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SlideSourceLipidsOnlineHDLasaTherapeuticTargetDanielJ.Rader,M.D.SlideSourceLipidsOnline1001602200.01

.02.03.0RiskofCHDLowHDL-CisanIndependentPredictorofCHDRiskEvenWhenLDL-CisLowHDL-C(mg/dL)LDL-C(mg/dL)25GordonTetal.AmJMed1977;62:707-714.456585

SlideSourceLipidsOnlineATPIII:NewDefinitionofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;

285:2486-2497.LowHDL-Cwasredefinedas<40mg/dLSlideSourceLipidsOnlineATPIII:TheMetabolicSyndromeDiagnosisisestablishedwhen3oftheser

iskfactorsarepresent.ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.RiskF

actorDefiningLevelAbdominalobesity(Waistcircumference)MenWomen>102cm(>40in)>88cm(>35in)TG150mg/dLHDL-CMenWomen<40mg/dL<50mg/dLBloodp

ressure130/85mmHgFastingglucose110mg/dLSlideSourceLipidsOnlineIsHDL-CSimplyaMarkerofIncreasedCardiovascularRisk?◼Smoke◼Aresedentary◼A

reobese◼Areinsulinresistantordiabetic◼Havehypertriglyceridemia◼HavechronicinflammatorydisordersLowHDL-Clevelsarecommon

lyfoundinpatientswho:SlideSourceLipidsOnlineProductionofApoA-IbyLiverandIntestineA-IA-IILiverIntestineHDLA-IHDLSlideSourceLi

pidsOnline◼Reducedinitiationandprogressionofatherosclerosisintransgenicmiceandrabbits◼Regressionofpre-existingathero

sclerosisinanimalsIncreasedApoA-IProductionisAntiatherogenicinAnimalsSlideSourceLipidsOnline◼IncreaseapoA

-Iproduction◼Promotereversecholesteroltransport◼DelaycatabolismofHDLHDLMetabolismasaTherapeuticTarget:PotentialStrategiesSlideSourceLipidsOnline

◼SmallmoleculeupregulationofapoA-Igenetranscription◼Intravenousinfusionofrecombinantprotein(wild-typeapoA-I,apoA-IMilano)◼Administrationof

peptidesbasedonapoA-Isequence◼SomaticgenetransferofapoA-IDNA(liver,intestine,muscle,hematopoeticcells)ApproachestoIncreasingApoA-IProduction

SlideSourceLipidsOnline◼IncreaseapoA-Iproduction◼Promotereversecholesteroltransport◼Delaycatabolismo

fHDLHDLasaTherapeuticTarget:PotentialStrategiesSlideSourceLipidsOnlineA-IHDLandReverseCholesterolTransportLiverCECEFCLCAT

FCBileSR-BIABCA1MacrophageMatureHDLNascentHDLA-IFCCEFCSlideSourceLipidsOnlineRegulationofCholesterolEffluxintheMacrophageFCFCoxyster

olsLXR/RXRABCA1PPARsA-ISlideSourceLipidsOnlinePharmacologicManipulationofCholesterolEffluxLXR/RXRPPARsFibrates,TZDs,newagentsNewagentsA-IFCABCA1S

lideSourceLipidsOnline◼IncreaseapoA-Iproduction◼Promotereversecholesteroltransport◼DelaycatabolismofHDLHDLasaTherapeuticTa

rget:PotentialStrategiesSlideSourceLipidsOnline◼Antioxidanteffects◼Inhibitionofadhesionmoleculeexpression◼Inhibitio

nofplateletactivation◼Prostacyclinstabilization◼PromotionofNOproductionMechanismsOtherThanReverseCholesterolTransportbyWhichHDLMaybeAntiatherogenicS

lideSourceLipidsOnlineLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-ITGCEHDLMetabolism:IntravascularRemodelin

gofHDLKidneyPLFCPLSlideSourceLipidsOnlineLiverHLA-ITGCEHDLMetabolism:RoleofHepaticLipaseKidneyPLHDL2A-ICE

PLHDL3SlideSourceLipidsOnlineLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEHDLMetabolism:RoleofCETPFCK

idneyLDLRCETGCETPBVLDL/LDLSlideSourceLipidsOnlineHDLMetabolisminCETPDeficiencyCEFCFCLCATA-IABCA1MacrophageA-ICEFCCETGCETPBVLDL/LDLD

elayedcatabolismXSlideSourceLipidsOnline05101520253035OkamotoHetal.Nature2000;406:203-207.InhibitionofCETPbyJTT-705inCholesterol-FedRabbitsSignific

antlyReducedAorticAtherosclerosis%AorticLesionControlSimvastatinJTT-705SlideSourceLipidsOnlineHDLMetabolism:In

fluenceofCETPInhibitionLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEFCLDLRCETGCETPBVLDL/LDLXSlideSourceLipidsOnlin

e◼Weightreductionandincreasedphysicalactivity◼LDL-Cisprimarytargetoftherapy◼Non-HDL-Cissecondarytargetoftherapy(iftriglycerides200mg/dL)◼Consi

dernicotinicacidorfibratesManagementofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCh

olesterolinAdults.JAMA2001;285:2486-2497.SlideSourceLipidsOnline◼Therapeuticlifestylechanges◼Smokingcessatio

n◼Regularaerobicexercise◼Weightloss◼Alcoholuse?ManagementofLowHDL-CSlideSourceLipidsOnline◼Therapeuti

clifestylechanges◼Pharmacologictherapy◼StatinsManagementofLowHDL-CSlideSourceLipidsOnline05101520253035PatientswithEvents(%)ScandinavianSimvastat

inSurvivalStudyGroup.Lancet1995;345:1274-1275.4S:MajorCoronaryEventsbyHDL-CSubgroupHDL-C(mg/dL)PlaceboSimvastatin3839–4445–5253R

R=0.67RR=0.71RR=0.57RR=0.70SlideSourceLipidsOnline024681012141618PatientswithEvents(%)LIPIDStudyGroup.NEn

glJMed1998;339:1349-1357.LIPID:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPravastatin39mg/dL<39mg/dL25%24%SlideSourceLipidsOnline0510152

02530PatientswithEvents(%)SacksFMetal.NEnglJMed1996;335:1001-1009.CARE:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPravastatin>37m

g/dL37mg/dLP=0.008P<0.001SlideSourceLipidsOnline01020304050607080Events(%)DownsJRetal.JAMA1998;279:1615-1622.AFCAPS/TexCAPS

:RiskReductionbyHDL-CTertileatBaselineHDL-CLevelsPlaceboLovastatin<34mg/dl35–39mg/dl>40mg/dl71406841443544%RR40%RR20%RRSlideSourceLipi

dsOnline◼Therapeuticlifestylechanges◼Pharmacologictherapy◼Statins◼FibratesManagementofLowHDL-CSlideSourceLipidsOnline0510152025VA-HIT:Maj

orCoronaryEventsinGemfibrozilvs.PlaceboGroupsCumulativeIncidence(%)0RubinsHBetal.NEnglJMed1999;341:410-418.Copyright©1999,Massachus

ettsMedicalSociety.Allrightsreserved.123456YearPlaceboGemfibrozil–22%reductionP=0.006SlideSourceLipidsOnline050100150200050100150

200303132333435VA-HIT:LipidConcentrationsAccordingtoYearofStudyandTreatmentGroup050100150200TC(mg/dL)012345YearLDL-C(mg/dL)Year01

2345HDL-C(mg/dL)YearTG(mg/dL)Year012345PlaceboGemfibrozil–4%,P<0.001NochangeGemfibrozil&PlaceboPlaceboGemfibrozil+6%,P<0.001012345PlaceboGemfi

brozil–31%,P<0.001RubinsHBetal.NEnglJMed1999;341:410-418.Copyright©1999,MassachusettsMedicalSociety.Allright

sreserved.SlideSourceLipidsOnlineVA-HIT:ChangesinPlasmaLipidsduringTreatmentasPredictorsofCoronaryEventsVariable(Change)Ris

kFactor(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.SlideSourceLi

pidsOnline◼Therapeuticlifestylechanges◼Pharmacologictherapy◼Statins◼Fibrates◼NiacinManagementofLowHDL-CSlideSou

rceLipidsOnline-50-40-30-20-100102030EfficacyofExtended-ReleaseNiacinChangefromBaseline2500mg3000mgGoldbergAetal.AmJCardiol2000;85:1100-1

105.2000mg1500mg1000mg500mgHDL-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%SlideSourceLipidsOnline◼Lifestylechangesandsecondarycauses◼Pharmacologictherapy◼IfLDL-Celevated:statin◼IfTGelevated:fibrate◼Ifisolatedlow

HDL-C:niacin◼CombinationtherapyManagementofLowHDL-CSlideSourceLipidsOnline-30-20-100102030Change(%)Wolf

eMLetal.AmJCardiol2001;87:476-479.Copyright©2001,ExcerptaMedicaInc.Reprintedwithpermission.Additionof

Extended-ReleaseNiacintoaStatinbecauseofPersistentlyLowHDL-CTCLDL-CHDL-CTGSlideSourceLipidsOnlineCVEvents0510

152025EventRate(%)BrownBGetal.Circulation1998;98:I-635.FamilialAtherosclerosisTreatmentStudy(FATS):10-YearFo

llow-upResultsUsualCare(n=101)DeathsLDL-C188→166mg/dL;HDL-C38→40mg/dL;TG208→220mg/dLLDL-C202→106mg/dL;H

DL-C43→53mg/dL;TG210→134mg/dLTripleTherapy(n=75)19.818.81.3**p<0.055.3*SlideSourceLipidsOnline◼LDL-Cremainstheprimarytargetoflipid-alteringtherapie

s◼HDL-CisanimportantCHDriskfactor◼EvensmallincreasesinHDL-Cmayconfersubstantialbenefit◼InterventiontoraiseHDL-Clevelsshouldbeconsidered

inhigh-riskpatientsSummarySlideSourceLipidsOnline◼48-year-oldmanwithmetabolicsyndromeandCHD◼Aftertherapeuticli

festylechangesandastartingdoseofstatin:Cholesterol179mg/dLTriglycerides252mg/dLLDL-C97mg/dLHDL-C32mg/dLGlucose

104mg/dLApproachtothePatientwithLowHDL-CSlideSourceLipidsOnline演讲完毕，谢谢观看！Thankyouforreading!Inordertofacilitatelearningandu

se,thecontentofthisdocumentcanbemodified,adjustedandprintedatwillafterdownloading.Welcometodownload!汇报人：XXX汇报日期：20XX年10月10日