替米沙坦与代谢综合征.ppt

WillaHsueh,M.D.ProfessorofMedicineChief,DivisionofEndocrinology,Diabetes,andHypertensionUCLADavidGeffenSchoolofMedicineLosAngeles,California,CardiovascularRiskContinuum:ImplicationsofInsulinResistanceandDiabetes,Diabetesisavasculardisease:AngiotensinIIhasbeenimplicatedinboththedevelopmentofdiabetesanditscomplications,Diabetes,Insulin-mediatedglucoseuptake,Skeletalmuscle,Adipose,FFAInflammatoryAdipokines,Liver,Glucoseproduction,Pancreas,Insulinproduction,Atherosclerosis,CAD,Stroke,Peripheralvasculardisease,DiabeticNephropathy,Albuminexcretion,DiabeticRetinopathy,VEGFneovascularization,Diastolicdysfunction,interstitialfibrosisheartfailure,Cardiomyopathy,IL6,PAI-1,TNF,adiponectin,leptin,Insulinsensitivity,insulinresistance,Vascularinflammation,endothelialdysfunction,angiotensinogen,FFA,Adipocyte,AdipokinesMediateInsulinResistanceandInflammation,ProgressionofAtherosclerosisinInsulinResistance,Endothelial,Dysfunction,TG,HDL-C,sdLDL-C,Hypertension,UricAcid,PAI-1,Inflammation,Thrombosis,Oxidation,Atherosclerosis,Atherosclerosis,Unstableplaque,Inflammation,FibrosisCap,ThrombosisandRupture,Event,Hyperinsulinemia,MetabolicSyndrome,ImpairedGlucoseTolerane,Type2Diabetes,Hsueh,WA,LawR.AJC,2019,InsulinResistance,Forindividualsbornin2000:Males32.8%Females38.5%Estimatedlossoflifeexpectancyifdiagnosedatage40:Males11.6yearsFemales14.3years,NarayanJAMA2019,LifetimeRiskforDiabetesintheUS,13NH3,13NH3,13NH3,Dipyridamole(0.56mg/kg),135,Rest,QuinonesetalAnnInternMed.,2019;140:700-8,NoninvasiveMeasurementsofMyocardialBloodFlow:PositronEmissionTomography,0,25,45,70,90,115,CPT,DIP,ApproachesthatImproveCoronaryVasomotorFunctioninInsulinResistance:,Insulinsensitizers:TZDs,PPARligandsAT1receptorblockers:ARBsGlucosecontrolintype2diabetes:Metformin,VALUE(ValsartanAntihypertensiveLong-TermUseEvaluation):23%lessnewonsetdiabeteswithvalsartancomparedtoamlodipineinpatientswithhypertension,HOPE(HeartOutcomesPreventionEvaluation):32%lessnewonsetdiabeteswithramiprilcomparedtoplaceboinhighcardiovascularriskpatients,LIFE(LosartanInterventionforEndpointReductioninHypertension):25%lessnewonsetdiabeteswithlosartancomparedtoatenololinpatientswithhypertensionandleftventricularhypertrophy,CHARM(CandesartaninHeartFailure:AssessmentofReductioninMortalityandMorbidity):40%lessnewonsetdiabeteswithcandesartaninpatientswithheartfailure,InhibitionoftheRenin-angiotensinSystemPreventsDiabetes:,MechanismsbyWhichACEIsandARBsPreventDiabetes:,Improveendothelialfunction:Upto40%ofinsulin-mediatedglucoseuptakemaybeendothelialdependentAllowfatcelldifferentiationProtectisletcells?Alteradipokineproduction?Alterliverglucoseproduction,AngiotensinII,inflammation,oxidation,thrombosis,vasculargrowthandremodeling,hypertension,PPARLigandsAT1ReceptorBlockers,reversecholesteroltransport,AngiotensinIIActivatesMultipleMechanismsPromotingTissueInjurythatareAntagonizedbyPPARLigands,NuclearReceptorsPPARs,Kidneyproteinuria,Pancreas-cellprotection,BloodVesselsatherosclerosisbloodpressure,Eyeneovascularization,Adipocyteinflammatoryfactorsantiinflammatoryfactors,glucoseuptakeinresponsetoinsulin,reversemetabolicsyndrome,PPARImpactsMultipleAspectsofDiabetes,EffectsofPPARgLigandsonAtherosclerosisinAngII-InfusedMaleLDLR-/-Mice,PPARgLigandsConsistentlyAttenuatesAlbuminuriainPatientsandAnimalModelswithType2Diabetes,Troglitazoneamelioratesalbuminuriainstreptozotocin-induceddiabeticrats.Fujii,Metal.Metabolism,2019Effectoftroglitazoneonmicroalbuminuriainpatientswithincipientdiabeticnephropathy.Imano,Eetal.DiabetesCare,2019Expressionandfunctionofperoxisomeproliferator-activatedreceptor-yinmesangialcells.NicholasetalHypertension,2019RosiglitazonereducesurinaryalbuminexcretionintypeIIdiabetes.BakrisetalJHumanHypertension,2019,LigandsPAI-1expressionGrowthTGFeffectsonECMproduction,NicholasSB,etalHypertension37(Part2):722-727,2019,PPARgExpressedonMesangialCell,TROInhibitsCapillary-TubeFormation,Control,TRO-treated,Murataetal.InvestOphthalmolVisSci.41:2309-2317,2000,RetinalNeovascularizationinControlandTZD-treatedHypoxicMice,Telmisartan,DoesithavedualactivitytoinhibittheAT1receptorandactivatePPAR?KurtzTW,etal,Hypertension43:993-1002,2019SchuppM.,etal,Circulation109:2054-7,2019ONTARGET:TelmisartanRamiprilinhighriskpatientsCVendpoints,newonsettype2diabetes,nephropathy,cognitionUngerT.,AmJ.Cardiol91(suppl):28G-34G,2019,CenterforConsumerFreedom,IdentificationofNewTreatmentStrategiesforInsulinResistance,MetabolicSyndromeandHypertension,TheodoreWKurtzUSA,Hypertension:MoreThanJustHighBP,MetabolicSyndrome,Insulinresistance,Dyslipidemia,11:309-317.,*Statisticallysignificant,hypertensivevsnormotensive.LVHonECG.,0,2,4,6,8,10,12,Prevalence(%),Myocardialinfarction,Stroke/Transientischemicattack,Leftventricularhypertrophy,NormotensivediabeticmalesHypertensivediabeticmalesNormotensivediabeticfemalesHypertensivediabeticfemales,HypertensionandType2Diabetes:aHigh-RiskPopulation,Referencegroup:femaleaged50years,TC=4mmol/L,HDL=1.6mmol/L,nonsmoker,nodiabetes,atSBPlevelsof110,120,130,140,150,160,170121-293-8.,Patient1,Patient2,Patient3,CVDriskthresholdforhypertensiontreatment,MultifactorCVRisk(%peryr),BloodPressurethresholdforequalbenefit,TargetOrganDiseaseand/orDiabetes,MultipleRiskFactors,onlyelevatedBloodPressure,HighRisk,HighBP,LowBP,HypertensionTreatmentBasedonAbsoluteCVDRisk,Intensityoftreatmentreflectprogressiveincreaseofthenumberanddosageofdrugs,includingantihypertensiveagentsandcotreatment(aspirin,statins,antidiabetics,etc.).Itisnotrelatedtolevelsofbloodpressurebutrathertoabsoluterisklevelinindividualsubjects.Componentsoftreatmentarechosenbasedontheidentificationofdifferentriskfactorsinindividuals.,LowRisk,Singletherapy,Intensityofdrugtreatment,Multipletherapy,modifiedfromAmJHyper2019;15(10):917-23,MV2019,ReductionofsingleormultipleRiskFactorsgeneratesabenefitproportionaltothelevelofRisk,BPlevels,GlobalCVRisk,Riskincreasesinrelationtocharacteristicsofindividual.SmallreductionsofBloodPressurewillproducelargerabsolutebenefitsinrelationtolevelofrisk.,NewParadigmsinCVDandDiabetes,DoesitMatterHowYouReduceBloodPressureinType2DiabetesandMetabolicSyndrome?,Yes,accordingtoHypertensionandDiabetesGuidelinesYes,accordingtoEvidenceBasedMedicine(HOPE,IRMA2,LIFE),HypertensionandDiabetes:GeneralGuidelines,LowerBloodPressuretotargetGetcontrolofplasmaglucoseBlocktherenin-angiotensinsystemUseastatinControlmodifiableRiskFactors,MV2019,AntihypertensiveAgentsandInsulinSensitivityIndex*,%Change,*Dataderivedfromvariousdouble-blindandopenstudies,Propranolol,Metoprolol,Atenolol,Pindolol,HCTZ,Isradipine,Furosemide,Diltiazem,Enalapril,Captopril,Prazosin,Doxazosin,LithellHO.DiabetesCare1991;14:203-209.AndersonPE,LithellH.AmJHypertens2019;323-33.,083,Beta-blocker,Captopril,Ramipril,-50,-25,0,25,50,%,*P0.05comparedtonondiabetics,PropensitytoDevelopmentofDiabetesAccordingtotheAntihypertensiveDrug,4944M,AldermanM.etal.,Hypertension2019,Rate/1000person-years,6.11,6.11-7.4,7.5,Bloodsugar(mmol/l),Baseline,In-treatment,Baseline,In-treatment,CVD,non-CVD,2.9,2.4,1.4,2.7,2.8,2.0,8.4,10.1,15.2*,8.2,10.7,15.2*,Age-Gender-AdjustedCVDandNon-CVDIncidenceRatesbyBloodSugaratBaselineandinTreatmentinTreatedHypertensivePatients,Cardiovasculareventsintreatedhypertensivesubjectswithoutdiabetes(groupA),new-onsetdiabetes(groupB)andpreviouslyknowndiabetes(groupC),VerdecchiaP.Hypertension2019;43:963-9,IntegratingCardiorenalCareinDiabetesBlockadeofAT1-Receptor,BP-dependentandIndependentEffects,RenalProtection,CardiovascularProtection,improves,improves,AverageNumberofAntihypertensiveAgentsNeededPerPatienttoAchieveTargetSystolicBPGoals,NumberofMedications,ALLHAT(138mmHg)IDNT(138mmHg)RENAAL(141mmHg)UKPDS(144mmHg)ABCD(132mmHg)MDRD(132mmHg)HOT(138mmHg)AASK(128mmHg),Trial/SBPachieved,UpdatedfromBakrisGL.AmJKidneyDis.2000,DoesitMatterWhichDrugsWeUseinCombination?,OutcomesData,Tolerability,NewonsetDiabetes,Diuretics,ACEinhibitors,AT1-receptorblockers,Calciumantagonists,-blockers,-blockers,ESH/ESCGuidelines,JHypertens2019,RationalNonrational,PossiblecombinationsofdifferentclassesofantihypertensiveagentsaccordingtoESH-ESCGuidelines.AreTheyValidinDiabetics?,NewOnsetDiabetes,Hypertensionpersedoublestheriskofdevelopingnewonsetdiabeteseta-blockersordiureticsincreasetheriskofnewonsetdiabetesespeciallywhencombined(RR+19%)RASblockadedecreasesnewonsetofdiabetes,TheIdealCombinationTherapyinHypertension,EffectiveBPreductionatlowdosesSoundpathophysiologicalandpharmacodynamicrationalProtectionofassociatedRiskFactorControlofTargetOrganDamageControlofeventsWelltoleratedandfewsideeffects,Antihypertensivetherapyisthemosteffectivepreventivemeasureindiabetes,Monotherapyisrarelysufficient,Increasedrationaluseofcombinationtherapyisthekeytoimprovingbloodpressurecontrol,ThetypeofdrugsusedincombinationinfluencestheBPloweringeffectofthecombination,theadverseeventprofileandmayultimatelyinfluencemorbidityandmort