从抑制胆固醇吸收谈如何减少血液中胆固醇.ppt
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1、,Reduce Blood Cholesterol by Targeting Cholesterol Absorption,Liqing Yu, M.D., Ph.D. Department of Pathology-Lipid Sciences Wake Forest University School of Medicine Winston-Salem, NC, USA Beijing, October 26, 2008,Plasma Cholesterol and Coronary Heart Disease (CHD),CHD Deaths Per 1000 patients per
2、10 yr,Serum Cholesterol Level (mg/dl),MRFIT: Multiple Risk Factor Intervention Trial,Shanghai,From Dr. John M. Dietschy,(USA),Mean LDL-Cholesterol,AGE (YEARS),Lifetime Exposure to LDL-Cholesterol American vs. Chinese Men,Lifetime LDL Exposure Index,From Dr. Helen H. Hobbs,Elbow Tuberous Xanthoma (15
3、Ys Chinese Girl, FH?),From Dr. Luya Wang in Beijing,Fluid-Mosaic Model of Cell Membrane: Cholesterol is a structural component of mammalian cell membranes,“Cholesterol Is Good”,Net Cholesterol Balance in Humans, 700 mg, 375 mg,Hepatic and Extrahepatic Synthesis,750 mg,Dietary+Biliary Cholesterol, 40
4、0 mg Bile FC, 375 mg Feces, 300 mg Bile acids,Von Bergmann K, Grundy SM, Gastroenterology 1979:77:1183,50%, 50 mg Steroids, 100 mg Skin slough,Intestinal absorption:50%, 100 mg Intestine slough,Molecular Mechanisms of Cholesterol Transport in Liver and Intestine,PCSK9, ARH,ABC transporters,ApoB,ApoB
5、,Monogenic Hypercholesterolemia,Autosomal Familial LDLR,Familial Defective APOB ApoB-100,Inheritance Disease Gene Defect,Dominant Hypercholesterolemia,Autosomal Autosomal Recessive ARH Hypercholesterolemia Sitosterolemia ABCG5/G8,Recessive,Autosomal Dominant Hypercholesterolemia,PSCK9,Targets of Cho
6、lesterol Lowering Drugs,Inhibit cholesterol synthesis: HMG-CoA reductase inhibitors statins Inhibit cholesterol absorption: Ezetimibe, bile acid resins, plant sterols Reduce lipoprotein-cholesterol production: ApoB antisense oligos (ISIS) Raise LDLR: statins, PCSK9 inhibition (drugs and antisense ol
7、igos),Targets of Cholesterol Lowering Drugs (continue),HDL-C is controversial. Just a marker or a real cause? The body does not need HDL to get rid of cholesterol. Consequence of raising HDL: Why did CETP inhibitor fail? Does reverse cholesterol transport (RCT) quantitatively important? Anti-inflamm
8、ation may delay heart attack, but when your LDL-C is below 70 mg/dL, your chance to develop atherosclerotic lesions is very, very low.,Why as low as 70?,Because what matters is “Not Just How Low, But Also How Long”. (PCSK9 mutants, Framingham study),How to get there?,Glucuronidation,Zetia,Intestinal
9、 Sterol Absorption and Excretion,Ch,Feces,Reduce Blood Cholesterol Levels by Ezetimibe and Statin in Humans,Bays HE, et al. Clin Ther 2004:26:1758,Switching to Ezetimibe/Simvastatin vs Doubling Statin Doses in Patients with CHD and/or Diabetes,The Ezetimibe And Simvastatin vs doublE statin reach new
10、 lipid treatment GOals (EASEGO) Study,Switching to Ezetimibe/Simvastatin More Effective Than Doubling Statin Dose,Adapted from Roeters van Lennep HWO, et al. Curr Med Res Opin. 2008;24(3):685694.,Patients at LDL-C Goal at Week 12, %,Patients at LDL-C Goal at Week 12, %,Doubling to Simvastatin 40 mg
11、Group,Doubling to Atorvastatin 20 mg Group,0,20,40,60,80,0,20,40,60,80,24% (n=115),73% (n=110),28% (n=74),57% (n=68),LDL-C Goal Attainment to 2.5 mmol/L,Switching to Ezetimibe/Simvastatin Superior to Doubling Statin Dose Across Most Lipid Subfractions,Adapted from Roeters van Lennep HWO, et al. Curr
12、 Med Res Opin. 2008;24(3):685694.,Mean Change From Statin Baseline at Week 12, %,Total Cholesterol,35,30,15,10,5,0,5,25,20,LDL-C,HDL-C,Triglycerides,Total Cholesterol/ HDL-C,apo B,17.7,6.6,11.5,29.1,2.6,1.0,0.1,2.8,13.5,6.1,19.7,7.2,Ezetimibe/simvastatin (n=178) Doubling to atorvastatin 20 mg or sim
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