降低胆固醇及额外作用

降低胆固醇及额外作用LDL-C

在动脉粥样硬化形成中的作用?LDL是含载脂蛋白B的颗粒MurphyHCetal.Biochemistry.2000;39(32):9763–9770.甘油三酯和胆固醇酯组成疏水核心ApoB表面覆以单层磷脂和游离胆固醇CVriskincreaseswithincreasedplasmaapoBlipoproteinsBloodApoBlipoprotein

particlesModificationMacrophageMonocytesbindto

adhesionmoleculesTabasIetal.Circulation.2007;116(16):1832–1844.WilliamsKJ,

TabasI.ArteriosclerThrombVascBiol.1995;15:551–561.WilliamsKJ,TabasI.ArteriosclerThrombVascBiol.2005;25:1536–1540.HoshigaMetal.CircRes.1995;77(6):1129–1135.MerrileesMJ,BeaumontB.JVascRes.1993;30(5):293–302.NakataAetal.Circulation.1996;94(11):2778–2786.SteinbergDetal.NEnglJMed.1989;320(14):915–924.Smoothmuscle循环中ApoB水平越低越不利于脂质沉积FoamcellMaladaptive

inflammatoryresponse大部分急性冠脉综合征的发病原因：

动脉板块破裂导致血栓形成超越降LDL-C的疗效聚焦降胆固醇的两个作用机制：合成与吸收其他脂质参数脂蛋白残粒植物甾醇Hs-CRP脂病（Adiposopathy）：流行病学Figure1.Distributionsofbodymassindex(BMI)inSHIELDandNHANESBaysHE,ChapmanRH,GrandyS.

IntJClinPract,May2007,61,5,737–747BMI和代谢性疾病的相关性

NHANES1999-2002 18.5-24.925-26.927-29.930-34.935-39.940010203040506070DiabetesMellitusHypertensionDyslipidemiaOVERALL<18.51.722.3244.217.638.25.725.36816.44467.527.351.362.5928.952.9BodyMassIndex(BMI)%ofPatientsLeanNormalOverweightObeseBaysHEetal.IntJClinPract.2007;61:737-747.BaysHE.“Sickfat,metabolicdisease,andatherosclerosis.AmJMed.2009;122:S26-37.代谢综合征患者的BMI水平

NHANES1999-2002 18.5BodyMassIndex(BMI)18.5-24.925-26.930-34.935-39.94027-29.9BaysHEetal.IntJClinPract.2007;61:737-747.BaysHE.“Sickfat,metabolicdisease,andatherosclerosis.AmJMed.2009;122:S26-37.LeanNormalOverweightObese脂病：流行病学为何超重患者会进展为代谢性疾病?脂病：流行病学并非所有超重患者患有代谢性疾病也非所有代谢性疾病患者体重超重脂病：定义脂病被定义为致病的脂肪组织:基因和环境易感患者因正性能量平衡和久坐的生活方式而促发解剖学上表现为脂肪细胞肥大，内脏脂肪组织聚集（肥胖），脂肪组织增生超过血管的承载能力，异位脂肪（甘油三酯）沉积在外周器官如肝脏、肌肉和胰腺生理学表现为代谢和免疫功能不良，并由此导致代谢性疾病BaysHEetal.FutureCardiology.2005;1(1):39-59BaysHE.ExpertRevCardiovasTher.2005;3(3):395-404BaysHE,et.al.ExpertRevCardiovasTher2008;6:343-68BaysH,BallantyneC.FutureLipidology.2006;1(4):389-4201.脂肪增殖能力削弱BaysHEetal.FutureCardiology.2005;1(1):39-59;BaysH,BallantyneC.FutureLipidology.2006;1(4):389-420BaysH,BallantyneC.FutureLipidology.2006;1(4):389-420;PausovaZ.CurrOpinNephrolHypertens.2006;15(2):173-178;KalantDetal.CanJDiabetes.2003;27(2):154-171“SickFat”导致的后果

BaysHE.“Sickfat,metabolicdisease,andatherosclerosis.AmJMed.2009;122:S26-37.脂病与治疗BaysH,BlondeL,RosensonR.ExpertRevCardiovasTher.4(6),871–895(2006)BaysH,BallantyneC.FutureLipidology.2006;1(4):389-420;BaysHetal.ExpertRevCardiovascTher.2005;3(5):789-820BaysH,BallantyneC.FutureLipidology.2006;1(4):389-420PeripheralcholesterolsynthesisIntestinalcholesterolabsorptionBiliary

cholesterolDietary

cholesterolHealthierarterywithdecreasedplaqueHepaticcholesterol

synthesisHDLHDLLiverSRReceptorLDL/apoB–EReceptorBaysH,DujovneC.ExpertOpinPharmacother2003;4:779-790.Intestinal

epithelialcellBile

acidCEFree

cholesterolexcretionuptakeMTPACATABCG5

ABCG8(esterification)ArteriallumenAtheroscleroticplaque/foamcells胆固醇的来源DecreasedliverLDL

receptoractivityincreasescirculatingLDL-COvaryIntestineMuscleSkinAdrenalIncreasedliverLDL

receptoractivitydecreasescirculatingLDL-CLuminal

cholesterolMicellar

cholesterolCMLDLAtheroscleroticplaqueDiseasedarterywithincreasedplaqueLDL肠道胆固醇吸收BaysH,DujovneC.ExpertOpinPharmacother2003;4:779-790.肠上皮细胞胆汁胆固醇饮食胆固醇肠腔内胆固醇微粒化胆固醇胆汁酸胆固醇酯游离胆固醇排泄摄取ACATABCG5

ABCG8(酯化)MTPCM通过淋巴系统进入肝脏不同人群中未经治疗的胆固醇水平Hunter-gathererhumans平均总胆固醇,mg/dLAdaptedfromO’KeefeJHJretal.JAmCollCardiol.2004;43(11):2142-2146.对高危患者的LDL-C目标值更为积极InATPI,high-riskpatientshadeitherdefiniteCHDor2otherCHDriskfactors.1TheATPIIguidelinesdefinehigh-riskpatientsashavingeitherpriorCHDorotheratheroscleroticdisease.2ATPIIIguidelinesandthe2004updatedefinehigh-riskpatientsasthosewithCHDorCHDriskequivalents.3,4TheinformationaboveisfocusedonlyontheLDL-Cgoalsforhigh-riskpatients.

aFactorsthatplaceapatientatveryhighriskareestablishedCVDplusanyofthefollowing:multiplemajorriskfactors(especiallydiabetes);severeandpoorlycontrolledriskfactors(eg,cigarettesmoking);metabolicsyndrome(TG≥200mg/dL+non-HDL-C≥130mg/dLwithHDL-C<40mg/dL);andrecentacutecoronarysyndromes.4 1.NCEPATPI.ArchInternMed.1988;148(1):36–69.2.NCEPATPII.JAMA.1993;269(23):3015–3023.3.NCEPATPIII.JAMA. 2001;285(19):2486–2497.4.GrundySMetal.Circulation.2004;110(2):227–239.Aspartoftherapeuticlifestylechanges,includingdiet,ATP-recommendedLDL-Ctreatmentgoalsforhigh-riskpatientshavebeenloweredovertime.Optionalgoal:

<70mg/dL41988

ATPI1993

ATPII2001

ATPIII2004

ATPIIIUpdateForveryhigh-riskpatientsaGoal:

<130mg/dL1Goal:

100mg/dL2Goal:

<100mg/dL3Goal:

<100mg/dL4Non–HDL-C作为降脂治疗的二线目标1aForpatientswithtriglycerides≥200mg/dL. HDL-C=high-densitylipoproteincholesterol;LDL-C=low-densitylipoproteincholesterol; Non–HDL-C=Non–high-densitylipoproteincholesterol;Non–HDL-C=totalcholesterol–HDL-C.

1.NCEPExpertPanel.NationalInstitutesofHealth,2002.NIHPublication02-5215.2.GrundySMetal.Circulation. 2004;110(2):227–239.3.Smithetal.Circulation.2006;113(19):2363–2372.RiskcategoryLDL-CGoalNon–HDL-CGoala0-1riskfactor<160mg/dL<190mg/dLMultiple(2+)riskfactorswith10yriskofCHD≤20%<130mg/dL<160mg/dLCoronaryheartdisease(CHD)orCHDequivalent(10-yriskofCHD>20%)<100mg/dL<130mg/dLVeryhighrisk2,3<70mg/dL<100mg/dLNon–HDL-C是ApoB的替代指标Non–HDL-C=Totalcholesterol–HDL-CMeasuresthecholesterolcontentofallApoB–containinglipoproteins,whichcandelivercholesteroltoarterialwall1Maybemorepredictiveofatherogenesisriskthan

LDL-Cmeasurementalone2TightcorrelationbetweenApoBandnon–HDL-Clevels(R2=0.92)instatin-treatedpatients2PredictivevalueforCHDissimilartoLDLparticlenumber3ADA/ACCrecommendsnon–HDL-C<100mg/dLastreatmenttargetforhighest-riskpatients4

Non–HDL-C=Non–high-densitylipoproteincholesterol. 1.ChapmanMJetal.EurHeartJSupplements.2004;6(supplA):A43–A48.

2.BallantyneCMetal.JAmCollCardiol.2008;52(8):626–632.

3.ElHarchaouiKetal.JAmCollCardiol.2007;49(5):547–553.

4.BrunzellJDetal.J.Am.Coll.Cardiol.2008;51(15):1512–1524.NEPTUNEII:即使已接受治疗

许多高危患者仍未达到LDL-C治疗目标a Notarecommendedgoalattimeofstudy. NEPTUNE=NCEPProgramEvaluationProjectUtilizingNovelE-Technology;HTN=hypertension. DavidsonMHetal.AmJCardiol.2005;96(4):556–563.已确诊CVD或极高危患者达到LDL-C<100mg/dL目标值的比例LDL-C<100mg/dLLDL-C<70mg/dLa代谢综合征糖尿病高血压

+HDL-C

<40mg/dLTG≥200mg/dL+HDL-C

<40mg/dL吸烟所有极高危患者(n=849)(n=526)(n=369)(n=254)(n=214)(n=1,082)78%–82%的患者未能达标35%–46%的患者未能达标LDL受体CholesterolAcetateHMG-CoAReductaseLDL他汀类:抑制胆固醇的合成胆固醇醋酸盐HMG-CoAReductase37双重抑制LiverDuodenumJejunumIleumColonCMApoB48CMRemnantApoB48VLDLApoB100LDLApoB100(—)Ezetimibe

InhibitsAbsorptionStatin

Inhibits

Production(—)38AdaptedwithpermissionfromCareyMC,DuaneWC.In:AriasIMetal,eds.TheLiver:BiologyandPathobiology.RavenPressLtd;1994:719–766.

2000年发现了一个与Niemann–PickC1样蛋白相关、且功能尚不明确的基因DNA序列分析预测其具有胆固醇转运作用

位于细胞表面的膜蛋白

与NPC1（已明确其具有胆固醇转运作用）具有同源性表达受胆固醇调控

甾醇敏感性蛋白

此蛋白的表达局限于小肠粘膜细胞的顶端Niemann-PickC1L1(NPC1L1)

SSDOUTIN依折麦布：作用机理依折麦布选择性抑制肠道胆固醇吸收

肠道向肝脏传送胆固醇

肝脏LDL受体表达

含胆固醇的致动脉粥样硬化脂蛋白颗粒依折麦布及其葡萄糖醛酸代谢产物进行肠肝循环将药物送回作用位点限制全身性的暴露BaysH.ExpertOpinInvestigDrugs2002;11:1587-1604.CatapanoAL.EurHeartJSuppl2001;3:E6-E10.PhotocourtesyofHarryR.Davis,PhD同位素标记的依折麦布分布于小肠绒毛刷状缘对照组

(西方膳食)依折麦布5mg/kg/d

(西方膳食)CourtesyofHarryDavis,Jr,PhD.Lipid依折麦布降低ApoE敲除小鼠的颈动脉粥样硬化SteinE.ResultsofphaseI/IIclinicaltrialswithezetimibe,anovelselectivecholesterolabsorptioninhibitor.Eur.HeartJ.3(Suppl.E),E11–E16(2001).BaysHE,NeffD,TomassiniJE,TershakovecAM.

Ezetimibe:

Cholesterolloweringandbeyond.

ExpertRevCardiovascTher.2008;4:447-70.依折麦布单药治疗小肠壁血浆肝脏胆汁肠腔3H-DPM(x10–6)依折麦布：代谢

依折麦布的全身暴露量低vanHeekMetal.BrJPharmacol2000;129:1748-1754.静脉注射3H标记的依折麦布3小时后LDL-C8周时自基线下降%依折麦布：疗效(“AddOn”研究)GagnéC,BaysHE,WeissSR,etal.AmJCardiol2002;90:1084-1091.*p<0.001

†p<0.05

‡p<0.01–25.1*1.0–2.9–14.0‡HDL-CTG–3.72.7†他汀+安慰剂(n=390)他汀+依折麦布10mg(n=379)1步联合治疗3步剂量加倍他汀联合在胃肠道起效的药物

VS他汀剂量加倍他汀起始剂量1st2nd3rd他汀起始剂量15–18%剂量加倍+GI-活性药物LDL-C降幅%5–6%5–6%5–6%BaysH,DujovneC.ExpertOpinPharmacother2003;4:779-790.阿托伐他汀40mg

(n=66)20mg

(n=60)10mg

(n=60)LDL-C自未治疗时基线的改变均值%依折麦布：疗效(“10+10=80”)BallantyneCMetal.Circulation2003;107:2409-2415.BaysHE.ExpertOpinionInvestig.Drugs.2002;11:1587-604P<0.0180mg

(n=62)依折麦布+

阿托伐他汀

10mg

(n=65)LDL-C的变化均值%VYTORIN®(依折麦布/辛伐他汀)提供卓越的降LDL-C疗效vs辛伐他汀VYTORIN–52%a–55%a–60%a–34%–41%–49%–60–50–40–30–20–100辛伐他汀10/20mg(n=140to153)20mg(n=144to147)40mg(n=150to154)10/40mg(n=138to146)80mg(n=150to156)10/80mg(n=146to154)

LDL-C基线均值:VYTORIN组为176mg/dL辛伐他汀组为178mg/dL

n=研究终点时参与疗效评估的患者人数aP<0.001forVYTORINvseachofthecorrespondingdosesofsimvastatin. BaysHEetal.ClinTher.2004;26(11):1758–1773.VYTORIN含有2种活性成分：依折麦布和辛伐他汀。目前尚无证据表明VYTORIN较辛伐他汀是否存在额外的降低心血管发病和死亡的益处。当单纯饮食控制效果不佳时，VYTORIN是饮食控制外的辅助治疗

aP<0.001.

VYTORIN含有2种活性成分：依折麦布和辛伐他汀。目前尚无证据表明VYTORIN较辛伐他汀是否存在额外的降低心血管发病和死亡的益处。 VYVA=VYTORINvsatorvastatin. AdaptedwithpermissionfromBallantyneCMetal.AmHeartJ.2005;149(3):464–473.VYVAStudy：VYTORIN®(依折麦布/辛伐他汀)提供卓越的降LDL-C疗效vs阿托伐他汀起始剂量,mg平均基线LDL-C=175mg/dL阿托伐他汀10mg平均基线LDL-C=179mg/dLVYTORIN10/20mg

VYTORINAtorvastatinLDL-C自基线的变化%10/20(n=233)10/40mg(n=236)10/80mg(n=224)40mg(n=232)80mg(n=230)10(n=235)20(n=230)当单纯饮食控制效果不佳时，VYTORIN是饮食控制外的辅助治疗–60–50–40–30–20–100–51%a–36%–44%–57%a–48%–59%a–53%VYTORIN®(ezetimibe/simvastatin)vs阿托伐他汀：采用选定剂量治疗达到LDL-C<100mg/dL和<70mg/dL的患者比例10/20mg10mg20mgVYTORIN10/20mgvsatorvastatin10/20mg40mg20mgVYTORIN10/40mgvsatorvastatin10/40mgP<0.001P<0.001VYTORIN含有2种活性成分：依折麦布和辛伐他汀。目前尚无证据表明VYTORIN较辛伐他汀是否存在额外的降低心血管发病和死亡的益处。当单纯饮食控制效果不佳时，VYTORIN是饮食控制外的辅助治疗PearsonTetal.AmJCardiol.2007;99(12):1706–1713.VYTORIN®(依折麦布/辛伐他汀)提供更强效的降LDL-C疗效vs瑞舒伐他汀

aP<0.001 CatapanoALetal.CurrMedResOpin.2006;22(10):2041–2053.Dose,mgVYTORIN®瑞舒伐他汀LDL-C自基线的平均降幅%瑞舒伐他汀10mg平均基线

LDL-C=172mg/dLVYTORIN10/20mg

平均基线

LDL-C=172mg/dL10/20(n=476)10/40(n=477)10/80(n=474)20(n=478)40(n=475)10(n=475)VYTORINisanadjuncttodietwhendietaloneisnotenoughVYTORIN含有2种活性成分：依折麦布和辛伐他汀。目前尚无证据表明VYTORIN较辛伐他汀是否存在额外的降低心血管发病和死亡的益处。–60–50–40–30–20–100–70–52%a–46%–55%a–52%–61%a–57%Rosuvastatin

10mgVYTORIN

10/20mgPatientsachieving

LDL-C<100mg/dLatWeek6,%VYTORIN®(ezetimibe/simvastatin)vs瑞舒伐他汀：采用选定剂量治疗达到LDL-C<100mg/dL和<70mg/dL的患者比例MeanBaseline

LDL-C=172mg/dLMeanBaseline

LDL-C=172mg/dLRosuvastatin

20mgVYTORIN

10/40mgPatientsachieving

LDL-C<70mg/dLatWeek6,%MeanBaseline

LDL-C=173mg/dLMeanBaseline

LDL-C=173mg/dL84%a72%41%a30%aP<0.001 CatapanoALetal.CurrMedResOpin.2006;22(10):2041–2053.VYTORINisanadjuncttodietwhendietaloneisnotenoughVYTORINcontains2activeingredients:ezetimibeandsimvastatin.

NoincrementalbenefitofVYTORINon

cardiovascularmorbidityandmortalityoverandabovethatdemonstratedforsimvastatinhasbeenestablished.在2型糖尿病亚组中

依折麦布降LDL-C的疗效-25-4-2-28-30-25-20-15-10-50全部人群自基线变化%他汀和依折麦布(n=90)他汀和安慰剂(n=98)

*p<0.001vsstatin+placebo*Simonsetal.EASD2002糖尿病亚组人群*依折麦布+他汀联合治疗代谢综合症患者TGHDL-CLDL-C自基线变化%他汀和依折麦布,N=160/379他汀和安慰剂,N=182/390Tonkonetal.ADA2003寻求超越LDL-C的疗效聚焦降胆固醇的两个作用机制：合成与吸收其他脂质参数脂蛋白残粒植物甾醇Hs-CRPVYTORIN®(依折麦布/辛伐他汀)vs阿托伐他汀

24周后Non–HDL-C和ApoB水平自基线的变化率(n=223)(n=432)自基线变化的百分比BallantyneCMetal.AmJCardiol.2004;93(12):1487–1494.Non-HDLCholesterolApolipoproteinB当单纯饮食控制效果不佳时，VYTORIN是饮食控制外的辅助治疗VYTORIN含有2种活性成分：依折麦布和辛伐他汀。目前尚无证据表明VYTORIN较辛伐他汀是否存在额外的降低心血管发病和死亡的益处。阿托伐他汀80mg

基线均值

non–HDL-C=220mg/dL基线均值

ApoB=170mg/dLVYTORIN

10/80mg

基线均值

non–HDL-C=218mg/dL基线均值

ApoB=170mg/dLVYTORIN10/80mg阿托伐他汀80mg–60%–50%–40%–30%–20%–10%0%–50%–55%–45%–49%Percentchange

frombaselineVYTORIN®(ezetimibe/simvastatin)vsRosuvastatin:PercentChangefromBaselineNon–HDL-Cholesterol

Over6WeeksRosuvastatin(n=1,428)10mg20mg40mg10/20mg10/40mg10/80mgCatapanoALetal.CurrMedResOpin.2006;22(10):2041–2053.VYTORIN(n=1,427)P<0.001forbetweentreatmentcomparisonsVYTORINcontains2activeingredients:ezetimibeandsimvastatin.

NoincrementalbenefitofVYTORINon

cardiovascularmorbidityandmortalityoverandabovethatdemonstratedforsimvastatinhasbeenestablished.–60–50–40–30–20–100–42%–48%–52%–47%–50%–56%VYTORIN®(ezetimibe/simvastatin)vsRosuvastatin:PercentChangeFromBaselineinApoBOver

6WeeksCatapanoALetal.CurrMedResOpin.2006;22(10):2041–2053.Percentchange

frombaselineRosuvastatin(n=1,481)10mg20mg40mg10/20mg10/40mg10/80mgVYTORIN(n=1,478)P<0.001P<0.05P<0.001VYTORINcontains2activeingredients:ezetimibeandsimvastatin.

NoincrementalbenefitofVYTORINon

cardiovascularmorbidityandmortalityoverandabovethatdemonstratedforsimvastatinhasbeenestablished.–60–50–40–30–20–100–37%–43%–47%–42%–44%–50%寻求超越LDL-C的疗效聚焦降胆固醇的两个作用机制：合成与吸收其他脂质参数脂蛋白残粒植物甾醇Hs-CRPVLDL残粒BaysH,McKenneyJ,DavidsonM.Exp.Rev.Cardio.Therapy2005

乳糜微粒残粒BaysH,McKenneyJ,DavidsonM.Exp.Rev.Cardio.Therapy2005

依折麦布降低恒河猴餐后乳糜微粒中的胆固醇含量对照组依折麦布组vanHeeketal.EurJPharmacol.2001;415:79.胆固醇酯游离胆固醇甘油三酯(µg/mL)0255075100125150P<0.05012345NS0152025303540105NS(µg/mL)(µg/mL)对照组依折麦布组对照组依折麦布组依折麦布+辛伐他汀降低脂蛋白残粒的疗效vs安慰剂+辛伐他汀BaysHE,JACC2004;43(5,Suppl.A):481A寻求超越LDL-C的疗效聚焦降胆固醇的两个作用机制：合成与吸收其他脂质参数脂蛋白残粒植物甾醇Hs-CRP植物甾醇植物甾烷醇Phytosterolsandphytostanols.Thesechemicalstructuresdemonstratethesimilarityofcholesteroltoplantsterols(sitosterol,stigmasterolandcampesterol)consumedlargelythroughvegetableoils,cereals,fruits,vegetables,seedsandnuts,andthelessconsumedsaturated(withoutthecarbon-carbondoublebondsfoundincholesterol)stanolstypicallyconsumedprimarilyfromcorn,wheat,ryeandrice.Stanolestersmaybederivedfromwoodpulpofpinetrees.Anincreaseinplantphytosterolsandphytostanolsmaybeatherogenic.BaysHE,SteinEA.ExpertOpinPharmacother2003Framingham后代研究：

危险因素与CVD的相关性OddsRatios–UnivariantAnalysisMatthen,NetalPoster-AHAScientificSessions,2005典型的危险因素合成的标记物吸收的标记物合成与吸收的比率谷甾醇

–依折麦布10mg治疗后，

血浆浓度自基线的平均变化率Salen,GCirculation.2004;109:966-971菜油甾醇

–依折麦布10mg治疗后，

血浆浓度自基线的平均变化率Salen,GCirculation.2004;109:966-971寻求超越LDL-C的疗效聚焦降胆固醇的两个作用机制：合成与吸收其他脂质参数脂蛋白残粒植物甾醇Hs-CRPCRPCRP的刺激启动机制脂肪组织肝脏心肌层动脉粥样硬化单核/巨噬细胞Pro-inflammatoryCytokines(IL-1,IL-6,etc)C-ReactiveProtein平滑肌细胞内皮细胞单核/巨噬细胞ReactiveOxygenSpeciesCytokines(IL-1,TNF,IL-6)ChemotaxisTissueFactorUptakeofOx-LDLA