從抑制膽固醇吸收談如何減少血液中膽固醇

從抑制膽固醇吸收談如何減少血液中膽固醇第1頁(yè)/共44頁(yè)P(yáng)lasmaCholesterolandCoronaryHeartDisease(CHD)CHDDeathsPer1000patientsper10yrSerumCholesterolLevel(mg/dl)MRFIT:MultipleRiskFactorInterventionTrial

ShanghaiFromDr.JohnM.Dietschy(USA)第2頁(yè)/共44頁(yè)MeanLDL-CholesterolAGE(YEARS)LifetimeExposuretoLDL-CholesterolAmericanvs.ChineseMenLifetimeLDLExposureIndexSMOKINGHTNDIABETESCHR.9etc.FEMALEFromDr.HelenH.Hobbs第3頁(yè)/共44頁(yè)ElbowTuberousXanthoma(15YsChineseGirl,FH?)FromDr.LuyaWanginBeijing第4頁(yè)/共44頁(yè)Fluid-MosaicModelofCellMembrane:

Cholesterolisastructuralcomponentofmammaliancellmembranes“CholesterolIsGood”第5頁(yè)/共44頁(yè)NetCholesterolBalanceinHumans~700mg~375mgHepaticandExtrahepaticSynthesis

TotalBodyCholesterol~750mgDietary+BiliaryCholesterol~400mgBileFC~375mgFeces~300mgBileacidsVonBergmannK,…GrundySM,Gastroenterology1979:77:1183

~50%~50mgSteroids~100mgSkinsloughIntestinalabsorption:~50%~100mgIntestineslough第6頁(yè)/共44頁(yè)MolecularMechanismsofCholesterolTransportinLiverandIntestinePCSK9,ARHABCtransportersApoBApoB第7頁(yè)/共44頁(yè)MonogenicHypercholesterolemiaAutosomal

Familial LDLRFamilialDefectiveAPOB

ApoB-100Inheritance DiseaseGeneDefectDominant

HypercholesterolemiaAutosomal

AutosomalRecessive ARH Hypercholesterolemia

Sitosterolemia

ABCG5/G8RecessiveAutosomalDominantHypercholesterolemiaPSCK9第8頁(yè)/共44頁(yè)TargetsofCholesterolLoweringDrugsInhibitcholesterolsynthesis:HMG-CoAreductaseinhibitorsstatinsInhibitcholesterolabsorption:Ezetimibe,bileacidresins,plantsterolsReducelipoprotein-cholesterolproduction:ApoBantisenseoligos(ISIS)RaiseLDLR:statins,PCSK9inhibition(drugsandantisenseoligos)第9頁(yè)/共44頁(yè)TargetsofCholesterolLoweringDrugs(continue)HDL-Ciscontroversial.Justamarkerorarealcause?ThebodydoesnotneedHDLtogetridofcholesterol.ConsequenceofraisingHDL:WhydidCETPinhibitorfail?Doesreversecholesteroltransport(RCT)quantitativelyimportant?Anti-inflammationmaydelayheartattack,butwhenyourLDL-Cisbelow70mg/dL,yourchancetodevelopatheroscleroticlesionsisvery,verylow.第10頁(yè)/共44頁(yè)Whyaslowas70?Becausewhatmattersis“NotJustHowLow,ButAlsoHowLong”.(PCSK9mutants,Framinghamstudy)Howtogetthere?第11頁(yè)/共44頁(yè)GlucuronidationZetia第12頁(yè)/共44頁(yè)IntestinalSterolAbsorptionandExcretionDietarySterolsBiliarySterolsBA,PLSterolsMixedmicellesABCG5ABCG8NPC1L1LymphEzetimibe(Zetia)GUTLUMENChFeces第13頁(yè)/共44頁(yè)ReduceBloodCholesterolLevelsbyEzetimibeandStatininHumansBaysHE,etal.ClinTher2004:26:1758第14頁(yè)/共44頁(yè)SwitchingtoEzetimibe/Simvastatin

vsDoublingStatinDosesinPatientswithCHDand/orDiabetesTheEzetimibeAndSimvastatinvsdoublEstatinreachnewlipidtreatmentGOals(EASEGO)Study第15頁(yè)/共44頁(yè)SwitchingtoEzetimibe/SimvastatinMoreEffectiveThanDoublingStatinDoseAdaptedfromRoetersvanLennepHWO,etal.CurrMedResOpin.2008;24(3):685–694.PatientsatLDL-CGoalatWeek12,%Ezetimibe/simvastatin Doublingtoatorvastatin20mgorsimvastatin40mgPatientsatLDL-CGoalatWeek12,%DoublingtoSimvastatin

40mgGroupDoublingtoAtorvastatin

20mgGroup02040608002040608024%

(n=115)73%

(n=110)28%

(n=74)57%

(n=68)LDL-CGoalAttainmentto<2.5mmol/L第16頁(yè)/共44頁(yè)SwitchingtoEzetimibe/Simvastatin

SuperiortoDoublingStatinDoseAcrossMostLipidSubfractionsAdaptedfromRoetersvanLennepHWO,etal.CurrMedResOpin.2008;24(3):685–694.MeanChangeFromStatinBaselineatWeek12,%Total

Cholesterol–35–30–15–10–505–25–20LDL-CHDL-CTriglyceridesTotalCholesterol/HDL-CapoB–17.7–6.6–11.5–29.1–2.61.0–0.1–2.8–13.5–6.1–19.7–7.2Ezetimibe/simvastatin(n=178) Doublingtoatorvastatin20mg

orsimvastatin40mg(n=189)第17頁(yè)/共44頁(yè)TheBestOption?Startearlyandstartaggressively,particularlyonhypercholesterolemicpatientswithotherriskfactorsandprevioushearteventsWiththenewgoalforbloodLDL-C,combinedtherapiesmaybethebestoption.Forexample:astatin+ezetimibe;VytorinDon’tforgetregularexercise,healthydiet,bloodpressurecontrol,anda“happyheart”Saynotosmoke第18頁(yè)/共44頁(yè)ClinicalTrial:ENHANCEEzetimibeandSimvastatininHypercholesterolemiaEnhancesAtherosclerosisRegression18CenterstudyinUnitedStates,Canada,SouthAfrica,Spain,Denmark,Norway,Sweden,andtheNetherlandsAugust2002–April20062Yearstudy720participantswithHeterozygousFamilialHypercholesterolemiaSimvastatin80mg+Placebovs+EzetimibeLDL–C=318+65mg/dl80%previouslyonastatin.BaselineIMT=.70vs.69(S+PvsS+E)2yearchangeinIMT=.006vs.011(S+PvsS+E)(NS)第19頁(yè)/共44頁(yè)ENHANCETRIALKasteleinJJPetal.NEJM2008第20頁(yè)/共44頁(yè)Mean(SE)Intima-MediaThicknessoftheCarotidArteryKasteleinJJPetal.NEJM2008第21頁(yè)/共44頁(yè)B-modeultrasoundtechnique第22頁(yè)/共44頁(yè)TRIALBaselineCommonAggregateCmnAggCompTestCompTestASAP

.86

.93-.010

-.020.015-.015ARBITER1

.61

.025

-.034ARBITER2

.88

.044

.014RADIANCE11.00

1.15-.004

.004

.005

.005RADIANCE21.15

1.30

.008

.013.030

.025METEOR1.02

1.16

.008

-.004.013

-.001ENHANCE

.68

.70

.001

.001.003

.005SANDS

.80

.013

-.004Baselinewallthickness(mm)andprogressionrate(mm/yr)第23頁(yè)/共44頁(yè)TRIALBaselineCommonAggregateCmnAggCompTestCompTestARBITER2.88

.044

.014CAIUS.881.05

.008-.003.009-.004ASAP.86

.93-.010

-.020.015-.015LIPID.80

.048-.014SANDS.80

.013-.004MARS.70

.015-.028ENHANCE.68

.70

.001

.001.003

.005CLAS.65

.013-.013ARBITER1.61

.025-.034Baselinewallthickness(mm)andprogressionrate(mm/yr)第24頁(yè)/共44頁(yè)TRIALBaselineCommonAggregateCmnAggCompTestCompTestKAPS1.66

.031

.017RADIANCE21.15

1.30

.008

.013.030

.025ACAPS06-.009METEOR1.02

1.16

.008-.004.013-.001PLAC-II1.011.32

.046

.030.068

.060RADIANCE11.00

1.15-.004

.004

.005

.005Baselinewallthickness(mm)andprogressionrate(mm/yr)FromDr.JohnR.Crouse第25頁(yè)/共44頁(yè)P(yáng)roblemswithENHANCEBaselinewallthickness:atthelowendofmultipletrialsthatshowedsomedifferencesLong-termhighdosestatintreatmenthistory:notmuchlipidsleft?collagen-richplaque?Shortdurationoftreatment:Only2yearsLimitedsubjects:720DataagainstthewellestablishedcorrelationbetweenLDL-ClevelsandCVDCommentsfromDr.HelenH.Hobbs:TheENHANCEworkis“justaterriblepaperfrombeginningtoend”第26頁(yè)/共44頁(yè)RelativeRiskofOnsetofCancerintheSEASTrialandinSHARPandIMPROVE-ITPetoR,etal.NEJM2008第27頁(yè)/共44頁(yè)EffectsofEzetimibeonSitosterolemia第28頁(yè)/共44頁(yè)CholesterolPlantSterols~400mg~200mg<200mg~400mgDailyIntakeofDietarySterols第29頁(yè)/共44頁(yè)CholesterolHOSitosterolHO<1mg/dL~200mg/dLSterolLevelsinNormalHumans200mg/Day~400mg/DayDietary:Plasma:第30頁(yè)/共44頁(yè)MajorFeaturesofSitosterolemiaInheritanceRecessiveXanthomasPrematureCAD+++Plasmasitosterol15-30mg/dLDiet-responsiveness+++Plasmacholesterol

100-800mg/dL第31頁(yè)/共44頁(yè)EzetimibeReducesBloodSitosterolinSitosterolemicHumansLutjohannD,etal.IntJClinPract2008:62:1499第32頁(yè)/共44頁(yè)Campesterol050100150Day0Day15Day30%ofthevalueonday0KO/ZetiaSitosterol050100150Day0Day15Day30KO/ChowEzetimibeReducesPlasmaPlantSterolLevelsintheAbsenceofABCG5/8第33頁(yè)/共44頁(yè)GeneticAblationofNPC1L1PreventsSitosterolemiainMiceLackingABCG5/G8TangW,etal.JLR2008第34頁(yè)/共44頁(yè)OtherPotentialBeneficialEffectsofEzetimibe1.Onfattyliver?第35頁(yè)/共44頁(yè)WT-T3.4±0.4a2.3±0.4a12.3±0.7a

241.8±29.1bL1KO-V4.1±0.3a3.6±0.2a18.8±0.5a48.0±7.5aL1KO-T3.0±0.3a2.9±0.3a

19.1±0.5a110.8±27.3a

GenotypeTCFCPLTGMean±SEM(mg/gwetliver)

WT-V4.4±0.3a2.9±0.1a19.3±4.0a

36.0±7.9a

HepaticLipidContentofWTandL1-KOMiceTreatedwithT0901317第36頁(yè)/共44頁(yè)OtherPotentialBeneficialEffectsofEzetimibe2.Onobesity?第37頁(yè)/共44頁(yè)NPC1L1deficiencypreventsahighfatdiet-inducedobesityinpureC57BL/6mice第38頁(yè)/共44頁(yè)NPC1L1deficiencypreventsahighfatdiet-inducedobesityinpureC57BL/6micePromotingfatstorageduringevolution?Whydowehaveintestinalcholest