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HDLasaTherapeuticTarget

DanielJ.Rader,M.D...HDLasaTherapeuticTarget

D100160220RiskofCHDLowHDL-CisanIndependentPredictorofCHDRiskEvenWhenLDL-CisLowHDL-C

(mg/dL)LDL-C(mg/dL)25GordonTetal.AmJMed1977;62:707-714.456585..100160220RiskofCHDLowHDL-CATPIII:NewDefinitionofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.LowHDL-Cwasredefinedas<40mg/dL..ATPIII:NewDefinitionofLoATPIII:TheMetabolicSyndromeDiagnosisisestablishedwhen3oftheseriskfactorsarepresent.ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.RiskFactorDefiningLevelAbdominalobesity

(Waistcircumference)Men

Women

>102cm(>40in)

>88cm(>35in)TG150mg/dLHDL-CMen

Women<40mg/dL

<50mg/dLBloodpressure130/85mmHgFastingglucose110mg/dL..ATPIII:TheMetabolicSyndromIsHDL-CSimplyaMarkerofIncreasedCardiovascularRisk?SmokeAresedentaryAreobeseAreinsulinresistantordiabeticHavehypertriglyceridemiaHavechronicinflammatorydisordersLowHDL-Clevelsarecommonlyfoundinpatientswho:..IsHDL-CSimplyaMarkerofInProductionofApoA-IbyLiverandIntestineA-IA-IILiverIntestineHDLA-IHDL..ProductionofApoA-IbyLiverReducedinitiationandprogressionofatherosclerosisintransgenicmiceandrabbitsRegressionofpre-existingatherosclerosisinanimalsIncreasedApoA-IProductionisAntiatherogenicinAnimals..ReducedinitiationandprogresIncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLMetabolismasaTherapeuticTarget:PotentialStrategies..IncreaseapoA-IproductionHDLSmallmoleculeupregulationofapoA-IgenetranscriptionIntravenousinfusionofrecombinantprotein(wild-typeapoA-I,apoA-IMilano)AdministrationofpeptidesbasedonapoA-IsequenceSomaticgenetransferofapoA-IDNA(liver,intestine,muscle,hematopoeticcells)ApproachestoIncreasingApoA-IProduction..SmallmoleculeupregulationofIncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLasaTherapeuticTarget:PotentialStrategies..IncreaseapoA-IproductionHDLA-IHDLandReverseCholesterolTransportLiverCECEFCLCATFCBileSR-BIABCA1MacrophageMature

HDLNascent

HDLA-IFCCEFC..A-IHDLandReverseCholesterolRegulationofCholesterolEffluxintheMacrophageFCFCoxysterolsLXR/RXRABCA1PPARsA-I..RegulationofCholesterolEfflPharmacologicManipulationofCholesterolEffluxLXR/RXRPPARsFibrates,TZDs,newagentsNewagentsA-IFCABCA1..PharmacologicManipulationofIncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLasaTherapeuticTarget:PotentialStrategies..IncreaseapoA-IproductionHDLAntioxidanteffectsInhibitionofadhesionmoleculeexpressionInhibitionofplateletactivationProstacyclinstabilizationPromotionofNOproductionMechanismsOtherThanReverseCholesterolTransportbyWhichHDLMaybeAntiatherogenic..AntioxidanteffectsMechanismsLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-ITGCEHDLMetabolism:IntravascularRemodelingofHDLKidneyPLFCPL..LiverCECEFCFCLCATFCBileSR-BIA-LiverHLA-ITGCEHDLMetabolism:RoleofHepaticLipaseKidneyPLHDL2A-ICEPLHDL3..LiverHLA-ITGCEHDLMetabolism:LiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEHDLMetabolism:RoleofCETPFCKidneyLDLRCE

TGCETPBVLDL/LDL..LiverCECEFCFCLCATFCBileSR-BIA-HDLMetabolisminCETPDeficiencyCEFCFCLCATA-IABCA1MacrophageA-ICEFCCE

TGCETPBVLDL/LDLDelayed

catabolismX..HDLMetabolisminCETPDeficieOkamotoHetal.Nature2000;406:203-207.InhibitionofCETPbyJTT-705inCholesterol-FedRabbitsSignificantlyReducedAorticAtherosclerosis%AorticLesionControlSimvastatinJTT-705..OkamotoHetal.Nature2000;4HDLMetabolism:InfluenceofCETPInhibitionLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEFCLDLRCE

TGCETPBVLDL/LDLX..HDLMetabolism:InfluenceofWeightreductionandincreasedphysicalactivityLDL-CisprimarytargetoftherapyNon-HDL-Cissecondarytargetoftherapy

(iftriglycerides200mg/dL)ConsidernicotinicacidorfibratesManagementofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497...WeightreductionandincreasedTherapeuticlifestylechangesSmokingcessationRegularaerobicexerciseWeightlossAlcoholuse?ManagementofLowHDL-C..TherapeuticlifestylechangesMTherapeuticlifestylechangesPharmacologictherapyStatinsManagementofLowHDL-C..TherapeuticlifestylechangesMPatientswithEvents(%)ScandinavianSimvastatinSurvivalStudyGroup.Lancet1995;345:1274-1275.4S:MajorCoronaryEventsbyHDL-CSubgroupHDL-C(mg/dL)PlaceboSimvastatin3839–4445–5253RR=0.67RR=0.71RR=0.57RR=0.70..PatientswithEvents(%)ScandiPatientswithEvents(%)LIPIDStudyGroup.NEnglJMed1998;339:1349-1357.LIPID:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPravastatin39mg/dL<39mg/dL25%24%..PatientswithEvents(%)LIPIDPatientswithEvents(%)SacksFMetal.NEnglJMed1996;335:1001-1009.CARE:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPravastatin>37mg/dL37mg/dLP=0.008P<0.001..PatientswithEvents(%)SacksEvents(%)DownsJRetal.JAMA1998;279:1615-1622.AFCAPS/TexCAPS:RiskReductionby

HDL-CTertileatBaselineHDL-CLevelsPlaceboLovastatin<34mg/dl35–39mg/dl>40mg/dl71406841443544%

RR40%

RR20%

RR..Events(%)DownsJRetal.JAMATherapeuticlifestylechangesPharmacologictherapyStatinsFibratesManagementofLowHDL-C..TherapeuticlifestylechangesMVA-HIT:MajorCoronaryEventsinGemfibrozilvs.PlaceboGroupsCumulativeIncidence(%)0RubinsHBetal.NEnglJMed1999;341:410-418.Copyright?1999,MassachusettsMedicalSociety.Allrightsreserved.123456YearPlaceboGemfibrozil–22%reductionP=0.006..VA-HIT:MajorCoronaryEventsVA-HIT:LipidConcentrationsAccordingtoYearofStudyandTreatmentGroupTC(mg/dL)012345YearLDL-C(mg/dL)Year012345HDL-C(mg/dL)YearTG(mg/dL)Year012345PlaceboGemfibrozil–4%,P<0.001NochangeGemfibrozil&PlaceboPlaceboGemfibrozil+6%,P<0.001012345PlaceboGemfibrozil–31%,P<0.001RubinsHBetal.NEnglJMed1999;341:410-418.Copyright?1999,MassachusettsMedicalSociety.Allrightsreserved...VA-HIT:LipidConcentrationsVA-HIT:ChangesinPlasmaLipidsduringTreatmentasPredictorsofCoronaryEventsVariable(Change)RiskFactor(95%CI)PDuringtreatmentHDL-C(5.0mg/dL)0.89(0.81–0.98).02Triglycerides(50mg/dL)1.03(0.95–1.11).48LDL-C(25mg/dL)1.09(0.98–1.21).13RobinsSJetal.JAMA2001;285:1585-1591.Copyright?2001,AmericanMedicalAssociation...VA-HIT:ChangesinPlasmaLipTherapeuticlifestylechangesPharmacologictherapyStatinsFibratesNiacinManagementofLowHDL-C..TherapeuticlifestylechangesMEfficacyofExtended-ReleaseNiacinChangefromBaseline2500mg3000

mgGoldbergAetal.AmJCardiol2000;85:1100-1105.2000mg1500mg1000mg500mgHDL-CLDL-CLp(a)TG–9%–14%–22%–21%–17%29.5%30%26%22%15%10%–28%–35%–44%–39%–11%–5%–26%–3%–12%–30%–24%–17%..EfficacyofExtended-ReleaseNLifestylechangesandsecondarycausesPharmacologictherapyIfLDL-Celevated:statinIfTGelevated:fibrateIfisolatedlowHDL-C:niacinCombinationtherapyManagementofLowHDL-C..LifestylechangesandsecondarChange(%)WolfeMLetal.AmJCardiol2001;87:476-479.Copyright?2001,ExcerptaMedicaInc.Reprintedwithpermission.AdditionofExtended-ReleaseNiacintoaStatinbecauseofPersistentlyLowHDL-CTCLDL-CHDL-CTG..Change(%)WolfeMLetal.AmJCVEventsEventRate(%)BrownBGetal.Circulation1998;98:I-635.FamilialAtherosclerosisTreatmentStudy(FATS):10-YearFollow-upResultsUsualCare(n=101)DeathsLDL-C188166mg/dL;HDL-C3840mg/dL;TG208220mg/dLLDL-C202106mg/dL;HDL-C4353mg/dL;TG210134mg/dLTripleTherapy(n=75)19.818.81.3**p<0.055.3*..CVEventsEventRate(%)BrownBLDL-Cremainstheprimarytargetoflipid-alteringtherapiesHDL-CisanimportantCHDriskfactorEvensmallincreasesinHDL-CmayconfersubstantialbenefitInterventiontoraiseHDL-Clevelsshouldbeconsideredinhigh-riskpatientsSummary..LDL-Cremainstheprimarytarg48-year-oldmanwithmetabolicsyndromeandCHDAftertherapeuticlifestylechangesandastartingdoseofstatin:Cholesterol179mg/dLTriglycerides252mg/dLLDL-C97mg/dLHDL-C32mg/dLGlucose104mg/dLApproachtothePatientwithLowHDL-C..48-year-oldmanwithmetabolicHDLasaTherapeuticTarget

DanielJ.Rader,M.D...HDLasaTherapeuticTarget

D100160220RiskofCHDLowHDL-CisanIndependentPredictorofCHDRiskEvenWhenLDL-CisLowHDL-C

(mg/dL)LDL-C(mg/dL)25GordonTetal.AmJMed1977;62:707-714.456585..100160220RiskofCHDLowHDL-CATPIII:NewDefinitionofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.LowHDL-Cwasredefinedas<40mg/dL..ATPIII:NewDefinitionofLoATPIII:TheMetabolicSyndromeDiagnosisisestablishedwhen3oftheseriskfactorsarepresent.ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.RiskFactorDefiningLevelAbdominalobesity

(Waistcircumference)Men

Women

>102cm(>40in)

>88cm(>35in)TG150mg/dLHDL-CMen

Women<40mg/dL

<50mg/dLBloodpressure130/85mmHgFastingglucose110mg/dL..ATPIII:TheMetabolicSyndromIsHDL-CSimplyaMarkerofIncreasedCardiovascularRisk?SmokeAresedentaryAreobeseAreinsulinresistantordiabeticHavehypertriglyceridemiaHavechronicinflammatorydisordersLowHDL-Clevelsarecommonlyfoundinpatientswho:..IsHDL-CSimplyaMarkerofInProductionofApoA-IbyLiverandIntestineA-IA-IILiverIntestineHDLA-IHDL..ProductionofApoA-IbyLiverReducedinitiationandprogressionofatherosclerosisintransgenicmiceandrabbitsRegressionofpre-existingatherosclerosisinanimalsIncreasedApoA-IProductionisAntiatherogenicinAnimals..ReducedinitiationandprogresIncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLMetabolismasaTherapeuticTarget:PotentialStrategies..IncreaseapoA-IproductionHDLSmallmoleculeupregulationofapoA-IgenetranscriptionIntravenousinfusionofrecombinantprotein(wild-typeapoA-I,apoA-IMilano)AdministrationofpeptidesbasedonapoA-IsequenceSomaticgenetransferofapoA-IDNA(liver,intestine,muscle,hematopoeticcells)ApproachestoIncreasingApoA-IProduction..SmallmoleculeupregulationofIncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLasaTherapeuticTarget:PotentialStrategies..IncreaseapoA-IproductionHDLA-IHDLandReverseCholesterolTransportLiverCECEFCLCATFCBileSR-BIABCA1MacrophageMature

HDLNascent

HDLA-IFCCEFC..A-IHDLandReverseCholesterolRegulationofCholesterolEffluxintheMacrophageFCFCoxysterolsLXR/RXRABCA1PPARsA-I..RegulationofCholesterolEfflPharmacologicManipulationofCholesterolEffluxLXR/RXRPPARsFibrates,TZDs,newagentsNewagentsA-IFCABCA1..PharmacologicManipulationofIncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLasaTherapeuticTarget:PotentialStrategies..IncreaseapoA-IproductionHDLAntioxidanteffectsInhibitionofadhesionmoleculeexpressionInhibitionofplateletactivationProstacyclinstabilizationPromotionofNOproductionMechanismsOtherThanReverseCholesterolTransportbyWhichHDLMaybeAntiatherogenic..AntioxidanteffectsMechanismsLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-ITGCEHDLMetabolism:IntravascularRemodelingofHDLKidneyPLFCPL..LiverCECEFCFCLCATFCBileSR-BIA-LiverHLA-ITGCEHDLMetabolism:RoleofHepaticLipaseKidneyPLHDL2A-ICEPLHDL3..LiverHLA-ITGCEHDLMetabolism:LiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEHDLMetabolism:RoleofCETPFCKidneyLDLRCE

TGCETPBVLDL/LDL..LiverCECEFCFCLCATFCBileSR-BIA-HDLMetabolisminCETPDeficiencyCEFCFCLCATA-IABCA1MacrophageA-ICEFCCE

TGCETPBVLDL/LDLDelayed

catabolismX..HDLMetabolisminCETPDeficieOkamotoHetal.Nature2000;406:203-207.InhibitionofCETPbyJTT-705inCholesterol-FedRabbitsSignificantlyReducedAorticAtherosclerosis%AorticLesionControlSimvastatinJTT-705..OkamotoHetal.Nature2000;4HDLMetabolism:InfluenceofCETPInhibitionLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEFCLDLRCE

TGCETPBVLDL/LDLX..HDLMetabolism:InfluenceofWeightreductionandincreasedphysicalactivityLDL-CisprimarytargetoftherapyNon-HDL-Cissecondarytargetoftherapy

(iftriglycerides200mg/dL)ConsidernicotinicacidorfibratesManagementofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497...WeightreductionandincreasedTherapeuticlifestylechangesSmokingcessationRegularaerobicexerciseWeightlossAlcoholuse?ManagementofLowHDL-C..TherapeuticlifestylechangesMTherapeuticlifestylechangesPharmacologictherapyStatinsManagementofLowHDL-C..TherapeuticlifestylechangesMPatientswithEvents(%)ScandinavianSimvastatinSurvivalStudyGroup.Lancet1995;345:1274-1275.4S:MajorCoronaryEventsbyHDL-CSubgroupHDL-C(mg/dL)PlaceboSimvastatin3839–4445–5253RR=0.67RR=0.71RR=0.57RR=0.70..PatientswithEvents(%)ScandiPatientswithEvents(%)LIPIDStudyGroup.NEnglJMed1998;339:1349-1357.LIPID:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPravastatin39mg/dL<39mg/dL25%24%..PatientswithEvents(%)LIPIDPatientswithEvents(%)SacksFMetal.NEnglJMed1996;335:1001-1009.CARE:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPravastatin>37mg/dL37mg/dLP=0.008P<0.001..PatientswithEvents(%)SacksEvents(%)DownsJRetal.JAMA1998;279:1615-1622.AFCAPS/TexCAPS:RiskReductionby

HDL-CTertileatBaselineHDL-CLevelsPlaceboLovastatin<34mg/dl35–39mg/dl>40mg/dl71406841443544%

RR40%

RR20%

RR..Events(%)DownsJRetal.JAMATherapeuticlifestylechangesPharmacologictherapyStatinsFibratesManagementofLowHDL-C..TherapeuticlifestylechangesMVA-HIT:MajorCoronaryEventsinGemfibrozilvs.PlaceboGroupsCumulativeIncidence(%)0RubinsHBetal.NEnglJMed1999;341:410-418.Copyright?1999,MassachusettsMedicalSociety.Allrightsreserved.123456YearPlaceboGemfibrozil–22%reductionP=0.006..VA-HIT:MajorCoronaryEventsVA-HIT:LipidConcentrationsAccordingtoYearofStudyandTreatmentGroupTC(mg/dL)012345YearLDL-C(mg/dL)Year012345HDL-C(mg/dL)YearTG(mg/dL)Year012345PlaceboGemfibrozil–4%,P<0.001NochangeGemfibrozil&PlaceboPlaceboGemfibrozil+6%,P<0.001012345PlaceboGemfibrozil–31%,P<0.001RubinsHBetal.NEnglJMed1999;341:410-418.Copyright?1999,MassachusettsMedicalSociety.Allrightsreserved...VA-HIT:LipidConcentrationsVA-HIT:ChangesinPlasmaLipidsduringTreatmentasPredictorsofCoronaryEventsVariable(Change)RiskFactor(95%CI)PDuringtreatmentHDL-C(5.0mg/dL)0.89(0.81–0.98).02Triglycerides(50mg/dL)1.03(0.95–1.11).48LDL-C(25mg/dL)1.09(0.98–1.21).13RobinsSJetal.JAMA2001;285:1585-1591.Copyright?2001,AmericanMedicalAssociation...VA-HIT:ChangesinPlasmaLipTherapeuticlifestylechangesPharmacologictherapyStatinsFibratesNiacinManagementofLowHDL-C..TherapeuticlifestylechangesMEfficacy

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