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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, USABeijing, October 26, 2008,Plasma Cholesterol and Coronary Heart Disease (CHD),CHD Deaths Per 1000 patients per 1
2、0 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 (15Y
3、s 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, 400
4、 mgBile FC, 375 mg Feces, 300 mgBile acids,Von Bergmann K, Grundy SM, Gastroenterology 1979:77:1183,50%, 50 mgSteroids, 100 mgSkin slough,Intestinal absorption:50%, 100 mgIntestine slough,Molecular Mechanisms of Cholesterol Transport in Liver and Intestine,PCSK9, ARH,ABC transporters,ApoB,ApoB,Monog
5、enic Hypercholesterolemia,Autosomal Familial LDLR,Familial Defective APOB ApoB-100,Inheritance Disease Gene Defect,Dominant Hypercholesterolemia,Autosomal Autosomal Recessive ARHHypercholesterolemia Sitosterolemia ABCG5/G8,Recessive,Autosomal Dominant Hypercholesterolemia,PSCK9,Targets of Cholestero
6、l Lowering Drugs,Inhibit cholesterol synthesis: HMG-CoA reductase inhibitors statinsInhibit cholesterol absorption: Ezetimibe, bile acid resins, plant sterolsReduce lipoprotein-cholesterol production: ApoB antisense oligos (ISIS)Raise LDLR: statins, PCSK9 inhibition (drugs and antisense oligos),Targ
7、ets 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-inflammation may del
8、ay 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 Sterol Absor
9、ption 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 lipid treatm
10、ent 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 Group,Doublin
11、g 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 Med Res Opin
12、. 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 simvastatin 40 m
13、g (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; VytorinDont forget regular e
14、xercise, healthy diet, blood pressure control, and a “happy heart” Say no to smoke,Clinical Trial: ENHANCE Ezetimibe and Simvastatin in HypercholesterolemiaEnhances Atherosclerosis Regression,18 Center study in United States, Canada, South Africa, Spain, Denmark, Norway, Sweden, and the Netherlands
15、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) (NS),ENHANCE T
16、RIAL,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 thickness (mm) and progression rate (mm/yr),
