Slide 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Slide 2Elevated Cholesterol Is a Risk Factor for CVD Elevated serum cholesterol is associated with increased risk of CHD Reinfarction CVD mortality All-cause CHD StrokeCVD = cardiovascular disease*Crude death rate (per 10,000 person-years)Adapted from 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;152:14901500.01020304050160160199 200239240CVD Mortality Rate*Multiple Risk Factor Intervention Trial (N=350,977)Serum Cholesterol, mg/dLSlide 3Relationship Between LDL-C and CHD Risk in Clinical TrialsHPS = 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 Targets *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/dLEvent*, %0300110170210252015105130701501904S4SCAREHPSTNT (atorvastatin 80 mg)90LIPIDStatin PlaceboTNT (atorvastatin 10 mg)HPSCARELIPIDSlide 4人类类胆固醇净净平衡肠道合成胆固醇 （800mg/天）胆汁胆固醇 胆汁酸粪固醇 （1100mg/天）肝外组织肝脏食物胆固醇 （300mg/天）乙酰辅酶A胆固 醇胆固醇Slide 5INHIBITION 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, Suppl. 2):A445-A446; Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.Inhibition of cholesterol synthesisLDL-C 31-46%synthesisabsorption(simvastatin 10-80 mg)Food Cholesterol excreted in the faecesHEPATIC BIOSYNTHESISINTESTINAL ABSORPTION30-50% absorption* Measured as the ratio of serum levels of cholesterol absorption marker (sitosterol) and total cholesterol.STATINSSlide 6胆固醇合成标志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*4871*-69-76 10080604020020406080100阿伐他汀 20 mg/日 阿伐他汀 80 mg/日Slide 7THE INHIBITION OF CHOLESTEROL ABSORPTION RESULTS IN INCREASED CHOLESTEROL BIOSYNTHESISCAI = 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.FoodCholesterol excreted in the faecesHEPATIC BIOSYNTHESISINTESTINAL ABSORPTION30-50% absorptionCAIInhibition of cholesterol absorptionLDL-C 20%synthesisabsorption(ezetimibe)Slide 8肠道内胆固醇吸收1000 mgNPC1L1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 Raven, 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):E2 E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:10821150; Davis JP et 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 mgACATSlide 9Uptake of a fluorescent cholesterolanalog in hamster small intestineSparrow et al. J Lipid Res. 1999; 10:1747125 I-Gluc-Ezetimibe Delivered I.V. Localizes to the Intestinal Brush Border in Bile-Duct Cannulated RatsEzetimibe appears to localize to Ezetimibe appears to localize to the site of cholesterol absorptionthe site of cholesterol absorptionSlide 10PNAS 102, 8132, 2005Science, 303, 1149, 2004Slide 11肠道胆固醇吸收被依折麦布抑制了肠道胆固醇吸收被依折麦布抑制了54% 54% (p 0.001)(p 0.001)01020304050607080安慰剂依折麦布Cholesterol Absorption (%)49.8 %22.7%Sudhop et al. Circulation 2002; 106;1943Slide 12依折麦布： 降低致粥样硬化脂蛋白中的胆固醇含量肠道肝脏食物胆固 醇血液动脉粥样硬化形 成粪固醇胆固 醇 胆 盐Slide 13依折麦布： 降低致粥样硬化脂蛋白中的胆固醇含量肠道肝脏食物胆固 醇血液动脉粥样硬化形 成粪固醇胆固 醇 胆 盐依折麦布Slide 14依折麦布： 降低致粥样硬化脂蛋白中的胆固醇含量肠道肝脏食物胆固 醇血液动脉粥样硬化形 成粪固醇胆固 醇 胆 盐依折麦布Slide 15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他汀类胆固醇依折麦布Slide 16LDL-CLDL-CLDL-C20%30-45%STATIN+As high as 60%10%20%30%40%50%MEAN LDL-C LOWERING2,3synthesis absorptionsynthesisabsorptionsynthesisabsorption双重抑制可降低LDL-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 MARKERS1Inhibition of absorptionDual inhibition Statin + EZETIMIBEInhibition of synthesisEZETIMIBESlide 17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 Pract 2001;55(10):710716; Shepherd J Eur Soc Cardiol