowedfor10yearsIntensiveConventionalTimefromrandomization(y)60391215Timefromrandomization(y)603912150100Median

FPG

(mg/dL)7896Median

HbA1c

(%)200180160140120?2019PPSFPGHbA1c?2019.AmericanCollegeofPhysicians.AllRightsReserved.UKPDS:ProgressiveDeteriorati-cellFunctionintheUKPDSYearsFromDiagnosis-cellFunction(%)1009080706050403020100 –12 –10 –8 –6 –4 –2 0 2 4 6UKPDS=UnitedKingdomProspectiveDiabetesStudy.HolmanRRetal.DiabetesResClinPract.2019;40(suppl):S21-S25.?2019.AmericanCollegeofPhysicians.AllRightsReserved.-cellFunctionintheUKPDSYeStrategiesforPrevention?2019.AmericanCollegeofPhysicians.AllRightsReserved.StrategiesforPrevention?2019TrialstoPrevent/DelayProgressionFromIGTtoType2DiabetesLifestyleChangesMalmoStudyDaQingStudyFinnishDiabetesPreventionStudyDiabetesPreventionProgramMedicationsDiabetesPreventionProgram:metformin,(troglitazone)TRIPOD:troglitazoneSTOP-NIDDM:acarboseNAVIGATOR:nateglinideandvalsartanDREAM:rosiglitazoneandramiprilXENDOS:orlistatORIGIN:glargineinsulinACTNOW:pioglitazoneTRIPOD=TroglitazoneinPreventionofDiabetesStudy;STOP-NIDDM=StudytoPreventNon–Insulin-DependentDiabetesMellitus;NAVIGATOR=NateglinideandValsartaninImpairedGlucoseToleranceOutcomesResearch;DREAM=DiabetesReductionApproacheswithRamiprilandRosiglitazone;XENDOS=XenicalinthePreventionofDiabetesinObeseSubjects;ORIGIN=OutcomesReductionwithInitialGlargineIntroduction.?2019.AmericanCollegeofPhysicians.AllRightsReserved.TrialstoPrevent/DelayProgTheDaQingIGTandDiabetesStudy

EffectsofdietandexerciseinpreventingNIDDMinpeoplewithimpairedglucosetolerance

577subjects(averageBMI25.8Kg/m2)Withimpairedglucosetolerance(accordingtoWHOcriteria)Clinicassignedeithertoacontrolgrouportooneofthreeactivetreatmentgroups:dietonly,exerciseonly,ordietplusexerciseOGTTevery2yearsFollow-upperiod6yearsPanetal.DiabetesCare2019,20(4):537-44?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheDaQingIGTandDiabetesSTheDaQingIGTandDiabetesStudy

P<0.05TheCumulativeIncidenceofDiabetesPanetal.DiabetesCare2019,20(4):537-44(after6yearsofintervention)

?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheDaQingIGTandDiabetesSDiabetesPreventionStudy(FinnishStudy)PreventionofType2DMbyChangesinLifestyleAmongSubjectswithIGT

Tuomilehtoetal.NEngJMed2019,344(18):1390-2522Middle-aged,overweightsubjects(172menand350women;meanage,55years;meanBMI31kg/m2)WithimpairedglucosetoleranceRandomlyassignedtoeithertheinterventiongrouporthecontrolgroupEachsubjectintheinterventiongroupreceivedindividualizedcounselingaimedatreducingweight,totalintakeoffat,andintakeofsaturatedfatandincreasingintakeoffiberandphysicalactivityAnOGTTwasperformedannually;thediagnosisofdiabeteswasconfirmedbyasecondtestThemeandurationoffollow-upwas3.2years

?2019.AmericanCollegeofPhysicians.AllRightsReserved.DiabetesPreventionStudy(FinChangesinBodyWeightintheFinnishStudy

P<0.001ChangeinBodyWeightinKg

Tuomilehtoetal.NEngJMed2019,344(18):1390-2?2019.AmericanCollegeofPhysicians.AllRightsReserved.ChangesinBodyWeightintheCumulativeIncidenceofDiabetesintheFinnishStudy

P<0.001TheCumulativeIncidenceofDiabetesTuomilehtoetal.NEngJMed2019,344(18):1390-2(after4yearsofintervention)

58%RiskReduction?2019.AmericanCollegeofPhysicians.AllRightsReserved.CumulativeIncidenceofDiabetTheFinnishStudy

Tuomilehtoetal.NEngJMed2019,344(18):1390-2Theriskofdiabetesisreducedby58%intheinterventiongroupTheriskreductionintheinterventiongroupisdirectlylinkedtolifestylechanges.Patientswholost5%ormoreoftheirbodyweighthada74%riskreductionPatientswhoexceededtherecommended4hoursexercise/weekhadan80%riskreduction?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheFinnishStudyTuomilehtoTheDiabetesPreventionProgram

ARandomizedClinicalTrial

toPreventType2Diabetes

inPersonsatHighRisk

SponsoredbytheNIH,NIDDK,NIA,NICHD,IHS,CDC,ADAandotheragenciesandcorporations?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheDiabetesPreventionPrograCaucasian55%AfricanAmerican20%HispanicAmerican16%Asian4%AmericanIndian5%StudyPopulationCaucasian 1768 African-American 645 Hispanic-American508 Asian-American&PacificIslander142AmericanIndian 171?2019.AmericanCollegeofPhysicians.AllRightsReserved.CaucasianAfricanHispanicAsianAStudyPopulation45-5949%25-4431%>6020%AgeDistribution?2019.AmericanCollegeofPhysicians.AllRightsReserved.StudyPopulation45-5925-44>StudyInterventionsEligibleparticipantsRandomizedStandardlifestylerecommendationsIntensiveLifestyle(n=1079)Metformin(n=1073)Placebo(n=1082)?2019.AmericanCollegeofPhysicians.AllRightsReserved.StudyInterventionsEligiblepaLifestyle&MetforminInterventionsIntensiveLifestyleGoals

ReductionoffatandcalorieintakePhysicalactivityatleast150minutes/weekAchieveandmaintainatleast7%weightloss

MetforminGoals

Metformin850mgtwicedaily

?2019.AmericanCollegeofPhysicians.AllRightsReserved.Lifestyle&MetforminIntervenPlaceboMetforminLifestyleMeanWeightChange?2019.AmericanCollegeofPhysicians.AllRightsReserved.PlaceboMetforminLifestyleMeanMeanChangeinLeisurePhysicalActivityPlaceboMetforminLifestyle?2019.AmericanCollegeofPhysicians.AllRightsReserved.MeanChangeinLeisurePhysicaPlacebo(n=1082)Metformin(n=1073,p<0.001vs.Placebo)Lifestyle(n=1079,p<0.001vs.Metformin,p<0.001vs.Placebo)IncidenceofDiabetes

Riskreduction31%bymetformin58%bylifestyle?2019.AmericanCollegeofPhysicians.AllRightsReserved.Placebo(n=1082)Metformin(n=1

AbouttheprevalenceoftheMetabolicSyndromeinpeoplewithIGT?

AbouttheeffectoftheDPPinterventionsontheincidenceand/orreversalofMetSynd?WhatcanwelearnfromtheDiabetesPreventionProgram??2019.AmericanCollegeofPhysicians.AllRightsReserved.AbouttheprevalenceoftheMTheEffectofMetforminandIntensiveLifestyleInterventiononthePreventionoftheMetabolicSyndrome:ResultsfromtheDiabetesPreventionProgramTheDiabetesPreventionProgramResearchGroupAnnalsInternalMedicine2019(inpress)?2019.AmericanCollegeofPhysicians.AllRightsReserved.TheEffectofMetforminandInObjectivesTodeterminetheprevalenceoftheMSinthemultiethnicDPPpopulationofsubjectswithImpairedGlucoseTolerance(IGT)ToevaluatetheeffectofthetwointerventionsontheincidenceoftheMSinthosesubjectswithoutthesyndromeatrandomizationToevaluatetheeffectofthetwointerventionsonthereversaloftheMSinthosesubjectswiththesyndromeatrandomization?2019.AmericanCollegeofPhysicians.AllRightsReserved.ObjectivesTodeterminethepreCumulativeIncidenceofMetabolicSyndromebyTreatmentGroup01234Yearfromrandomization0.000.150.300.450.600.75Cumulativeincidenceof

metabolicsyndrome(%)LifestylePlaceboMetforminRiskreduction:17%*byMetformin41%#byLifestyleLifestylevs.Metformin29%#*p<0.05;#p<0.001?2019.AmericanCollegeofPhysicians.AllRightsReserved.CumulativeIncidenceofMetabo3yearincidence(%)ofcomponentsbytreatmentgroupPlaceboMetforminLifestyleWaistCirc.33

15***8***LowHDLc706768HighTrig.273018***HighFPG40

29***

28***HighBP414435******p<0.001,comparisonvplacebo?2019.AmericanCollegeofPhysicians.AllRightsReserved.3yearincidence(%)ofcomponQUESTION

CanTZDsorOtherMedicationsPreventorDelaytheOnsetofType2Diabetes??2019.AmericanCollegeofPhysicians.AllRightsReserved.QUESTION

CanTZDsorOtherMedTroglitazone

In

the

Prevention

Of

DiabetesTRIPOD:ATestofChronicB-cell“Rest”Subjects

Non-pregnant,non-diabeticHispanicwomenRecentgestationaldiabetes(<4years)

oGTTglucosesum>medianforwomenwithGDMProcedures

Placebovs400mgtroglitazonedailyFastingglucoseeverythreemonthsoGTTeveryyearivGTTat0and3monthsMainOutcomeVariables

Diabetesincidencerates

B-cellfunctionBuchananetal:Diabetes51:2796-2803,2019?2019.AmericanCollegeofPhysicians.AllRightsReserved.TroglitazoneInthePreventionTRIPOD:

DiabetesRatesMonthsonStudyPeoplewithDiabetes55%ReductionPlacebo12.1%/yrTroglitazone5.4%/yr60%40%20%0%010203040506050%19%Buchananetal:Diabetes,2019?2019.AmericanCollegeofPhysicians.AllRightsReserved.TRIPOD:DiabetesRatesMonthsoTroglitazoneintheDPPInvestigationaluseinDPP2019-98DiscontinuedinDPPonJune4,2019followingfatalliverfailureinaDPPparticipantTroglitazoneparticipantsofferedgrouplifestyleclasses(lessintensivethanILSgroup)andsamefollow-upasothersApprovedinUSAfromJanuary2019toMarch2000?2019.AmericanCollegeofPhysicians.AllRightsReserved.TroglitazoneintheDPPApproveDiabetesCumulativeIncidence(2,343)(1,568)(739)(237)YearsfromRandomization(totalno.ofparticipants)31%58%75%?2019.AmericanCollegeofPhysicians.AllRightsReserved.DiabetesCumulativeIncidence(TROGdiscontinuedJune4,2019DiabetesIncidenceDuringTROG

TreatmentPeriod&Beyond?2019.AmericanCollegeofPhysicians.AllRightsReserved.TROGdiscontinuedJune4,2019

Conclusions

1.PPARgammaAgonistsdohavethepotentialto

preventordelaythedevelopmentofType2Diabetesinhighriskindividuals.

2.Theireffectivenessappearstobeasgoodorbetterthanlifestylechanges---BUT--

3.Morecompletestudiesareneededtodeterminelong-termeffectiveness.\?2019.AmericanCollegeofPhysicians.AllRightsReserved.CoSTOP-NIDDM:AcarboseReducesDiabetesRiskAdaptedfromChiassonJ-Letal.Lancet.2019;359:2072-2077.0.400.500.600.700.800.901.0001002003004005006007008009001000110012001300DaysAfterRandomizationCumulativeProbabilityofNoDiabetesAcarbosePlaceboP=.0022

25%reductioninRR?2019.AmericanCollegeofPhysicians.AllRightsReserved.STOP-NIDDM:AcarboseReducesDSTOP-NIDDM:EffectofAcarboseontheProbabilityofRemainingFreeofCVDiseaseProbability

ofAny

Cardiovascular

Event14001300120011001000900800700600500400300200100000.010.020.030.040.050.06DaysAfterRandomizationPlaceboAcarboseP=0.04(Log-RankTest)P=0.03(CoxProportionalModel)No.atrisk Placebo 686 675 667 658 643 638 633 627 615 611 604 519 424 332 232Acarbose 682 659 635 622 608 601 596 590 577 567 558 473 376 286 203ChiassonJ-Letal.JAMA.2019;290:486-494.49%reductioninRR?2019.AmericanCollegeofPhysicians.AllRightsReserved.STOP-NIDDM:EffectofAcarbosSummaryWorldwideepidemicofdiabetesMetabolicSyndromeandIGTaremoreprevalentthandiabetesMetabolicSyndrome,IGTandtype2diabetesareknownriskfactorsforcardiovasculardiseaseTreatingIGTmaysubstantiallyreducetheprogressiontoDMandpotentiallyreducetheincidenceofCVeventsCurrentstrategiesfocusonreducinginsulinresistance,and/orimprovingbetacellfunctionBothLifestyleModificationandMedicationshavebeeneffectiveinreducingprogressiontoDMinclinicaltrials,buttheireffectivenessinreducingCVDisnotyetknown?2019.AmericanCollegeofPhysicians.AllRightsReserved.SummaryWorldwideepidemicofQuestionsForDiscussionCanLifestyleModificationInterventionsbeimplementedsuccessfully?CanLifestylechangesbesustainedoverlongperiodsoftime?IsLifestyleModificationcosteffective?Whataretherelativecontributionsofweightlossandincreasedphysicalactivitytothebeneficialeffects?ShouldLifestyleModificationbecombinedwithPharmacologicalTreatmentstopreventtype2diabetesandreduceCVDrisk??2019.AmericanCollegeofPhysicians.AllRightsReserved.QuestionsForDiscussionCanLApproachtoTreatment?2019.AmericanCollegeofPhysicians.AllRightsReserved.ApproachtoTreatment?2019.ACNutritionTherapy,Exercise,

LifestyleChangesNutritiontherapydecreasefatcontentandtotalcaloriesdecreasesaturatedfat,substitutemono/polyunsatsLowglycemicindexCHOsIncreasedietaryfiberdecreasesaltforhypertensionhealthydietweightreductioninobesepatientsExerciseincreaseenergyexpenditurewith

moderate-intensityexerciseLifestylechangestoreducecardiovascularriskfactors

(eg,smokingcessation)Traininginself-managementandSMBG?2019PPS?2019.AmericanCollegeofPhysicians.AllRightsReserved.CNutritionTherapy,Exercise,ThereismuchcurrentinterestinLOWCHO,LOWFATandHIGHPROTEINdiets,butonlylimiteddatainhumanstodate.Thenewdiabeticdiet?40%CHO:30%FAT:30%PRONewTrendsinDietaryManagement?2019.AmericanCollegeofPhysicians.AllRightsReserved.ThereismuchcurrentinterestDrugstoTreatHyperglycemia,CorrectInsulinResistance,orImprove/PreserveB-CellFunction?2019.AmericanCollegeofPhysicians.AllRightsReserved.DrugstoTreatHyperglycemia,DeFronzoRA.Diabetes.1988;37:667-687.LebovitzHE.InJoslin'sDiabetesMellitus.1994:508-529.BloodglucoseInsulinresistance1 Intestine:glucoseabsorption2 Muscleandadiposetissue:

decreasedglucoseuptake4 Liver:increasedhepatic

glucoseoutput3 Pancreas:impairedinsulinsecretion

Insulin

resistanceCCausesofHyperglycemiainType2Diabetes?2019PPS?2019.AmericanCollegeofPhysicians.AllRightsReserved.DeFronzoRA.Diabetes.1988;37PharmacotherapyTailoredfortheMultipleDefectsofType2DiabetesType2DiabetesSulfonylureas__________Generalizedinsulinsecretagogue-glucosidaseInhibitors________DelaysCHOabsorptionBiguanide________ReduceshepaticInsulinresistanceTZD’s________ReduceperipheralinsulinresistanceMeglitinides__________RestorepostprandialinsulinpatternsPhenylalanineDerivatives__________RestoreearlypostprandialinsulinreleasePhysiologicInsulinReplacementTherapy?2019.AmericanCollegeofPhysicians.AllRightsReserved.PharmacotherapyTailoredfort20192000TrendsinAntidiabeticTherapy?2019.AmericanCollegeofPhysicians.AllRightsReserved.20192000TrendsinAntidiabeticThemajorityofpatientswillultimatelyneedcombinationtherapywithoralagentsand/orinsulintreatment.?2019.AmericanCollegeofPhysicians.AllRightsReserved.ThemajorityofpatientswillDeFronzoRAetal.NEnglJMed.2019;333:541-549.*P<0.001

?P<0.001glyburide-metforminvsglyburide

?P<0.001metforminvsglyburide

§P<0.01metforminvsglyburide40??Changein

fastingplasma

glucose(mg/dL)Diet+placeboDiet+metforminMetforminMetformin+glyburideGlyburideWeek200-20-40-800591317212529Week0591317212529200-20-40-60?????§§???????*********EffectsofMetforminMonotherapyorCombinationTherapyWithGlyburide-60C?2019PPS?2019.AmericanCollegeofPhysicians.AllRightsReserved.DeFronzoRAetal.NEnglJMePlaceboNateglinide120mgacMetformin500mgtidNateglinide120mgac+Metformin500mgtid*P<0.0001vsplacebo–1.6*–0.8*–0.7*+0.30.50–0.5–1.0–1.5–2.0ChangeinHbA1cin

Drug-Na?vePatientsMeanChangeinHbA1c(%)HortonES.DiabetesCare.2000;23(11):1660–1665.?2019.AmericanCollegeofPhysicians.AllRightsReserved.Placebo*P<0.0001vsplaceboMeanChangesFromBaselineinHbA1c

inPatientsInadequatelyControlledonMetformin*-0.1-0.1-0.4-0.8-1.40–1.6–1.4–1.2–1–0.8–0.6–0.4–0.20HbA