降低胆固醇及额外作用.ppt

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1、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,Murphy HC et al.Biochemistry.2000;39(32):97639770.,甘油三酯和胆固醇酯组成疏水核心,Apo B,表面覆以单层磷脂和游离胆固醇,CV risk increases with increased plasma apo B lipoproteins,Blood,Apo B lipoproteinparticles,Modification,Macrophage,Monocytes bind toadhesion molecules,Tabas I et al.C

2、irculation.2007;116(16):18321844.Williams KJ,Tabas I.Arterioscler Thromb Vasc Biol.1995;15:551561.Williams KJ,Tabas I.Arterioscler Thromb Vasc Biol.2005;25:15361540.Hoshiga M et al.Circ Res.1995;77(6):11291135.Merrilees MJ,Beaumont B.J Vasc Res.1993;30(5):293302.Nakata A et al.Circulation.1996;94(11

3、):27782786.Steinberg D et al.N Engl J Med.1989;320(14):915924.,Smooth muscle,循环中Apo B 水平越低越不利于脂质沉积,Foam cell,Maladaptiveinflammatory response,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,Figure 1.Distributions of body mass index(BMI)in SHIEL

4、D and NHANES,Bays HE,Chapman RH,Grandy S.Int J Clin Pract,May 2007,61,5,737747,BMI 和 代谢性疾病的相关性NHANES 1999-2002,25-26.9,27-29.9,30-34.9,35-39.9,40,0,10,20,30,40,50,60,70,Diabetes Mellitus,Hypertension,Dyslipidemia,OVERALL,18.5,1.7,22.3,24,4.2,17.6,38.2,5.7,25.3,53.1,10.1,30.8,62.2,12.2,39.3,68,16.4,4

5、4,67.5,27.3,51.3,62.5,9,28.9,52.9,Body Mass Index(BMI),%of Patients,Lean,Normal,Overweight,Obese,Bays HE et al.Int J Clin Pract.2007;61:737-747.Bays HE.“Sick fat,metabolic disease,and atherosclerosis.Am J Med.2009;122:S26-37.,代谢综合征患者的BMI 水平NHANES 1999-2002,18.5,Body Mass Index(BMI),25-26.9,30-34.9,3

6、5-39.9,40,27-29.9,Bays HE et al.Int J Clin Pract.2007;61:737-747.Bays HE.“Sick fat,metabolic disease,and atherosclerosis.Am J Med.2009;122:S26-37.,Lean,Normal,Overweight,Obese,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

7、，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,Bays HE et al.Future Cardiology.2005;1(1):39-59,Bays HE.Expert Rev Cardiovas Ther.2005;3(3):395-404,Bays HE,et.al.Expert Rev Cardiovas Ther 2008;6:343-68,Bays H,Ballantyne C.Future Lipidology.2006;1(4):389-420,1.脂肪增殖能

8、力削弱,Bays HE et al.Future Cardiology.2005;1(1):39-59;Bays H,Ballantyne C.Future Lipidology.2006;1(4):389-420,Bays H,Ballantyne C.Future Lipidology.2006;1(4):389-420;Pausova Z.Curr Opin Nephrol Hypertens.2006;15(2):173-178;Kalant D et al.Can J Diabetes.2003;27(2):154-171,“Sick Fat”导致的后果,Bays HE.“Sick

9、fat,metabolic disease,and atherosclerosis.Am J Med.2009;122:S26-37.,脂病与治疗,Bays H,Blonde L,Rosenson R.Expert Rev Cardiovas Ther.4(6),871895(2006),http:/,Bays H,Ballantyne C.Future Lipidology.2006;1(4):389-420;Bays H et al.Expert Rev Cardiovasc Ther.2005;3(5):789-820,Bays H,Ballantyne C.Future Lipidol

10、ogy.2006;1(4):389-420,Peripheral cholesterol synthesis,Intestinal cholesterol absorption,Biliarycholesterol,Dietarycholesterol,Healthier artery with decreased plaque,Hepatic cholesterol synthesis,HDL,HDL,Liver,SRReceptor,LDL/apo BEReceptor,Bays H,Dujovne C.Expert Opin Pharmacother 2003;4:779-790.,In

11、testinal epithelial cell,Bileacid,CE,Freecholesterol,excretion,uptake,MTP,ACAT,ABC G5ABC G8,(esterification),胆固醇的来源,Decreased liver LDLreceptor activity increases circulating LDL-C,Increased liver LDLreceptor activity decreases circulating LDL-C,Luminalcholesterol,Micellarcholesterol,CM,LDL,Atherosc

12、lerotic plaque,Diseased artery with increased plaque,LDL,肠道胆固醇吸收,Bays H,Dujovne C.Expert Opin Pharmacother 2003;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,ABCG5ABCG8,(酯化),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-gatherer humans,平均总胆固醇,mg/dL,Adapted from OKeefe JH Jr et al.J Am Coll Car

13、diol.2004;43(11):2142-2146.,对高危患者的LDL-C 目标值更为积极,In ATP I,high-risk patients had either definite CHD or 2 other CHD risk factors.1The ATP II guidelines define high-risk patients as having either prior CHD or other atherosclerotic disease.2ATP III guidelines and the 2004 update define high-risk patien

14、ts as those with CHD or CHD risk equivalents.3,4The information above is focused only on the LDL-C goals for high-risk patients.,aFactors that place a patient at very high risk are established CVD plus any of the following:multiple major risk factors(especially diabetes);severe and poorly controlled

15、 risk factors(eg,cigarette smoking);metabolic syndrome(TG 200 mg/dL+non-HDL-C 130 mg/dL with HDL-C 40 mg/dL);and recent acute coronary syndromes.41.NCEP ATP I.Arch Intern Med.1988;148(1):3669.2.NCEP ATP II.JAMA.1993;269(23):30153023.3.NCEP ATP III.JAMA.2001;285(19):24862497.4.Grundy SM et al.Circula

16、tion.2004;110(2):227239.,As part of therapeutic lifestyle changes,including diet,ATP-recommended LDL-C treatment goals for high-risk patients have been lowered over time.,Optional goal:70 mg/dL4,1988ATP I,1993ATP II,2001ATP III,2004ATP III Update,For very high-risk patientsa,Goal:130 mg/dL1,Goal:100

17、 mg/dL2,Goal:100 mg/dL3,Goal:100 mg/dL4,NonHDL-C 作为降脂治疗的二线目标1,aFor patients with triglycerides 200 mg/dL.HDL-C=high-density lipoprotein cholesterol;LDL-C=low-density lipoprotein cholesterol;NonHDL-C=Nonhigh-density lipoprotein cholesterol;NonHDL-C=total cholesterol HDL-C.1.NCEP Expert Panel.National

18、 Institutes of Health,2002.NIH Publication 02-5215.2.Grundy SM et al.Circulation.2004;110(2):227239.3.Smith et al.Circulation.2006;113(19):23632372.,NonHDL-C 是Apo B的替代指标,NonHDL-C=Total cholesterol HDL-C Measures the cholesterol content of all Apo Bcontaining lipoproteins,which can deliver cholestero

19、l to arterial wall1May be more predictive of atherogenesis risk than LDL-C measurement alone2Tight correlation between Apo B and nonHDL-C levels(R2=0.92)in statin-treated patients2Predictive value for CHD is similar to LDL particle number3ADA/ACC recommends nonHDL-C 100 mg/dL as treatment target for

20、 highest-risk patients4,NonHDL-C=Nonhigh-density lipoprotein cholesterol.1.Chapman MJ et al.Eur Heart J Supplements.2004;6(suppl A):A43A48.2.Ballantyne CM et al.J Am Coll Cardiol.2008;52(8):626632.3.El Harchaoui K et al.J Am Coll Cardiol.2007;49(5):547553.4.Brunzell JD et al.J.Am.Coll.Cardiol.2008;5

21、1(15):15121524.,NEPTUNE II:即使已接受治疗许多高危患者仍未达到 LDL-C 治疗目标,aNot a recommended goal at time of study.NEPTUNE=NCEP Program Evaluation Project Utilizing Novel E-Technology;HTN=hypertension.Davidson MH et al.Am J Cardiol.2005;96(4):556563.,已确诊 CVD或 极高危患者达到 LDL-C 100 mg/dL目标值的比例,LDL-C 100 mg/dL,LDL-C 70 mg/

22、dLa,代谢综合征,糖尿病,高血压+HDL-C40 mg/dL,TG 200 mg/dL+HDL-C40 mg/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,Cholesterol,Acetate,HMG-CoA Reductase,LDL,他汀类:抑制胆固醇的合成,37,双重抑制,Liver,Duodenum,Jejunum,Ileum,Colon,CMApo B48,CM RemnantApo B48,VLDLApo B100,LDLApo

23、B100,(),EzetimibeInhibits Absorption,StatinInhibitsProduction,(),38,Adapted with permission from Carey MC,Duane WC.In:Arias IM et al,eds.The Liver:Biology and Pathobiology.Raven Press Ltd;1994:719766.,2000年发现了一个与Niemann Pick C1 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 NPC 1（已明确其具有胆固醇转运作用）具

24、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-Pick C1L1(NPC1L1),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,Bays H.Expert Opin Investig Drugs 2002;11:1587-1604.Catapano AL.Eur Heart J Suppl 2001;3:E6-E10.,Photo courtesy of Harry R.Davis,

25、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 5 mg/kg/d(西方膳食),Courtesy of Harry Davis,Jr,PhD.,Lipid,依折麦布降低ApoE敲除小鼠的颈动脉粥样硬化,Stein E.Results of phase I/II clinical trials with ezetimibe,a novel selective cholesterol absorption inhibitor.Eur.Heart J.3(Suppl.E),E11E16(2001).Bays HE,Neff D,Tomassini JE,Tershak

26、ovec AM.Ezetimibe:Cholesterol lowering and beyond.Expert Rev Cardiovasc Ther.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(x 106),依折麦布：代谢依折麦布的全身暴露量低,van Heek M et al.Br J Pharmacol 2000;129:1748-1754.,静脉注射3H 标记的依折麦布3小时后,LDL-C,8周时自基线下降%,依折麦布：疗效(“Add On”研究),Gagn C,Bays HE,Weiss SR,et al.Am J Cardiol

27、2002;90:1084-1091.,*p0.001p0.05p0.01,25.1*,1.0,2.9,14.0,HDL-C,TG,3.7,2.7,他汀+安慰剂(n=390)他汀+依折麦布 10 mg(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,1st,2nd,3rd,他汀起始剂量,1518%,剂量加倍,+GI-活性药物,LDL-C降幅%,56%,56%,56%,Bays H,Dujovne C.Expert Opin Pharmacother 2003;4:779-790.,阿托伐他汀,40 mg(n=66),20 mg(n=60),

28、10 mg(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”),Ballantyne CM et al.Circulation 2003;107:2409-2415.Bays HE.Expert Opinion Investig.Drugs.2002;11:1587-604,P0.01,80 mg(n=62),依折麦布+阿托伐他汀10 mg(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%,60,50,40,30,20,1

29、0,0,辛伐他汀,10/20 mg(n=140 to 153),20 mg(n=144 to 147),40 mg(n=150 to 154),10/40 mg(n=138 to 146),80 mg(n=150 to 156),10/80 mg(n=146 to 154),LDL-C基线均值:VYTORIN组为 176 mg/dL辛伐他汀组为178 mg/dL,n=研究终点时参与疗效评估的患者人数aP0.001 for VYTORIN vs each of the corresponding doses of simvastatin.Bays HE et al.Clin Ther.2004;

30、26(11):17581773.,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,aP0.001.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=VYTORIN vs atorvastatin.Adapted with permission from Ballantyne CM et al.Am Heart J.2005;149(3):4644

31、73.,VYVA Study：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=175 mg/dL,阿托伐他汀 10 mg,平均基线 LDL-C=179 mg/dL,VYTORIN 10/20 mg,VYTORIN,Atorvastatin,LDL-C自基线的变化%,10/20(n=233),10/40 mg(n=236),10/80 mg(n=224),40 mg(n=232),80 mg(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,60,50,4

32、0,30,20,10,0,51%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 100 mg/dL 和 70 mg/dL 的患者比例,10/20 mg,10 mg,20 mg,VYTORIN 10/20 mg vs atorvastatin,10/20 mg,40 mg,20 mg,VYTORIN 10/40 mg vs atorvastatin,10/40 mg,P0.001,P0.001,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

33、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,Pearson T et al.Am J Cardiol.2007;99(12):17061713.,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,aP0.001Catapano AL et al.Curr Med Res Opin.2006;22(10):20412053.,Dose,mg,VYTORIN,瑞舒伐他汀,LDL-C自基线的平均降幅%,瑞舒伐他汀 10 mg平均基线 LDL-C=172 mg/dL,VYTORIN 10/20

34、 mg 平均基线 LDL-C=172 mg/dL,10/20(n=476),10/40(n=477),10/80(n=474),20(n=478),40(n=475),10(n=475),VYTORIN is an adjunct to diet when diet alone is not enough,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。,60,50,40,30,20,10,0,70,52%a,46%,55%a,52%,61%a,57%,Rosuvastatin10 mg,VYTORIN 1

35、0/20 mg,Patients achieving LDL-C 100 mg/dL at Week 6,%,VYTORIN(ezetimibe/simvastatin)vs 瑞舒伐他汀：采用选定剂量治疗达到 LDL-C 100 mg/dL 和 70 mg/dL 的患者比例,Mean BaselineLDL-C=172 mg/dL,Mean BaselineLDL-C=172 mg/dL,Rosuvastatin20 mg,VYTORIN 10/40 mg,Patients achieving LDL-C 70 mg/dL at Week 6,%,Mean BaselineLDL-C=173

36、mg/dL,Mean BaselineLDL-C=173 mg/dL,84%a,72%,41%a,30%,aP0.001Catapano AL et al.Curr Med Res Opin.2006;22(10):20412053.,VYTORIN is an adjunct to diet when diet alone is not enough,VYTORIN contains 2 active ingredients:ezetimibe and simvastatin.No incremental benefit of VYTORIN on cardiovascular morbid

37、ity and mortality over and above that demonstrated for simvastatin has been established.,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,-5,0,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),*p0.001 vs statin+placebo,*,Simons et al.EASD 2002,糖尿病亚组人群,*,依折麦布+他汀联合治疗代谢综合症患者,TG,HDL-C,LDL-C,自基线变化%,他汀 和

38、 依折麦布,N=160/379,他汀 和 安慰剂,N=182/390,Tonkon et al.ADA 2003,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,VYTORIN(依折麦布/辛伐他汀)vs 阿托伐他汀 24周后 NonHDL-C 和 Apo B 水平自基线的变化率,(n=223),(n=432),自基线变化的百分比,Ballantyne CM et al.Am J Cardiol.2004;93(12):14871494.,Non-HDL Cholesterol,Apolipoprotein B,当单纯饮食控制效果不佳时

39、，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 80 mg基线均值 nonHDL-C=220 mg/dL基线均值 Apo B=170 mg/dL,VYTORIN 10/80 mg 基线均值 nonHDL-C=218 mg/dL基线均值 Apo B=170 mg/dL,VYTORIN 10/80 mg,阿托伐他汀 80 mg,60%,50%,40%,30%,20%,10%,0%,50%,55%,45%,49%,Percent change from ba

40、seline,VYTORIN(ezetimibe/simvastatin)vs Rosuvastatin:Percent Change from Baseline NonHDL-Cholesterol Over 6 Weeks,Rosuvastatin(n=1,428),10 mg,20 mg,40 mg,10/20 mg,10/40 mg,10/80 mg,Catapano AL et al.Curr Med Res Opin.2006;22(10):20412053.,VYTORIN(n=1,427),P0.001 for between treatment comparisons,VYT

41、ORIN contains 2 active ingredients:ezetimibe and simvastatin.No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.,60,50,40,30,20,10,0,42%,48%,52%,47%,50%,56%,VYTORIN(ezetimibe/simvastatin)vs Rosuvastatin:Pe

42、rcent Change From Baseline in Apo B Over 6 Weeks,Catapano AL et al.Curr Med Res Opin.2006;22(10):20412053.,Percent change from baseline,Rosuvastatin(n=1,481),10 mg,20 mg,40 mg,10/20 mg,10/40 mg,10/80 mg,VYTORIN(n=1,478),P0.001,P0.05,P0.001,VYTORIN contains 2 active ingredients:ezetimibe and simvasta

43、tin.No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.,60,50,40,30,20,10,0,37%,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-CRP,VLDL 残粒,Bays H,McKenney J,Davidson M.Exp.Rev.Cardio

44、.Therapy 2005,乳糜微粒残粒,Bays H,McKenney J,Davidson M.Exp.Rev.Cardio.Therapy 2005,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,van Heek et al.Eur J Pharmacol.2001;415:79.,胆固醇酯,游离胆固醇,甘油三酯,(g/mL),0,25,50,75,100,125,150,P0.05,0,1,2,3,4,5,NS,NS,(g/mL),(g/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,Bays HE,J

45、ACC 2004;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,Phytosterols and phytostanols.These chemical structures demonstrate the similarity of cholesterol to plant sterols(sitosterol,stigmasterol and campesterol)consumed largely through vegetable oils,cereals,frui

46、ts,vegetables,seeds and nuts,and the less consumed saturated(without the carbon-carbon double bonds found in cholesterol)stanols typically consumed primarily from corn,wheat,rye and rice.Stanol esters may be derived from wood pulp of pine trees.An increase in plant phytosterols and phytostanols may

47、be atherogenic.,Bays HE,Stein EA.Expert Opin Pharmacother 2003,Framingham 后代研究：危险因素与CVD的相关性,Odds Ratios Univariant Analysis,Matthen,N et al Poster-AHA Scientific Sessions,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,G Circulation.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

48、均变化率,Salen,G Circulation.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-CRP,CRP,CRP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-inflammatory Cytokines(IL-1,IL-6,etc),C-Reactive Protein,平滑肌细胞,内皮细胞,单核/巨噬细胞,Reactive Oxygen Species Cytokines(IL-1,TNF,IL-6)Chemotaxis Tissue Factor Uptake of

49、Ox-LDL Adhesion to EC MMP-1,eNOS Prostacyclin PAI-1 ET-1 IL-8 MCP-1 ICAM,VCAM,E-selectin IL-6,AT1 receptor(ROS,VSMC Proliferation)NFKb MAP kinase iNOS,Jialal et al,Hypertension.2004,Relative Risk,LDL Cholesterol mg/dl,Hs-CRP,mg/L,Framingham 10-Year Risk(%),1.0,3.0,Relative Risk for CVE in Healthy Am

50、erican Women,1.0,3.0,Hs-CRP,mg/L,2005 PPS,Ridker PM et al.N Engl J Med.2005;352:20-28.,LDL-C 70 mg/dL,CRP 2 mg/L,LDL-C 2 mg/L,LDL-C 70 mg/dL,CRP 2 mg/L,LDL-C 70 mg/dL,CRP 2 mg/L,PROVE-IT:Outcomes Related to CRP,LDL-C,依折麦布联合辛伐他汀对hs-CRP的疗效,辛伐他汀,依折麦布+辛伐他汀,hs-CRP自基线的平均变化率%,Sager PT,et al.Atherosclerosis