新治疗目标：HDL课件

1、HDL as a Therapeutic TargetDaniel J. Rader, M.D.HDL as a Therapeutic TargetD100160220Risk 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 ATP III: New Definition of L

2、ow 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 SyndromIs

3、 HDL-C Simply a Marker of Increased Cardiovascular Risk? SmokeAre sedentaryAre obeseAre insulin resistant or diabeticHave hypertriglyceridemiaHave chronic inflammatory disordersLow HDL-C levels are commonly found in patients who:Is HDL-C Simply a Marker of InProduction of Apo A-I by Liver and Intest

4、ineA-IA-IILiverIntestineHDLA-IHDLProduction of Apo A-I by LiverReduced initiation and progression of atherosclerosis in transgenic mice and rabbitsRegression of pre-existing atherosclerosis in animalsIncreased Apo A-I Production is Antiatherogenic in AnimalsReduced initiation and progresIncrease apo

5、 A-I productionPromote reverse cholesterol transportDelay catabolism of HDLHDL Metabolism as a Therapeutic Target: Potential StrategiesIncrease apo A-I productionHDLSmall molecule upregulation of apo A-I gene transcriptionIntravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano)

6、Administration of peptides based on apo A-I sequenceSomatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells)Approaches to Increasing Apo A-I ProductionSmall molecule upregulation ofIncrease apo A-I productionPromote reverse cholesterol transportDelay catabolism of HDLHDL a

7、s a Therapeutic Target: Potential StrategiesIncrease apo A-I productionHDLA-IHDL and Reverse Cholesterol TransportLiverCECEFCLCATFCBileSR-BIABCA1MacrophageMature HDLNascent HDLA-IFCCEFCA-IHDL and Reverse CholesterolRegulation of Cholesterol Efflux in the MacrophageFCFCoxysterolsLXR/RXRABCA1PPARsA-IR

8、egulation of Cholesterol EfflPharmacologic Manipulation of Cholesterol EffluxLXR/RXRPPARsFibrates, TZDs, new agents New agentsA-IFCABCA1Pharmacologic Manipulation of Increase apo A-I productionPromote reverse cholesterol transportDelay catabolism of HDLHDL as a Therapeutic Target: Potential Strategi

9、esIncrease apo A-I productionHDLAntioxidant effectsInhibition of adhesion molecule expressionInhibition of platelet activationProstacyclin stabilizationPromotion of NO productionMechanisms Other Than Reverse Cholesterol Transport by Which HDL May be AntiatherogenicAntioxidant effectsMechanisms Liver

10、CECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-ITGCEHDL Metabolism: Intravascular Remodeling of HDLKidneyPLFCPLLiverCECEFCFCLCATFCBileSR-BIA-LiverHLA-ITGCEHDL Metabolism: Role of Hepatic LipaseKidneyPLHDL2A-ICEPLHDL3LiverHLA-ITGCEHDL Metabolism: LiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEHDL M

11、etabolism: Role of CETPFCKidneyLDLRCETGCETPBVLDL/LDLLiverCECEFCFCLCATFCBileSR-BIA-HDL Metabolism in CETP DeficiencyCEFCFCLCATA-IABCA1MacrophageA-ICEFCCETGCETPBVLDL/LDLDelayedcatabolismXHDL Metabolism in CETP DeficieOkamoto H et al. Nature 2000;406:203-207.Inhibition of CETP by JTT-705 in Cholesterol

12、-Fed Rabbits Significantly Reduced Aortic Atherosclerosis% Aortic Lesion ControlSimvastatinJTT-705Okamoto H et al. Nature 2000;4HDL Metabolism: Influence of CETP InhibitionLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEFCLDLRCETGCETPBVLDL/LDLXHDL Metabolism: Influence of Weight reduction and i

13、ncreased physical activityLDL-C is primary target of therapyNon-HDL-C is secondary target of therapy (if triglycerides 200 mg/dL)Consider 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

14、.Weight reduction and increasedTherapeutic lifestyle changesSmoking cessationRegular aerobic exerciseWeight lossAlcohol use?Management of Low HDL-CTherapeutic lifestyle changesMTherapeutic lifestyle changesPharmacologic therapyStatinsManagement of Low HDL-CTherapeutic lifestyle changesMPatients with

15、 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 (%)ScandiPatients with Events (%)LIPID Study Group. N Engl J Med 1998;339:1349-13

16、57.LIPID: CHD Events by HDL-C SubgroupsHDL-CPlaceboPravastatin39 mg/dL37 mg/dL37 mg/dLP = 0.008P 0.001Patients with Events (%)Sacks Events (%)Downs JR et al. JAMA 1998;279:1615-1622.AFCAPS/TexCAPS: Risk Reduction by HDL-C Tertile at BaselineHDL-C LevelsPlaceboLovastatin40 mg/dl71406841443544% RR40%

17、RR20% RREvents (%)Downs JR et al. JAMATherapeutic lifestyle changesPharmacologic therapyStatinsFibratesManagement of Low HDL-CTherapeutic lifestyle changesMVA-HIT: Major Coronary Events in Gemfibrozil vs. Placebo GroupsCumulative Incidence (%)0Rubins HB et al. N Engl J Med 1999;341:410-418.Copyright

18、 1999, Massachusetts Medical Society. All rights reserved.123456YearPlaceboGemfibrozil22% reductionP = 0.006VA-HIT: Major Coronary EventsVA-HIT: Lipid Concentrations According to Year of Study and Treatment GroupTC (mg/dL)012345YearLDL-C (mg/dL)Year012345HDL-C (mg/dL)YearTG (mg/dL)Year012345PlaceboG

19、emfibrozil4%, 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 VA-HIT: Changes in Plasma Lipids during Tre

20、atment 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: C

21、hanges in Plasma LipTherapeutic lifestyle changesPharmacologic therapyStatinsFibratesNiacinManagement of Low HDL-CTherapeutic lifestyle changesMEfficacy of Extended-Release NiacinChange from Baseline2500 mg3000 mgGoldberg A et al. Am J Cardiol 2000;85:1100-1105.2000 mg1500 mg1000 mg500mgHDL-CLDL-CLp

22、(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 NLifestyle changes and secondary causesPharmacologic therapyIf LDL-C elevated: statinIf TG elevated: fibrateIf isolated low HDL-C: niacinCombination therapyManagement of Low HDL-CLifestyle changes a

23、nd secondarChange (%)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 JCV 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