高脂血癥治療目標(biāo)高密度脂蛋白

1、高脂血癥治療目標(biāo)高密度脂蛋白100160220Risk 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;62:707-714.456585ATP III: New Definition of Low HDL-CExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Ad

2、ults. 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/dLIs HDL-C Simply a Marker of Increased Cardiovascular Risk? SmokeAre sedentaryAre obeseAre insulin resistant or diabeticHave

3、hypertriglyceridemiaHave chronic inflammatory disordersLow HDL-C levels are commonly found in patients who:Production of Apo A-I by Liver and IntestineA-IA-IILiverIntestineHDLA-IHDLReduced initiation and progression of atherosclerosis in transgenic mice and rabbitsRegression of pre-existing atherosc

4、lerosis in animalsIncreased Apo A-I Production is Antiatherogenic in AnimalsIncrease apo A-I productionPromote reverse cholesterol transportDelay catabolism of HDLHDL Metabolism as a Therapeutic Target: Potential StrategiesSmall molecule upregulation of apo A-I gene transcriptionIntravenous infusion

5、 of recombinant protein (wild-type apo A-I, apo A-IMilano)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 ProductionIncrease apo A-I productionPromote reverse cholesterol transport

6、Delay catabolism of HDLHDL as a Therapeutic Target: Potential StrategiesA-IHDL and Reverse Cholesterol TransportLiverCECEFCLCATFCBileSR-BIABCA1MacrophageMature HDLNascent HDLA-IFCCEFCRegulation of Cholesterol Efflux in the MacrophageFCFCoxysterolsLXR/RXRABCA1PPARsA-IPharmacologic Manipulation of Cho

7、lesterol EffluxLXR/RXRPPARsFibrates, TZDs, new agents New agentsA-IFCABCA1Increase apo A-I productionPromote reverse cholesterol transportDelay catabolism of HDLHDL as a Therapeutic Target: Potential StrategiesAntioxidant effectsInhibition of adhesion molecule expressionInhibition of platelet activa

8、tionProstacyclin stabilizationPromotion of NO productionMechanisms Other Than Reverse Cholesterol Transport by Which HDL May be AntiatherogenicLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-ITGCEHDL Metabolism: Intravascular Remodeling of HDLKidneyPLFCPLLiverHLA-ITGCEHDL Metabolism: Role of Hepatic

9、 LipaseKidneyPLHDL2A-ICEPLHDL3LiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEHDL Metabolism: Role of CETPFCKidneyLDLRCETGCETPBVLDL/LDLHDL Metabolism in CETP DeficiencyCEFCFCLCATA-IABCA1MacrophageA-ICEFCCETGCETPBVLDL/LDLDelayedcatabolismXOkamoto H et al. Nature 2000;406:203-207.Inhibition of CE

10、TP by JTT-705 in Cholesterol-Fed Rabbits Significantly Reduced Aortic Atherosclerosis% Aortic Lesion ControlSimvastatinJTT-705HDL Metabolism: Influence of CETP InhibitionLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEFCLDLRCETGCETPBVLDL/LDLXWeight reduction and increased physical activityLDL-C

11、 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.Therapeutic lifestyle changesS

12、moking cessationRegular aerobic exerciseWeight lossAlcohol use?Management of Low HDL-CTherapeutic lifestyle changesPharmacologic therapyStatinsManagement of Low HDL-CPatients with Events (%)Scandinavian Simvastatin Survival Study Group. Lancet 1995;345:1274-1275.4S: Major Coronary Events by HDL-C Su

13、bgroupHDL-C (mg/dL)PlaceboSimvastatin383944455253RR=0.67RR=0.71RR=0.57RR=0.70Patients 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 0.001Events (%)Downs JR et al. JAMA 1998;279:1615-1622

14、.AFCAPS/TexCAPS: Risk Reduction by HDL-C Tertile at BaselineHDL-C LevelsPlaceboLovastatin40 mg/dl71406841443544% RR40% RR20% RRTherapeutic lifestyle changesPharmacologic therapyStatinsFibratesManagement of Low HDL-CVA-HIT: Major Coronary Events in Gemfibrozil vs. Placebo GroupsCumulative Incidence (

15、%)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: Lipid Concentrations According to Year of Study and Treatment GroupTC (mg/dL)012345YearLDL-C (mg/dL)Year012345HDL-C (mg/dL)Ye

16、arTG (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: Changes in Plasma Lipids during Tr

17、eatment 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.Therapeu

18、tic lifestyle changesPharmacologic therapyStatinsFibratesNiacinManagement of Low HDL-CEfficacy 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

19、%3%12%30%24%17%Lifestyle changes and secondary causesPharmacologic therapyIf LDL-C elevated: statinIf TG elevated: fibrateIf isolated low HDL-C: niacinCombination therapyManagement of Low HDL-CChange (%)Wolfe ML et al. Am J Cardiol 2001;87:476-479.Copyright 2001, Excerpta Medica Inc. Reprinted with permission.Addition of E