替米沙坦與代謝綜合征

替米沙坦與代謝綜合征第1頁，課件共66頁，創(chuàng)作于2023年2月Diabetesisavasculardisease:AngiotensinIIhasbeenimplicatedinboththedevelopmentofdiabetesanditscomplicationsDiabetes

Insulin-mediatedglucoseuptakeSkeletalmuscleAdipose

FFAInflammatoryAdipokinesLiver

GlucoseproductionPancreas

InsulinproductionAtherosclerosisCAD,Stroke,

PeripheralvasculardiseaseDiabeticNephropathy

AlbuminexcretionDiabeticRetinopathy

VEGF

neovascularizationDiastolicdysfunction,interstitialfibrosisheartfailureCardiomyopathy

第2頁，課件共66頁，創(chuàng)作于2023年2月IL6PAI-1TNF

adiponectinleptinInsulinsensitivityinsulinresistanceVascularinflammationendothelialdysfunctionangiotensinogenFFAAdipocyteAdipokinesMediateInsulinResistanceandInflammation第3頁，課件共66頁，創(chuàng)作于2023年2月ProgressionofAtherosclerosisinInsulinResistance

EndothelialDysfunctionTG,HDL-C

sdLDL-CHypertensionUricAcidPAI-1

Inflammation

ThrombosisOxidationAtherosclerosis

Atherosclerosis

UnstableplaqueInflammation,FibrosisCap

ThrombosisandRupture

EventHyperinsulinemia

MetabolicSyndromeImpairedGlucoseTolerane

Type2DiabetesHsueh

WA,LawR.AJC,2003

InsulinResistance第4頁，課件共66頁，創(chuàng)作于2023年2月Forindividualsbornin2000:Males–32.8%Females–38.5%Estimatedlossoflifeexpectancyifdiagnosedatage40:Males–11.6yearsFemales–14.3yearsNarayanJAMA2003

LifetimeRiskforDiabetesintheUS第5頁，課件共66頁，創(chuàng)作于2023年2月13NH3

13NH3

13NH3

Dipyridamole(0.56mg/kg)135’RestQuinonesetalAnnInternMed.,2004;140:700-8NoninvasiveMeasurementsof

MyocardialBloodFlow:PositronEmissionTomography0’25’45’70’90’115’CPTDIP第6頁，課件共66頁，創(chuàng)作于2023年2月ApproachesthatImproveCoronaryVasomotorFunctioninInsulinResistance:Insulinsensitizers:TZDs,PPARligandsAT1receptorblockers:ARBsGlucosecontrolintype2diabetes:Metformin

第7頁，課件共66頁，創(chuàng)作于2023年2月VALUE(ValsartanAntihypertensiveLong-TermUseEvaluation):23%lessnewonsetdiabeteswithvalsartancomparedtoamlodipineinpatientswithhypertensionHOPE(HeartOutcomesPreventionEvaluation):32%lessnewonsetdiabeteswithramiprilcomparedtoplaceboinhighcardiovascularriskpatientsLIFE(LosartanInterventionforEndpointReductioninHypertension):25%lessnewonsetdiabeteswithlosartancomparedtoatenololinpatientswithhypertensionandleftventricularhypertrophyCHARM(CandesartaninHeartFailure:AssessmentofReductioninMortalityandMorbidity):40%lessnewonsetdiabeteswithcandesartaninpatientswithheartfailureInhibitionoftheRenin-angiotensinSystemPreventsDiabetes:第8頁，課件共66頁，創(chuàng)作于2023年2月MechanismsbyWhichACEIsandARBsPreventDiabetes:Improveendothelialfunction:Upto40%ofinsulin-mediatedglucoseuptakemaybeendothelialdependentAllowfatcelldifferentiationProtectisletcells?Alteradipokineproduction?Alterliverglucoseproduction

第9頁，課件共66頁，創(chuàng)作于2023年2月AngiotensinIIinflammationoxidationthrombosisvasculargrowthandremodelinghypertensionPPARLigandsAT1ReceptorBlockersreversecholesteroltransportAngiotensinIIActivatesMultipleMechanismsPromotingTissueInjurythatareAntagonizedbyPPARLigands第10頁，課件共66頁，創(chuàng)作于2023年2月NuclearReceptorsPPARsKidneyproteinuriaPancreas-cellprotectionBloodVesselsatherosclerosisbloodpressureEyeneovascularizationAdipocyteinflammatoryfactorsantiinflammatoryfactorsglucoseuptakeinresponsetoinsulin,reversemetabolicsyndromePPARImpactsMultipleAspectsofDiabetes第11頁，課件共66頁，創(chuàng)作于2023年2月EffectsofPPARgLigandsonAtherosclerosisin

AngII-InfusedMaleLDLR-/-Mice第12頁，課件共66頁，創(chuàng)作于2023年2月PPARgLigandsConsistentlyAttenuatesAlbuminuriainPatientsandAnimalModelswithType2DiabetesTroglitazoneamelioratesalbuminuriainstreptozotocin-induceddiabeticrats.Fujii,Metal.Metabolism,1997Effectoftroglitazoneonmicroalbuminuriainpatientswithincipientdiabeticnephropathy.Imano,Eetal.DiabetesCare,1998Expressionandfunctionofperoxisomeproliferator-activatedreceptor-yinmesangialcells.NicholasetalHypertension,2001RosiglitazonereducesurinaryalbuminexcretionintypeIIdiabetes.BakrisetalJHumanHypertension,2003第13頁，課件共66頁，創(chuàng)作于2023年2月LigandsPAI-1expressionGrowthTGFeffectsonECMproductionNicholasSB,etalHypertension37(Part2):722-727,2001PPARgExpressedonMesangialCell第14頁，課件共66頁，創(chuàng)作于2023年2月TROInhibitsCapillary-TubeFormationControlTRO-treatedMurataetal.InvestOphthalmolVisSci.41:2309-2317,2000RetinalNeovascularizationinControlandTZD-treatedHypoxicMice第15頁，課件共66頁，創(chuàng)作于2023年2月TelmisartanDoesithavedualactivitytoinhibittheAT1receptorandactivatePPAR?KurtzTW,etal,Hypertension43:993-1002,2004

SchuppM.,etal,Circulation109:2054-7,2004

ONTARGET:TelmisartanRamiprilinhighriskpatientsCVendpoints,newonsettype2diabetes,nephropathy,cognitionUngerT.,AmJ.Cardiol91(suppl):28G-34G,2003第16頁，課件共66頁，創(chuàng)作于2023年2月?CenterforConsumerFreedom第17頁，課件共66頁，創(chuàng)作于2023年2月IdentificationofNewTreatmentStrategiesforInsulinResistance,MetabolicSyndromeandHypertension

TheodoreWKurtzUSA

第18頁，課件共66頁，創(chuàng)作于2023年2月Hypertension:MoreThanJustHighBP

MetabolicSyndromeInsulinresistance,Dyslipidemia,&IncreasedBP

Affects15-25%ofindividualsinindustrializedpopulations

2-4foldriskincardiovascularmortality

5-9foldriskfordevelopingtype2diabetes*Noteffectivelytreatedbycurrentantihypertensivedrugs*

第19頁，課件共66頁，創(chuàng)作于2023年2月AngiotensinIIReceptorBlockers(ARBs)

Hypertension

InsulinResistance

Dyslipidemia

?

?

第20頁，課件共66頁，創(chuàng)作于2023年2月H

O

O

C

N

N

N

N

O

S

N

H

O

O

N

AIIReceptorBlockerTelmisartan

PPARLigandPioglitazone

第21頁，課件共66頁，創(chuàng)作于2023年2月PPAR

Acellularreceptorthatisaproventherapeutic

targetinthetreatmentofinsulinresistance,

diabetes,andthemetabolicsyndrome

Peroxisomeproliferatoractivatedreceptor-gamma

第22頁，課件共66頁，創(chuàng)作于2023年2月PPARActivatorsApprovedfortheTreatmentofType2Diabetes

FattyAcids/TriglyceridesInsulinSensitivity

HDL

Actos?(Lilly/Takeda)

(Avandia?-GSK)

MillionsofPrescriptionsWritten第23頁，課件共66頁，創(chuàng)作于2023年2月2Losartan

46810121416Eprosartan

Irbesartan

Valsartan

Candesartan

Telmisartan

Foldactivation

Olmesartan

5micromolar

AbilityofDifferentARBsToActivatePPAR

(S.C.Bensonetal.,Hypertension,43:993-1002,2004)

第24頁，課件共66頁，創(chuàng)作于2023年2月TelmisartanisaPartialAgonistofPPAR

(Schuppetal.,Circulation,109:2054-2057,2004)Luciferaseactivity[x-foldinductionovervehicletreatedcells]Pioglitazone

Telmisartan

μmol/Liter第25頁，課件共66頁，創(chuàng)作于2023年2月MechanismWherebyPPARActivatorsImproveInsulinResistanceandtheMetabolicSyndrome

PPAR

Activator

ExpressionofKeyTargetGenes

Receptorcomplex

DBD

PPAR

DNAresponseelements

CytoplasmNucleus

RXR

第26頁，課件共66頁，創(chuàng)作于2023年2月AbilityofTelmisartantoActivateKey

Anti-DiabeticTargetGenesofPPAR

GeneEncodingPEPCK

Telmisartan

22.5micromolar

3Val

Irb

14FoldactivaitonCan

Olm

Epro

Exp

(Bensonetal.,Hypertension,43:993-1002,2004)第27頁，課件共66頁，創(chuàng)作于2023年2月ItisalsoaPPARActivator-TelmisartanisNotJustanARB-

Cellulardifferentiationassays

Targetgeneexpressionassays

ReceptortransactivationassaysWhatistheclinicalevidencethattelmisartan

canimproveglucoseandlipidmetabolismasonewouldexpectforaPPARactivator?

Studiesinanimalmodelsofinsulinresistance第28頁，課件共66頁，創(chuàng)作于2023年2月Valsartan160mg/dayTelmisartan80mg/day

Glucose

105

110

115

120

125

Week:0

mg/dl=

481216ValsartanTelmisartan

Insulin

10

15

20

25

30

Week:0

uU/ml=

481216ClinicalCaseObservations52yearoldmalewiththemetabolicsyndrome

2020TelmisartanTelmisartan第29頁，課件共66頁，創(chuàng)作于2023年2月Triglycerides

Telmisartan60

80

100

120

140

Week:04mg/dl=

81216ValsartanClinicalCaseObservations52yearoldmalewiththemetabolicsyndrome

20Telmisartan

(PershadsinghandKurtz,DiabetesCare,27:1015,2004)

第30頁，課件共66頁，創(chuàng)作于2023年2月OpenLabel,PostMarketingSurveillanceStudyofTelmisartan,40-80mg/dayx6months,in3,643Diabetics

(Micheletal.,DrugSafety,27:335-344,2004)

-20-10mg/dl

Triglycerides

-300Glucose

第31頁，課件共66頁，創(chuàng)作于2023年2月Telmisartan40mg/day

(n=40)Placebocontrol

(n=40)

Eprosartan600mg/day

(n=39)

Double-Blind,Placebo-ControlledStudyoftheMetabolicEffectsofTelmisartaninPatientswithMildHypertension&Type2DM(DeRosaetal.HypertensionResearch,2004)

HypertensiveDiabetics

After12months,comparechangesininsulin,

glucose,andtriglyceridelevelsfrombaseline第32頁，課件共66頁，創(chuàng)作于2023年2月EffectsonTriglycerides

(DeRosaetal.HypertensionResearch,2004)

After

After

40

80

120

mg/dl

Eprosartan600mg/day140

20

60

100

40

80

120

mg/dl

Placebocontrol140

20

60

100

40

80

120

mg/dl

BeforeBeforeBeforeTelmisartan40mg/day140

20

60

100

pAfter*

P<.05

第33頁，課件共66頁，創(chuàng)作于2023年2月Telmisartan80mg/day

(n=20)Losartan50mg/day

(n=20)

Randomized,ParallelStudyComparingTelmisartantoLosartaninPatientswiththeMetabolicSyndrome

40PatientsHypertensionMetabolicSyndrome

Changesfrombaselineinfastingglucose,

insulin,andoralglucosetoleranceafter3months(G.Rosanoetal.,VIIForumontheRenin-AngiotensinSystem,2004)

第34頁，課件共66頁，創(chuàng)作于2023年2月ChangesinGlucose,Insulin,andInsulinResistanceFrom

BaselineinPatientswiththeHypertensionMetabolicSyndrome

Glucose-8

-6

-4

-2

0

2

4

%changecomparedtobaseline

Losartan

Telmisartanp<0.05

Insulin

Losartan

Telmisartanp<0.06

HOMAIndexLosartan

Telmisartanp<0.05

InsulinResistance(G.Rosanoetal.,VIIForumontheRenin-AngiotensinSystem,2004)第35頁，課件共66頁，創(chuàng)作于2023年2月ItisalsoaPPARActivator-TelmisartanisNotJustanARB-

Cellulardifferentiationassays

Targetgeneexpressionassays

Receptortransactivationassays

StudiesinanimalmodelsWhyisTelmisartantheonlyARBthatcanclearlyactivatePPARwhentestedatconcentrations

thatcanbeachievedwithconventionaloraldosing?

Preliminaryclinicalstudies第36頁，課件共66頁，創(chuàng)作于2023年2月OLMESARTANMEDOXOMILTheChemicalStructuresofARBs

第37頁，課件共66頁，創(chuàng)作于2023年2月50100150200250300350400Telmisartan

LitersVolumeofDistributionofDifferentARBs(IndexoftheAbilityofaDrugtoEnterTissuesThroughouttheBody)

450500Valsartan

Olmesartan

Losartan

LosartanMetabolite

Candesartan

Irbesartan

第38頁，課件共66頁，創(chuàng)作于2023年2月MolecularModelingofTelmisartanintheLigandBindingDomain(LBD)ofPPAR

Telmisartan(Bensonetal.,Hypertension,43:993-1002,2004)

第39頁，課件共66頁，創(chuàng)作于2023年2月

TwoClassesofPPARActivatorsConventionalPPARActivators

SelectivePPARModulators

PioglitazoneRosiglitazone

TelmisartannTZDpa(Merck)

Weightgain

Yes

No

Fluidretention

Yes

No

Markedadipogenesis

Yes

No

Improveglucose&lipidmetabolism

Yes

Yes

Differenteffectsonreceptoractivation&geneexpressionprofiles

第40頁，課件共66頁，創(chuàng)作于2023年2月ClinicalImplications:

TelmisartanisBothanARBandaSelectivePPARModulator

Treatmentofthemetabolicsyndrome

andthepreventionoftype2diabetes

Preventionandtreatmentofatherosclerosis第41頁，課件共66頁，創(chuàng)作于2023年2月InsulinresistanceHypertensionCellinflammation

Cellproliferation

Oxidativestress

DyslipidemiaTelmisartan

PPARpathways

Angiotensinpathways

Atherosclerosis

ActivatesBlocks第42頁，課件共66頁，創(chuàng)作于2023年2月ONTARGETandTRANSCEND-TrialDesigns-ONTARGET

25,260

5,926

Telmisartan

Ramipril

Telmisartan

Ramipril

+

Telmisartan

Placebo

TRANSCEND

Cardiovascularandmetabolicendpointsinhighriskpopulations

第43頁，課件共66頁，創(chuàng)作于2023年2月SUMMARY

Inpreliminaryclinicalstudies,telmisartanshows

metaboliceffectsthatdistinguishitfromotherARBs

TelmisartanisadualARB/selectivePPARmodulator

Implicationsforprevention&treatmentofthe

metabolicsyndrome,type2diabetes,&atherosclerosis

Newstrategiesfordeveloping3rdgeneration

angiotensinIIreceptorblockersandPPARactivators第44頁，課件共66頁，創(chuàng)作于2023年2月WhatDoestheFutureHoldforCardiovascularProtectionofDiabeticPatients?

MassimoVolpeItaly

第45頁，課件共66頁，創(chuàng)作于2023年2月MostHypertensivePatientsHaveComplexHypertension≥1CVadditionalCVriskfactorNoadditionalCVriskfactorCOMPLEXHYPERTENSIONHTN≥additionalriskfactorCAD,LVHDiabetes,MetabolicsyndromeRenalDiseaseHigh-riskpopulationFraminghamOffspringStudy(menaged18-74)Thrombosis2003.pptCopyrightCMFLearningSystems第46頁，課件共66頁，創(chuàng)作于2023年2月EpidemicsofDiabetesinHypertensionAgrowingproportionofhypertensivepatientshaveordevelopmetabolicsyndromeortype2diabetes(13–22%indifferentstudies!)

第47頁，課件共66頁，創(chuàng)作于2023年2月*

*

*

*

*

TheHypertensioninDiabetesStudyGroup.

JHypertens1993a;11:309-317.*Statisticallysignificant,hypertensivevsnormotensive.?LVHonECG.0

2

4

6

8

10

12Prevalence

(%)

Myocardial

infarction

Stroke/TransientischemicattackLeftventricularhypertrophy?

Normotensive

diabeticmalesHypertensive

diabeticmalesNormotensive

diabeticfemalesHypertensive

diabeticfemalesHypertensionandType2Diabetes:

aHigh-RiskPopulation第48頁，課件共66頁，創(chuàng)作于2023年2月Referencegroup:femaleaged50years,TC=4mmol/L,HDL=1.6mmol/L,nonsmoker,nodiabetes,atSBPlevels

of110,120,130,140,150,160,170&180mmHgDerivedfromAndersonetal.,AmHeartJ1991;121-293-8.

03545502030Reference

group5yearCVDriskper100persons

TC

=7mmol/L&smokermale402510155&diabetes60yrs&HDL

=1mmol/L3%<1%6%12%18%24%33%44%第49頁，課件共66頁，創(chuàng)作于2023年2月Patient1Patient2Patient3CVDriskthresholdforhypertensiontreatmentMultifactorCVRisk(%peryr)BloodPressurethresholdforequalbenefitTargetOrganDiseaseand/orDiabetesMultipleRiskFactorsonlyelevatedBloodPressureHighRiskHighBPLowBPHypertensionTreatmentBasedonAbsoluteCVDRiskIntensityoftreatmentreflectprogressiveincreaseofthenumberanddosageofdrugs,includingantihypertensiveagentsandcotreatment(aspirin,statins,antidiabetics,etc.).Itisnotrelatedtolevelsofbloodpressurebutrathertoabsoluterisklevelinindividualsubjects.Componentsoftreatmentarechosenbasedontheidentificationofdifferentriskfactorsinindividuals.LowRiskSingletherapyIntensityofdrugtreatment

MultipletherapymodifiedfromAmJHyper2002;15(10):917-23第50頁，課件共66頁，創(chuàng)作于2023年2月MV2004ReductionofsingleormultipleRiskFactorsgeneratesabenefit

proportionaltothelevelofRisk

BPlevelsGlobalCVRiskRiskincreasesinrelationtocharacteristicsofindividual.SmallreductionsofBloodPressurewillproducelargerabsolutebenefitsinrelationtolevelofrisk.NewParadigmsinCVDandDiabetes

第51頁，課件共66頁，創(chuàng)作于2023年2月DoesitMatterHowYouReduceBloodPressureinType2DiabetesandMetabolicSyndrome?

Yes,accordingtoHypertensionand

DiabetesGuidelinesYes,accordingtoEvidenceBasedMedicine

(HOPE,IRMA2,LIFE…)

第52頁，課件共66頁，創(chuàng)作于2023年2月HypertensionandDiabetes:

GeneralGuidelinesLowerBloodPressuretotargetGetcontrolofplasmaglucoseBlocktherenin-angiotensinsystemUseastatinControlmodifiableRiskFactors

MV2004第53頁，課件共66頁，創(chuàng)作于2023年2月AntihypertensiveAgentsandInsulinSensitivityIndex*

%Change*Dataderivedfromvariousdouble-blindandopenstudiesPropranolol

Metoprolol

Atenolol

Pindolol

HCTZIsradipine

Furosemide

Diltiazem

Enalapril

Captopril

Prazosin

Doxazosin

LithellHO.DiabetesCare1991;14:203-209.AndersonPE,LithellH.AmJHypertens1996;323-33.

第54頁，課件共66頁，創(chuàng)作于2023年2月083Beta-blocker

Captopril

Ramipril

-50

-25

0

25

50

%

*P<0.05comparedtonondiabetics

AthhoselRiskStudyCAPPStudy

HOPEStudy

PropensitytoDevelopmentofDiabetesAccordingtotheAntihypertensiveDrug第55頁，課件共66頁，創(chuàng)作于2023年2月4944MAldermanM.etal.,Hypertension1999Rate/1000person-years<6.116.11-7.4≥7.5Bloodsugar(mmol/l)BaselineIn-treatmentBaselineIn-treatmentCVDnon-CVD2.92.41.42.72.82.08.410.115.2*8.210.715.2*Age-Gender-AdjustedCVDandNon-CVDIncidenceRatesbyBloodSugaratBaselineandinTreatmentinTreatedHypertensivePatients

第56頁，課件共66頁，創(chuàng)作于2023年2月Cardiovasculareventsintreatedhypertensivesubjectswithoutdiabetes(groupA),new-onsetdiabetes(groupB)andpreviouslyknowndiabetes(groupC)VerdecchiaP.Hypertension2004;43:963-9第57頁，課件共66頁，創(chuàng)作于2023年2月IntegratingCardiorenalCareinDiabetes

BlockadeofAT1-Receptor

BP-dependentandIndependentEffectsRenalProtectionCardiovascularProtectionimprovesimproves第58頁，課件共66頁，創(chuàng)作于2023年2月AverageNumberofAntihypertensiveAgentsNeededPerPatienttoAchieveTargetSystolicBPGoalsNumberofMedications

ALLHAT(138mmHg)IDNT (138mmHg)RENAAL (141mmHg)UKPDS (144mmHg)ABCD (132mmHg)MDRD (132mmHg)HOT (138mmHg)AASK (128mmHg)Trial/SBPachievedUpdatedfromBakrisGL.AmJKidneyDis.2000第59頁，課件共66頁，創(chuàng)作于2023年2月DoesitMatterWhichDrugsWeUseinCombination?

OutcomesDa