高脂血症治疗目标高密度脂蛋白课件

HDLasaTherapeuticTarget

DanielJ.Rader,M.D...100160220RiskofCHDLowHDL-CisanIndependentPredictorofCHDRiskEvenWhenLDL-CisLowHDL-C

(mg/dL)LDL-C(mg/dL)25GordonTetal.AmJMed1977;62:707-714.456585..ATPIII:NewDefinitionofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.LowHDL-Cwasredefinedas<40mg/dL..ATPIII: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..IsHDL-CSimplyaMarkerofIncreasedCardiovascularRisk?SmokeAresedentaryAreobeseAreinsulinresistantordiabeticHavehypertriglyceridemiaHavechronicinflammatorydisordersLowHDL-Clevelsarecommonlyfoundinpatientswho:..ProductionofApoA-IbyLiverandIntestineA-IA-IILiverIntestineHDLA-IHDL..ReducedinitiationandprogressionofatherosclerosisintransgenicmiceandrabbitsRegressionofpre-existingatherosclerosisinanimalsIncreasedApoA-IProductionisAntiatherogenicinAnimals..IncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLMetabolismasaTherapeuticTarget:PotentialStrategies..SmallmoleculeupregulationofapoA-IgenetranscriptionIntravenousinfusionofrecombinantprotein(wild-typeapoA-I,apoA-IMilano)AdministrationofpeptidesbasedonapoA-IsequenceSomaticgenetransferofapoA-IDNA(liver,intestine,muscle,hematopoeticcells)ApproachestoIncreasingApoA-IProduction..IncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLasaTherapeuticTarget:PotentialStrategies..A-IHDLandReverseCholesterolTransportLiverCECEFCLCATFCBileSR-BIABCA1MacrophageMature

HDLNascent

HDLA-IFCCEFC..RegulationofCholesterolEffluxintheMacrophageFCFCoxysterolsLXR/RXRABCA1PPARsA-I..PharmacologicManipulationofCholesterolEffluxLXR/RXRPPARsFibrates,TZDs,newagentsNewagentsA-IFCABCA1..IncreaseapoA-IproductionPromotereversecholesteroltransportDelaycatabolismofHDLHDLasaTherapeuticTarget:PotentialStrategies..AntioxidanteffectsInhibitionofadhesionmoleculeexpressionInhibitionofplateletactivationProstacyclinstabilizationPromotionofNOproductionMechanismsOtherThanReverseCholesterolTransportbyWhichHDLMaybeAntiatherogenic..LiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-ITGCEHDLMetabolism:IntravascularRemodelingofHDLKidneyPLFCPL..LiverHLA-ITGCEHDLMetabolism:RoleofHepaticLipaseKidneyPLHDL2A-ICEPLHDL3..LiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEHDLMetabolism:RoleofCETPFCKidneyLDLRCE

TGCETPBVLDL/LDL..HDLMetabolisminCETPDeficiencyCEFCFCLCATA-IABCA1MacrophageA-ICEFCCE

TGCETPBVLDL/LDLDelayed

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

TGCETPBVLDL/LDLX..WeightreductionandincreasedphysicalactivityLDL-CisprimarytargetoftherapyNon-HDL-Cissecondarytargetoftherapy

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

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

RR40%

RR20%

RR..TherapeuticlifestylechangesPharmacologictherapyStatinsFibratesManagementofLowHDL-C..VA-HIT:MajorCoronaryEventsinGemfibrozilvs.PlaceboGroupsCumulativeIncidence(%)0RubinsHBetal.NEnglJMed1999;341:410-418.Copyright©1999,MassachusettsMedicalSociety.Allrightsreserved.123456YearPlaceboGemfibrozil–22%reductionP=0.006..VA-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: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...TherapeuticlifestylechangesPharmacologictherapyStatinsFibratesNiacinManagementofLowHDL-C..EfficacyofExtended-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%..LifestylechangesandsecondarycausesPharmacologictherapyIfLDL-Celevated:statinIfTGelevated:fibrateIfisolatedlowHDL-C:niacinCombinationtherapyManagementofLowHDL-C..Change(%)WolfeMLetal.AmJCardiol2001;87:476-479.Copyright©2001,ExcerptaMedicaInc.Reprintedwithpermission.AdditionofExtended-ReleaseNiacintoaStatinbecauseofPersistentlyLowHDL-CTCLDL-CHDL-CTG..CVEventsEventRate(%)BrownBGetal.Circulation1998;98:I-635.FamilialAtherosclerosisTreatmentStudy(FATS):10-YearFollow-upResultsUsualCar