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1、脂代谢与动脉粥样硬化,抗动脉粥样硬化新途径双重抑制胆固醇的吸收与合成,华中科技大学协和医院心内科 廖玉华,Elevated Cholesterol Is a Risk Factor for CVD,Elevated serum cholesterol is associated with increased risk of CHD Reinfarction CVD mortality All-cause CHD Stroke,CVD = cardiovascular disease *Crude death rate (per 10,000 person-years) Adapted from
2、 Kannel WB. Am J Cardiol. 1995;76:69C77C; Anderson KM, et al. JAMA. 1987;257:21762180; Kannel WB, et al. Ann Intern Med. 1971;74:112; Neaton JD, et al. Arch Intern Med. 1992;152:14901500.,0,10,20,30,40,50,160,160199,200239,240,CVD Mortality Rate*,Multiple Risk Factor Intervention Trial (N=350,977),S
3、erum Cholesterol, mg/dL,Relationship Between LDL-C and CHD Risk in Clinical Trials,HPS = Heart Protection Study; CARE = Cholesterol And Recurrent Events Trial; LIPID = Long-term Intervention with Pravastatin in Ischaemic Disease; 4S = Scandinavian Simvastatin Survival Study; TNT = Treating to New Ta
4、rgets *Event rates for HPS, CARE, and LIPID are for death from CHD and nonfatal myocardial infarction (MI). Event rates for 4S and the TNT study also include resuscitation after cardiac arrest. Adapted from LaRosa JC, et al. N Engl J Med. 2005;352:14251435.,LDL-C, mg/dL,Event*, %,0,30,0,110,170,210,
5、25,20,15,10,5,130,70,150,190,4S,4S,CARE,HPS,TNT (atorvastatin 80 mg),90,LIPID,Statin Placebo,TNT (atorvastatin 10 mg),HPS,CARE,LIPID,人类胆固醇净平衡,INHIBITION OF CHOLESTEROL SYNTHESIS RESULTS IN A HIGHER ABSORPTION RATE OF CHOLESTEROL FROM THE INTESTINE*,Assmann G, et al. J Am Coll Cardiol 2004;43(5, Supp
6、l. 2):A445-A446; Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.,Food,Cholesterol excreted in the faeces,HEPATIC BIOSYNTHESIS,INTESTINAL ABSORPTION,30-50% absorption,* Measured as the ratio of serum levels of cholesterol absorption marker (sitosterol) and total cholesterol.,STATINS,胆固醇合成标志
7、物下降与胆固醇吸收标志物升高相关 阿托伐他汀降低了胆固醇的合成，但增加了胆固醇的吸收,Lamon-Fava S et al. J Lipid Res. 2007;48:17461753.,在一项为期8周交叉研究中， 9名高胆固醇血症患者接受阿伐他汀治疗,菜油甾醇 (胆固醇吸收标志物) (n=9),7-烯胆甾烷醇 (胆固醇合成标志物) (n=9),阿伐他汀 vs 安慰剂的变化 %,*P0.005 vs 安慰剂,100,80,60,40,20,0,20,40,60,80,100,阿伐他汀 20 mg/日,阿伐他汀 80 mg/日,THE INHIBITION OF CHOLESTEROL ABSO
8、RPTION RESULTS IN INCREASED CHOLESTEROL BIOSYNTHESIS,CAI = cholesterol absorption inhibitor Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.,Food,Cholesterol excreted in the faeces,HEPATIC BIOSYNTHESIS,INTESTINAL ABSORPTION
9、,30-50% absorption,Inhibition of cholesterol absorption,LDL-C 20%,synthesis,absorption,(ezetimibe),肠道内胆固醇吸收,1000 mg,NPC1L1抑制剂：依折麦布,ACAT=acyl-coenzyme A:cholesterol acyltransferase; NPC1L1=Niemann-Pick C1 Like 1 Adapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Rave
10、n, 1994; Ginsberg HN, Goldberg IJ. In Harrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:21382149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:10821150; Davis JP e
11、t al Genomics 2000;65:137145.,树脂类,植物固醇,ACAT抑制剂,饮食胆固醇,胆汁胆固醇,肠腔中的胆固醇,胆汁酸,胆固醇微团,胆固醇转运蛋白:NPC1L1,胆固醇,酯化胆固醇,肠上皮细胞,乳糜微粒,300 mg,ACAT,Uptake of a fluorescent cholesterol analog in hamster small intestine,Sparrow et al. J Lipid Res. 1999; 10:1747,125 I-Gluc-Ezetimibe Delivered I.V. Localizes to the Intestinal
12、 Brush Border in Bile-Duct Cannulated Rats,Ezetimibe appears to localize to the site of cholesterol absorption,PNAS 102, 8132, 2005,Science, 303, 1149, 2004,肠道胆固醇吸收被依折麦布抑制了54% (p 0.001),0,10,20,30,40,50,60,70,80,安慰剂,依折麦布,Cholesterol Absorption (%),22.7%,Sudhop et al. Circulation 2002; 106;1943,依折麦布：
13、 降低致粥样硬化脂蛋白中的胆固醇含量,依折麦布： 降低致粥样硬化脂蛋白中的胆固醇含量,依折麦布： 降低致粥样硬化脂蛋白中的胆固醇含量,依折麦布他汀提供对胆固醇合成与吸收的双重抑制,胆汁酸,合成,致动脉粥样硬化脂蛋白,小肠,粪便排泄,胆汁,吸收,肝脏,食物,胆固醇,LDL-C,LDL-C,LDL-C,20%,30-45%,STATIN,+,As high as 60%,10%,20%,30%,40%,50%,MEAN LDL-C LOWERING2,3,synthesis,absorption,synthesis,absorption,synthesis,absorption,双重抑制可降低LD
14、L-C 高达60%,1. Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; 2. Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.; 3. Davidson M et al. J Am Coll Cardiol 2002; 40:2125-34.,CHANGE OF SYNTHESIS AND ABSORPTION MARKERS1,Inhibition of absorption,Dual inhibition Statin + EZETIM
15、IBE,Inhibition of synthesis,EZETIMIBE,依折麦布（益适纯 ）与他汀类 联合给药的原理,胆固醇的动态平衡取决于胆固醇吸收和生物合成的平衡 他汀通过抑制HMG CoA还原酶影响肝脏胆固醇合成 减少肝脏胆固醇储存 导致LDL受体上调和从血循环中清除更多胆固醇 胆汁的肠肝循环将胆固醇转运至肠道 益适纯抑制胆固醇的肠内吸收 减少向肝脏输送的胆固醇总量 导致肝脏LDL受体上调, 促进血液中的胆固醇清除 通过益适纯与他汀类的联合应用，双重抑制胆固醇的吸收与合成，比两种药物单独使用（单一途径）对降低LDL-C的疗效更好,摘自Miettinen TA Int J Clin P
16、ract 2001;55(10):710716; Shepherd J Eur Soc Cardiol 2001;3(suppl E):E2E5.,益适纯与他汀类联合用药: 研究结果的一致性,摘自data from Registration File, MSP; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134; Melani L et al Eur Heart J 2003;24:717-728.,益适纯加他汀类导致 LDL-C 比单用他汀类进一步降低18到24%,正在进行的他汀类 治疗,研究结束时的平均 LDL-C (mmol/L)
17、,2.7,3.4,3.4,辛伐他汀 开始,阿托伐他汀 开始,洛伐他汀 开始,普伐他汀 开始,2.0,2.6,2.2,2.9,2.8,2.7,3.4,23%,24%,18%,21%,21%,*p0.01 益适纯 +汇总的他汀类剂量与单用汇总的他汀类剂量比较; *p=0.03益适纯 +汇总的他汀类剂量与单用汇总的他汀类剂量比较 摘自Ballantyne CM et al Circulation 2003;107:2409-2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134; Melani L et al Eur Heart J 2
18、003;24:717-728; Kerzner B et al Am J Cardiol 2003;91:418-424.,对 HDL-C的疗效:益适纯与他汀类 联合给药汇总结果增加1%-5%,HDL-C从基线到12周的平均 % 变化,*中位变化; *p0.01 益适纯 +汇总的他汀类剂量与单用汇总的他汀类剂量比较 摘自Ballantyne CM et al Circulation 2003;107:2409-2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134; Melani L et al Eur Heart J 2003;
19、24:717-728; Kerzner B et al Am J Cardiol 2003;91:418-424.,对TG的疗效: 益适纯与他汀类 联合给药汇总结果降低7%-11%,TG 从基线到12周的平均 % 变化,35,30,25,20,10,0,40,益适纯 + 阿托伐他汀 (n=255),阿托伐他汀 (n=248),益适纯 + 辛伐他汀 (n=274),辛伐他汀 (n=263),益适纯 + 洛伐他汀 (n=192),洛伐他汀 (n=220),益适纯 + 普伐他汀 (n=204),普伐他汀 (n=205),33*,25*,24,17,22,11,18,8,15,5,用益适纯+辛伐他汀显
20、著改变其它 脂蛋白成分和炎症反应标志物,CRP=C反应蛋白 *除 CRP外, 以中位百分比变化表示 *p0.001 比辛伐他汀 1080 mg 摘自Goldberg AC et al Mayo Clin Proc 2004;79:620629.,从基线到12周的平均* % 变化,20,40,60,0,29%,42%*,9%,33%*,Apo B,CRP,34%,49%*,非HDL-C,益适纯 /辛伐他汀 10/1010/80 mg 汇总剂量 辛伐他汀 1080 mg汇总剂量,(n=340),(n=328),(n=353),(n=345),(n=209),(n=204),Third Joint
21、Task Force Guidelines for CVD Prevention: Lipid Management,Treatment Goals Patient Group LDL-C Total-C General population 115 mg/dL 190 mg/dL (3 mmol/L) (5 mmol/L) Clinical CVD 100 mg/dL 175 mg/dL (2.5 mmol/L) (4.5 mmol/L) Diabetes 100 mg/dL 175 mg/dL (2.5 mmol/L) (4.5 mmol/L),Adapted from De Backer
22、 C, et al. Eur Heart J. 2003;24:16011610.,Goals for Management of Hyperlipidemia in Patients With Diabetes,LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for the Study of Diabetes; ADA = American Diabetes A
23、ssociation; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 = Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III aOptional/reasonable goals; bOr LDL-C reduction of 30% from baseline Rydn L, et al. Eur Heart J.
24、2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4S41; Smith SC, et al. Circulation. 2006;113:23632372; Buse JB, et al. Circulation. 2007;115:114126; Joint British Societies 2. Heart. 2005; 91(suppl V):v1v52; Grundy SM, et al. Circulation. 2004;110:2
25、27239.,病人*LDL-C总体NCEP ATP III达标 和根据NCEP 危险分层的达标,病人达标,所有 病人,冠心病或 冠心病等危症,*病人在基线未达标 各治疗组之间的差异具统计学意义，p0.001 Data from Registration File, MSP.,他汀安慰剂 益适纯 他汀,71.0,20.6,69.5,17.3,75.1,32.2,90.7,52.4,(n=1584),(n=783),(n=1276),(n=641),(n=265),(n=121),(n=43),(n=21),非CHD 但有 2 危险因素,非CHD 但有 2 危险因素,EASE study,依折麦布
26、联合他汀治疗良好的安全性-汇总结果 4个多中心、随机、双盲、安慰剂对照研究，共入组2382个病人，包括依折麦布和阿托伐他汀、辛伐他汀、普伐他汀和洛伐他汀所有剂量的联合治疗,依折麦布联合他汀治疗的安全性、耐受性与他汀单药治疗相当 依折麦布单药治疗的安全性、耐受性与安慰剂相当,依折麦布联合他汀治疗相对于他汀单药治疗未增加肝脏和血液生化检验异常的风险 依折麦布联合他汀治疗的病人未发生肌溶解或肌病 无具临床意义的他汀和依折麦布的药物相互作用,依折麦布 安慰剂 依折麦布 他汀 + 他汀 (n=259) (n=262) (n=936) (n=925) 治疗相关不良事件 (%) 18.1 15.6 16.9
27、 19.5 由于不良事件停药 (%) 3.9 2.7 2.5 3.7 严重治疗相关不良事件 (%) 0 0.4 0.1 1.1,Adapted from Kosoglou T et al. Presented at the European Atherosclerosis Society Meeting, 2004; Summary of Product Characteristics, EZETROLTM, MSP; Data from Registration File, MSP.,*都无症状，继续或停用药物后可逆。 ULN=正常值上限; ALT=alanine aminotransfer
28、ase; AST=aspartate aminotransferase; GGT=gamma-glutamyl transpeptidase; CPK=creatine phosphokinase Adapted from Data from Registration File, MSP.,依折麦布联合他汀治疗良好的安全性(汇总结果) 4个多中心、随机、双盲、安慰剂对照研究，共入组2382个病人，包括依折麦布和阿托伐他汀、辛伐他汀、普伐他汀和洛伐他汀所有剂量的联合治疗,REVERSAL The Need for Intensive LDL-C Lowering: Relationship Be
29、tween Degree of LDL-C Reduction and Change in Atheroma Volume,The solid blue line indicates the relationship between mean change in LDL-C and change in atheroma volume from linear regression analysis. The dashed green lines indicate the upper and lower 95% confidence limits for the mean values. Adap
30、ted from Nissen S, et al. JAMA. 2004;291:10711080.,Change in LDL-C, %,Change in Atheroma Volume, mm3,15,10,5,0,5,10,15,20,80,70,60,50,40,30,20,10,0,10,20,N=502,Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia,The ENHANCE trial ClinicalTrials.gov number: NCT00552097,John J.P. Ka
31、stelein, MD, PhD* Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands,*On behalf of all ENHANCE investigators,ENHANCE,Kastelein, et al, N Eng J Med 2008; In Press,Background,ENHANCE,Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of LDL-c when added to st
32、atin treatment. However, the effect of Ezetimibe on the progression of atherosclerosis is unknown,ENHANCE Study Design,Simvastatin 80 mg,RANDOMI ZAT I ON,0,24,Months,3,6,9,12,15,18,21,Pre-randomization Phase,FH: LDL-c 210 mg/dL,Screening and Fibrate Washout,Placebo Lead-In/ Drug Washout,Weeks,-6,-10
33、 to -7,Ezetimibe 10 mg-Simvastatin 80 mg,IMT assessment,Months,LDL-cholesterol,ENHANCE,-40,0,6,12,18,24,-50,-60,-70,0,-10,-20,-30,10,Percentage change from baseline,P0.01,-16.5 % incremental reduction,Other Lipids and Apolipoproteins,ENHANCE,hsCRP,ENHANCE,-26 % incremental reduction,Baseline 24 mont
34、hs (mg/L) (mg/L) Simva 1.7(0.8-4.1) 1.2(0.6-2.4) Eze-Simva 1.7(0.8-3-9) 0.9(0.5-1.9),Mean cIMT during 24 months of therapy Longitudinal, repeated measures analysis,ENHANCE,Mean IMT (mm),Conclusion,The addition of Ezetimibe to Simvastatin did lead to expected changes in LDL-c and hsCRP, but did not r
35、educe any cIMT parameter The reason(s) for this discrepancy currently remains unknown,ENHANCE,脂质代谢机制,LPL=脂蛋白脂肪酶；CE=胆固醇脂;FC=游离胆固醇;PL=胰脂酶,依折麦布与他汀类联合应用：总结,益适纯联合应用他汀与单用他汀比较 能显著改善对LDL-C、 TC、TG、和 HDL-C的疗效 显著改善LDL-C治疗达标率 益适纯 + 小剂量他汀降低LDLC的疗效与最大剂量的他汀相当 益适纯联用他汀同时较单用他汀能够显著改善其他血脂指标，如Apo B、非HDLC、CRP等。 益适纯（长期）联用他汀的安全性、耐受性与他汀单用相当,摘自Ballantyne CM et al Circulation 2003;107:2409-2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134; Melani L et al Eur Heart J 2003;24:717-728; Kerzner B et al Am J Cardiol 2003;91:418-424.,调脂治疗增加Apo A1-HDL-c与逆转斑块效应有待继续研究,