从抑制胆固醇吸收谈如何减少血液中胆固醇.pptx

Reduce Blood Cholesterol by Targeting Cholesterol AbsorptionLiqing Yu,M.D.,Ph.D.Department of Pathology-Lipid SciencesWake Forest University School of MedicineWinston-Salem,NC,USABeijing,October 26,2008Plasma Cholesterol and CoronaryHeart Disease(CHD)CHD DeathsPer 1000 patients per 10 yrSerum Cholesterol Level(mg/dl)MRFIT:Multiple Risk Factor Intervention Trial ShanghaiFrom Dr.John M.Dietschy(USA)Mean LDL-CholesterolAGE(YEARS)Lifetime Exposure to LDL-Cholesterol American vs.Chinese MenLifetime LDL Exposure IndexSMOKINGHTNDIABETESCHR.9etc.FEMALEFrom Dr.Helen H.HobbsElbow Tuberous Xanthoma(15Ys Chinese Girl,FH?)From Dr.Luya Wang in BeijingFluid-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 mgHepatic andExtrahepaticSynthesis Total Body Cholesterol750 mgDietary+BiliaryCholesterol 400 mg Bile FC 375 mgFeces 300 mg Bile acidsVon Bergmann K,Grundy SM,Gastroenterology 1979:77:1183 50%50 mg Steroids 100 mg Skin sloughIntestinal absorption:50%100 mg Intestine sloughMolecular Mechanisms of Cholesterol Transport in Liver and IntestinePCSK9,ARHABC transportersApoBApoBMonogenic HypercholesterolemiaAutosomal Familial LDLR Familial Defective APOB ApoB-100 Inheritance Disease Gene DefectDominant Hypercholesterolemia Autosomal Autosomal Recessive ARHHypercholesterolemia Sitosterolemia ABCG5/G8RecessiveAutosomal DominantHypercholesterolemia PSCK9Targets of Cholesterol Lowering Drugs1.Inhibit cholesterol synthesis:HMG-CoA reductase inhibitors statins2.Inhibit cholesterol absorption:Ezetimibe,bile acid resins,plant sterols3.Reduce lipoprotein-cholesterol production:ApoB antisense oligos(ISIS)4.Raise LDLR:statins,PCSK9 inhibition(drugs and antisense oligos)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-inflammation 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?GlucuronidationZetiaIntestinal Sterol Absorption and ExcretionDietarySterolsBiliary SterolsBA,PLSterolsMixedmicellesABCG5ABCG8NPC1L1LymphEzetimibe(Zetia)GUT LUMENChFecesReduce Blood Cholesterol Levels by Ezetimibe and Statin in HumansBays HE,et al.Clin Ther 2004:26:1758Switching to Ezetimibe/Simvastatin vs Doubling Statin Doses in Patients with CHD and/or DiabetesThe Ezetimibe And Simvastatin vs doublE statin reach new lipid treatment GOals(EASEGO)StudySwitching to Ezetimibe/Simvastatin More Effective Than Doubling Statin DoseAdapted from Roeters van Lennep HWO,et al.Curr Med Res Opin.2008;24(3):685694.Patients at LDL-C Goal at Week 12,%Ezetimibe/simvastatinDoubling to atorvastatin 20 mg or simvastatin 40 mgPatients at LDL-C Goal at Week 12,%Doubling to Simvastatin 40 mg GroupDoubling to Atorvastatin 20 mg Group02040608002040608024%(n=115)73%(n=110)28%(n=74)57%(n=68)LDL-C Goal Attainment to 2.5 mmol/LSwitching to Ezetimibe/Simvastatin Superior to Doubling Statin Dose Across Most Lipid SubfractionsAdapted from Roeters van Lennep HWO,et al.Curr Med Res Opin.2008;24(3):685694.Mean Change From Statin Baseline at Week 12,%Total Cholesterol353015105052520LDL-CHDL-CTriglyceridesTotal Cholesterol/HDL-Capo B17.76.611.529.12.61.00.12.813.56.119.77.2Ezetimibe/simvastatin(n=178)Doubling to atorvastatin 20 mg or simvastatin 40 mg(n=189)The Best Option?Start early and start aggressively,particularly on hypercholesterolemic patients with other risk factors and previous heart eventsWith the new goal for blood LDL-C,combined therapies may be the best option.For example:a statin+ezetimibe;VytorinDont forget regular exercise,healthy diet,blood pressure control,and a“happy heart”Say no to smokeClinical Trial:ENHANCEEzetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression18 Center study in United States,Canada,South Africa,Spain,Denmark,Norway,Sweden,and the NetherlandsAugust 2002 April 20062 Year study720 participants with Heterozygous Familial HypercholesterolemiaSimvastatin 80 mg+Placebo vs+EzetimibeLDL C=318+65 mg/dl80%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 TRIALKastelein JJP et al.NEJM 2008Mean(SE)Intima-Media Thickness of the Carotid ArteryKastelein JJP et al.NEJM 2008B-mode ultrasound techniqueTRIALBaselineCommonAggregateCmnAggCompTestCompTestASAP .86 .93-.010-.020.015-.015ARBITER 1 .61 .025-.034ARBITER 2 .88 .044 .014RADIANCE 11.00 1.15-.004 .004 .005 .005RADIANCE 21.15 1.30 .008 .013.030 .025METEOR1.02 1.16 .008-.004.013 -.001ENHANCE.68 .70 .001 .001.003 .005SANDS.80 .013-.004Baseline wall thickness(mm)and progression rate(mm/yr)TRIALBaselineCommonAggregateCmnAggCompTestCompTestARBITER 2.88 .044 .014CAIUS.881.05 .008-.003.009-.004ASAP.86 .93-.010-.020.015-.015LIPID.80 .048-.014SANDS.80 .013-.004MARS.70 .015-.028ENHANCE.68 .70 .001 .001.003 .005CLAS.65 .013-.013ARBITER 1.61 .025-.034Baseline wall thickness(mm)and progression rate(mm/yr)TRIALBaselineCommonAggregateCmnAggCompTestCompTestKAPS1.66.031.017RADIANCE 21.15 1.30.008 .013.030 .025ACAPS1.141.31.006-.009METEOR1.02 1.16.008-.004.013-.001PLAC-II1.011.32.046 .030.068 .060RADIANCE 11.00 1.15-.004 .004 .005 .005Baseline wall thickness(mm)and progression rate(mm/yr)From Dr.John R.CrouseProblems with ENHANCE1.Baseline wall thickness:at the low end of multiple trials that showed some differences2.Long-term high dose statin treatment history:not much lipids left?collagen-rich plaque?3.Short duration of treatment:Only 2 years4.Limited subjects:7205.Data against the well established correlation between LDL-C levels and CVDComments 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-ITPeto R,et al.NEJM 2008Effects of Ezetimibe on SitosterolemiaCholesterolPlant Sterols 400 mg 200 mg 200 mg 400 mgDaily Intake of Dietary SterolsCholesterolHOSitosterolHO 1 mg/dL 200 mg/dLSterol Levels in Normal Humans200 mg/Day 400 mg/DayDietary:Plasma:Major Features of SitosterolemiaInheritanceRecessiveXanthomasPremature CAD+Plasma sitosterol 15-30 mg/dLDiet-responsiveness+Plasma cholesterol 100-800 mg/dL Ezetimibe Reduces Blood Sitosterol in Sitosterolemic HumansLutjohann D,et al.Int J Clin Pract 2008:62:1499Campesterol050100150Day 0Day 15Day 30%of the value on day 0KO/ZetiaSitosterol050100150Day 0Day 15Day 30KO/ChowEzetimibe Reduces Plasma Plant Sterol Levelsin the Absence of ABCG5/8Genetic Ablation of NPC1L1 Prevents Sitosterolemia in Mice Lacking ABCG5/G8Tang W,et al.JLR 2008Other Potential Beneficial Effects of Ezetimibe1.On fatty liver?WT-T 3.40.4a 2.30.4a 12.30.7a 241.829.1bL1KO-V 4.10.3a 3.60.2a 18.80.5a 48.07.5aL1KO-T 3.00.3a 2.90.3a 19.10.5a 110.827.3a Genotype TC FC PL TGMean 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 T0901317Other Potential Beneficial Effects of Ezetimibe2.On obesity?NPC1L1 deficiency prevents a high fat diet-induced obesity in pure C57BL/6 miceNPC1L1 deficiency prevents a high fat diet-induced obesity in pure C57BL/6 micePromoting 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,Diabetes,Dyslipidemia,and Nonalcoholic Fatty Liver Diseases)?AcknowledgmentsWake Forest UniversityDepartment of PathologyJohn R.CrouseYinyan MaWeiqing TangJia LinLawrence L.RudelUT SouthwesternDepartment of Cell BiologyHelen H.HobbsJonathan C.CohenMount Sinai School of MedicineDepartment of Human GeneticsJoanna P.DaviesYiannis A.IoannouSwitching to Ezetimibe/Simvastatin Superior to Doubling Statin DoseAdapted from Roeters van Lennep HWO,et al.Curr Med Res Opin.2008;24:685Ezetimibe/simvastatinDoubling to atorvastatin 20 mg or simvastatin 40 mgLDL-C 2.5 mmol/LLDL-C 2.0 mmol/L26%(n=189)67%(n=178)0204060800102030403%(n=189)30%(n=178)Patients at LDL-C Goal at Week 12,%Patients at LDL-C Goal at Week 12,%