新治疗目标：HDL课件

Slide SourceLipidsOnlineHDL as a Therapeutic TargetDaniel J.Rader,M.D.HDL as a Therapeutic TargetDSlide SourceLipidsOnline100160220Risk of CHDLow HDL-C is an Independent Predictor of CHD Risk Even When LDL-C is LowHDL-C(mg/dL)LDL-C(mg/dL)25Gordon T et al.Am J Med 1977;62:707-714.456585100160220Risk of CHDLow HDL-C Slide SourceLipidsOnlineATP III:New Definition of Low HDL-CExpert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA 2001;285:2486-2497.Low HDL-C was redefined as 102 cm(40 in)88 cm(35 in)TG150 mg/dLHDL-C Men Women40 mg/dL50 mg/dLBlood pressure130/85 mm HgFasting glucose110 mg/dLATP III:The Metabolic SyndromSlide SourceLipidsOnlineIs HDL-C Simply a Marker of Increased Cardiovascular Risk?nSmokenAre sedentarynAre obesenAre insulin resistant or diabeticnHave hypertriglyceridemianHave chronic inflammatory disordersLow HDL-C levels are commonly found in patients who:Is HDL-C Simply a Marker of InSlide SourceLipidsOnlineProduction of Apo A-I by Liver and IntestineA-IA-IA-IIA-IILiverLiverIntestineIntestineHDLHDLA-IA-IHDLHDLProduction of Apo A-I by LiverSlide SourceLipidsOnlinenReduced initiation and progression of atherosclerosis in transgenic mice and rabbitsnRegression of pre-existing atherosclerosis in animalsIncreased Apo A-I Production is Antiatherogenic in AnimalsReduced initiation and progresSlide SourceLipidsOnlinenIncrease apo A-I productionnPromote reverse cholesterol transportnDelay catabolism of HDLHDL Metabolism as a Therapeutic Target:Potential StrategiesIncrease apo A-I productionHDLSlide SourceLipidsOnlinenSmall molecule upregulation of apo A-I gene transcriptionnIntravenous infusion of recombinant protein(wild-type apo A-I,apo A-IMilano)nAdministration of peptides based on apo A-I sequencenSomatic gene transfer of apo A-I DNA(liver,intestine,muscle,hematopoetic cells)Approaches to Increasing Apo A-I ProductionSmall molecule upregulation ofSlide SourceLipidsOnlinenIncrease apo A-I productionnPromote reverse cholesterol transportnDelay catabolism of HDLHDL as a Therapeutic Target:Potential StrategiesIncrease apo A-I productionHDLSlide SourceLipidsOnlineA-IHDL and Reverse Cholesterol TransportLiverLiverCECECEFCLCATLCATFCFCBileBileSR-BISR-BIABCA1ABCA1MacrophageMacrophageMature Mature HDLHDLNascent Nascent HDLHDLA-IA-IFCCECEFCA-IHDL and Reverse CholesterolSlide SourceLipidsOnlineRegulation of Cholesterol Efflux in the MacrophageFCFCoxysterolsLXR/RXRLXR/RXRABCA1PPARsPPARsA-IRegulation of Cholesterol EfflSlide SourceLipidsOnlinePharmacologic Manipulation of Cholesterol EffluxLXR/RXRPPARsPPARsFibrates,TZDs,new agents Fibrates,TZDs,new agents New agentsA-IFCABCA1Pharmacologic Manipulation of Slide SourceLipidsOnlinenIncrease apo A-I productionnPromote reverse cholesterol transportnDelay catabolism of HDLHDL as a Therapeutic Target:Potential StrategiesIncrease apo A-I productionHDLSlide SourceLipidsOnlinenAntioxidant effectsnInhibition of adhesion molecule expressionnInhibition of platelet activationnProstacyclin stabilizationnPromotion of NO productionMechanisms Other Than Reverse Cholesterol Transport by Which HDL May be AntiatherogenicAntioxidant effectsMechanisms Slide SourceLipidsOnlineLiverLiverCECECEFCFCFCLCATLCATFCFCBileBileSR-BISR-BIA-IABCA1ABCA1MacrophageMacrophageA-IA-ITGTGCECEHDL Metabolism:Intravascular Remodeling of HDLKidneyKidneyPLPLFCFCPLPLLiverCECEFCFCLCATFCBileSR-BIA-Slide SourceLipidsOnlineLiverLiverHLHLA-IA-ITGTGCECEHDL Metabolism:Role of Hepatic LipaseKidneyKidneyPLPLHDLHDL2A-IA-ICECEPLPLHDLHDL3LiverHLA-ITGCEHDL Metabolism:Slide SourceLipidsOnlineLiverLiverCECECEFCFCFCLCATLCATFCFCBileBileSR-BISR-BIA-IABCA1ABCA1MacrophageMacrophageA-IA-IFCCECEHDL Metabolism:Role of CETPFCFCKidneyKidneyLDLRLDLRCETGCETPCETPB BVLDL/LDLVLDL/LDLLiverCECEFCFCLCATFCBileSR-BIA-Slide SourceLipidsOnlineHDL Metabolism in CETP DeficiencyCEFCFCFCLCATLCATA-IABCA1ABCA1MacrophageMacrophageA-IA-ICECEFCFCCETGCETPCETPB BVLDL/LDLVLDL/LDLDelayedDelayedcatabolismcatabolismXHDL Metabolism in CETP DeficieSlide SourceLipidsOnlineOkamoto H et al.Nature 2000;406:203-207.Inhibition of CETP by JTT-705 in Cholesterol-Fed Rabbits Significantly Reduced Aortic Atherosclerosis%Aortic Lesion ControlSimvastatinJTT-705Okamoto H et al.Nature 2000;4Slide SourceLipidsOnlineHDL Metabolism:Influence of CETP InhibitionLiverLiverCECECEFCFCFCLCATLCATFCFCBileBileSR-BISR-BIA-IABCA1ABCA1MacrophageMacrophageA-IA-IFCCECEFCFCLDLRLDLRCETGCETPCETPB BVLDL/LDLVLDL/LDLXHDL Metabolism:Influence of Slide SourceLipidsOnlinenWeight reduction and increased physical activitynLDL-C is primary target of therapynNon-HDL-C is secondary target of therapy(if triglycerides 200 mg/dL)nConsider nicotinic acid or fibratesManagement of Low HDL-CExpert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA 2001;285:2486-2497.Weight reduction and increasedSlide SourceLipidsOnlinenTherapeutic lifestyle changesnSmoking cessationnRegular aerobic exercisenWeight lossnAlcohol use?Management of Low HDL-CTherapeutic lifestyle changesMSlide SourceLipidsOnlinenTherapeutic lifestyle changesnPharmacologic therapynStatinsManagement of Low HDL-CTherapeutic lifestyle changesMSlide SourceLipidsOnlinePatients with Events(%)Scandinavian Simvastatin Survival Study Group.Lancet 1995;345:1274-1275.4S:Major Coronary Events by HDL-C SubgroupHDL-C(mg/dL)PlaceboSimvastatin383944455253RR=0.67RR=0.71RR=0.57RR=0.70Patients with Events(%)ScandiSlide SourceLipidsOnlinePatients with Events(%)LIPID Study Group.N Engl J Med 1998;339:1349-1357.LIPID:CHD Events by HDL-C SubgroupsHDL-CPlaceboPravastatin39 mg/dL37 mg/dL37 mg/dLP=0.008P 0.001Patients with Events(%)Sacks Slide SourceLipidsOnlineEvents(%)Downs JR et al.JAMA 1998;279:1615-1622.AFCAPS/TexCAPS:Risk Reduction by HDL-C Tertile at BaselineHDL-C LevelsPlaceboLovastatin40 mg/dl71714068684144443544%44%RRRR40%40%RRRR20%20%RRRREvents(%)Downs JR et al.JAMASlide SourceLipidsOnlinenTherapeutic lifestyle changesnPharmacologic therapynStatinsnFibratesManagement of Low HDL-CTherapeutic lifestyle changesMSlide SourceLipidsOnlineVA-HIT:Major Coronary Events in Gemfibrozil vs.Placebo GroupsCumulative Incidence(%)0Rubins HB et al.N Engl J Med 1999;341:410-418.Copyright 1999,Massachusetts Medical Society.All rights reserved.123456YearPlaceboGemfibrozil22%reductionP=0.006VA-HIT:Major Coronary EventsSlide SourceLipidsOnlineVA-HIT:Lipid Concentrations According to Year of Study and Treatment GroupTC(mg/dL)012345YearLDL-C(mg/dL)Year012345HDL-C(mg/dL)YearTG(mg/dL)Year012345PlaceboGemfibrozil4%,P0.001No changeGemfibrozil&PlaceboPlaceboGemfibrozil+6%,P0.001012345PlaceboGemfibrozil31%,P0.001Rubins HB et al.N Engl J Med 1999;341:410-418.Copyright 1999,Massachusetts Medical Society.All rights reserved.VA-HIT:Lipid Concentrations Slide SourceLipidsOnlineVA-HIT:Changes in Plasma Lipids during Treatment as Predictors of Coronary EventsVariable(Change)Risk Factor(95%CI)PDuring treatmentHDL-C(5.0 mg/dL)0.89(0.810.98).02Triglycerides(50 mg/dL)1.03(0.951.11).48LDL-C(25 mg/dL)1.09(0.981.21).13Robins SJ et al.JAMA 2001;285:1585-1591.Copyright 2001,American Medical Association.VA-HIT:Changes in Plasma LipSlide SourceLipidsOnlinenTherapeutic lifestyle changesnPharmacologic therapynStatinsnFibratesnNiacinManagement of Low HDL-CTherapeutic lifestyle changesMSlide SourceLipidsOnlineEfficacy of Extended-Release NiacinChange from Baseline2500 mg3000 mgGoldberg A et al.Am J Cardiol 2000;85:1100-1105.2000 mg1500 mg1000 mg500mgHDL-CLDL-CLp(a)TG9%14%22%21%17%29.5%30%26%22%15%10%28%35%44%39%11%5%26%3%12%30%24%17%Efficacy of Extended-Release NSlide SourceLipidsOnlinenLifestyle changes and secondary causesnPharmacologic therapynIf LDL-C elevated:statinnIf TG elevated:fibratenIf isolated low HDL-C:niacinnCombination therapyManagement of Low HDL-CLifestyle changes and secondarSlide SourceLipidsOnlineChange(%)Wolfe ML et al.Am J Cardiol 2001;87:476-479.Copyright 2001,Excerpta Medica Inc.Reprinted with permission.Addition of Extended-Release Niacin to a Statin because of Persistently Low HDL-CTCLDL-CHDL-CTGChange(%)Wolfe ML et al.Am JSlide SourceLipidsOnlineCV EventsEvent Rate(%)Brown BG et al.Circulation 1998;98:I-635.Familial Atherosclerosis Treatment Study(FATS):10-Year Follow-up ResultsUsual Care(n=101)DeathsLDL-C 188166 mg/dL;HDL-C 3840 mg/dL;TG 208220 mg/dLLDL-C 202106 mg/dL;HDL-C 4353 mg/dL;TG 210134 mg/dLTriple Therapy(n=75)19.818.81.3*p0.055.3*CV EventsEvent Rate(%)Brown BSlide SourceLipidsOnlinenLDL-C remains the primary target of lipid-altering therapiesnHDL-C is an important CHD risk factornEven small increases in HDL-C may confer substantial benefitnIntervention to raise HDL-C levels should be considered in high-risk patientsSummaryLDL-C remains the primary targSlide SourceLipidsOnlinen48-year-old man with metabolic syndrome and CHDnAfter therapeutic lifestyle changes and a starting dose of statin:Cholesterol 179 mg/dL Triglycerides 252 mg/dL LDL-C 97 mg/dL HDL-C 32 mg/dL Glucose 104 mg/dLApproach to the Patient with Low HDL-C48-year-old man with metabolicSlide SourceLipidsOnline演讲完毕，谢谢观看！Thank you for reading!In order to facilitate learning and use,the content of this document can be modified,adjusted and printed at will after downloading.Welcome to download!汇报人：XXX汇报日期：20XX年10月10日演讲完毕，谢谢观看！Thank you for readin