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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
13、vastatin 40 mg (n=189),The Best Option?,Start early and start aggressively, particularly on hypercholesterolemic patients with other risk factors and previous heart events,With the new goal for blood LDL-C, combined therapies may be the best option. For example: a statin + ezetimibe; Vytorin Dont fo
14、rget regular exercise, healthy diet, blood pressure control, and a “happy heart” Say no to smoke,Clinical Trial: ENHANCE Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression,18 Center study in United States, Canada, South Africa, Spain, Denmark, Norway, Sweden, and t
15、he Netherlands August 2002 April 2006 2 Year study 720 participants with Heterozygous Familial Hypercholesterolemia Simvastatin 80 mg + Placebo vs + Ezetimibe,LDL C = 318 + 65 mg/dl 80% previously on a statin. Baseline IMT = .70 vs .69 (S + P vs S + E) 2 year change in IMT = .006 vs .011 (S+P vs S+E
16、) (NS),ENHANCE TRIAL,Kastelein JJP et al. NEJM 2008,Mean (SE) Intima-Media Thickness of the Carotid Artery,Kastelein JJP et al. NEJM 2008,B-mode ultrasound technique,Baseline wall thickness (mm) and progression rate (mm/yr),Baseline wall thickness (mm) and progression rate (mm/yr),Baseline wall thic
17、kness (mm) and progression rate (mm/yr),From Dr. John R. Crouse,Problems with ENHANCE,Baseline wall thickness: at the low end of multiple trials that showed some differences Long-term high dose statin treatment history: not much lipids left? collagen-rich plaque? Short duration of treatment: Only 2
18、years Limited subjects: 720 Data against the well established correlation between LDL-C levels and CVD,Comments from Dr. Helen H. Hobbs: The ENHANCE work is “just a terrible paper from beginning to end”,Relative Risk of Onset of Cancer in the SEAS Trial and in SHARP and IMPROVE-IT,Peto R, et al. NEJ
19、M 2008,Effects of Ezetimibe on Sitosterolemia,Cholesterol,Plant Sterols, 400 mg, 200 mg, 200 mg, 400 mg,Daily Intake of Dietary Sterols,Cholesterol,Sitosterol, 1 mg/dL, 200 mg/dL,Sterol Levels in Normal Humans,200 mg/Day, 400 mg/Day,Dietary:,Plasma:,Major Features of Sitosterolemia,Inheritance,Reces
20、sive,Xanthomas,Premature CAD,+,+,Plasma sitosterol,15 - 30 mg/dL,Diet-responsiveness,+,Plasma cholesterol,100 - 800 mg/dL,Ezetimibe Reduces Blood Sitosterol in Sitosterolemic Humans,Lutjohann D, et al. Int J Clin Pract 2008:62:1499,Ezetimibe Reduces Plasma Plant Sterol Levels in the Absence of ABCG5
21、/8,Genetic Ablation of NPC1L1 Prevents Sitosterolemia in Mice Lacking ABCG5/G8,Tang W, et al. JLR 2008,Other Potential Beneficial Effects of Ezetimibe,1. On fatty liver ?,WT-T 3.40.4a 2.30.4a 12.30.7a 241.829.1b L1KO-V 4.10.3a 3.60.2a 18.80.5a 48.07.5a L1KO-T 3.00.3a 2.90.3a 19.10.5a 110.827.3a,Geno
22、type TC FC PL TG,Mean SEM (mg/g wet liver),WT- V 4.40.3a 2.90.1a 19.34.0a 36.07.9a,Hepatic Lipid Content of WT and L1-KO Mice Treated with T0901317,Other Potential Beneficial Effects of Ezetimibe,2. On obesity ?,NPC1L1 deficiency prevents a high fat diet-induced obesity in pure C57BL/6 mice,NPC1L1 d
23、eficiency prevents a high fat diet-induced obesity in pure C57BL/6 mice,Promoting fat storage during evolution?,Why do we have intestinal cholesterol absorption while the body can synthesize cholesterol?,Is Ezetimibe a Solution of Modern Diseases (High Fat Diet-Induced Obesity, Insulin Resistance, D
24、iabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Diseases)?,Acknowledgments,Wake Forest University Department of Pathology John R. Crouse Yinyan Ma Weiqing Tang Jia Lin Lawrence L. Rudel,UT Southwestern Department of Cell Biology Helen H. Hobbs Jonathan C. Cohen,Mount Sinai School of Medicine Dep
25、artment of Human Genetics Joanna P. Davies Yiannis A. Ioannou,Switching to Ezetimibe/Simvastatin Superior to Doubling Statin Dose,Adapted from Roeters van Lennep HWO, et al. Curr Med Res Opin. 2008;24:685,LDL-C 2.5 mmol/L,LDL-C 2.0 mmol/L,26% (n=189),67% (n=178),0,20,40,60,80,0,10,20,30,40,3% (n=189),30% (n=178),Patients at LDL-C Goal at Week 12, %,Patients at LDL-C Goal at Week 12, %,