Slide SourceLipidsOnlinewww.lipidsonline.orgHDL as a Therapeutic TargetDaniel J. Rader, M.D.Slide SourceLipidsOnlinewww.lipidsonline.org100160220Risk 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;62:707-714.456585Slide SourceLipidsOnlinewww.lipidsonline.orgATP 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/dLSlide SourceLipidsOnlinewww.lipidsonline.orgIs 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:Slide SourceLipidsOnlinewww.lipidsonline.orgProduction of Apo A-I by Liver and IntestineA-IA-IA-IIA-IILiverLiverIntestineIntestineHDLHDLA-IA-IHDLHDLSlide SourceLipidsOnlinewww.lipidsonline.orgnReduced initiation and progression of atherosclerosis in transgenic mice and rabbitsnRegression of pre-existing atherosclerosis in animalsIncreased Apo A-I Production is Antiatherogenic in AnimalsSlide SourceLipidsOnlinewww.lipidsonline.orgnIncrease apo A-I productionnPromote reverse cholesterol transportnDelay catabolism of HDLHDL Metabolism as a Therapeutic Target: Potential StrategiesSlide SourceLipidsOnlinewww.lipidsonline.orgnSmall 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 ProductionSlide SourceLipidsOnlinewww.lipidsonline.orgnIncrease apo A-I productionnPromote reverse cholesterol transportnDelay catabolism of HDLHDL as a Therapeutic Target: Potential StrategiesSlide SourceLipidsOnlinewww.lipidsonline.orgA-IHDL and Reverse Cholesterol TransportLiverLiverCECECEFCLCATLCATFCFCBileBileSR-BISR-BIABCA1ABCA1MacrophageMacrophageMature Mature HDLHDLNascent Nascent HDLHDLA-IA-IFCCECEFCSlide SourceLipidsOnlinewww.lipidsonline.orgRegulation of Cholesterol Efflux in the MacrophageFCFCoxysterolsLXR/RXRLXR/RXRABCA1PPARsPPARsA-ISlide SourceLipidsOnlinewww.lipidsonline.orgPharmacologic Manipulation of Cholesterol EffluxLXR/RXRPPARsPPARsFibratesFibrates, , TZDsTZDs, new agents , new agents New agentsA-IFCABCA1Slide SourceLipidsOnlinewww.lipidsonline.orgnIncrease apo A-I productionnPromote reverse cholesterol transportnDelay catabolism of HDLHDL as a Therapeutic Target: Potential StrategiesSlide SourceLipidsOnlinewww.lipidsonline.orgnAntioxidant effectsnInhibition of adhesion molecule expressionnInhibition of platelet activationnProstacyclin stabilizationnPromotion of NO productionMechanisms Other Than Reverse Cholesterol Transport by Which HDL May be AntiatherogenicSlide SourceLipidsOnlinewww.lipidsonline.orgLiverLiverCECECEFCFCFCLCATLCATFCFCBileBileSR-BISR-BIA-IABCA1ABCA1MacrophageMacrophageA-IA-ITGTGCECEHDL Metabolism: Intravascular Remodeling of HDLKidneyKidneyPLPLFCFCPLPLSlide SourceLipidsOnlinewww.lipidsonline.orgLiverLiverHLHLA-IA-ITGTGCECEHDL Metabolism: Role of Hepatic LipaseKidneyKidneyPLPLHDLHDL2A-IA-ICECEPLPLHDLHDL3Slide SourceLipidsOnlinewww.lipidsonline.orgLiverLiverCECECEFCFCFCLCATLCATFCFCBileBileSR-BISR-BIA-IABCA1ABCA1MacrophageMacrophageA-IA-IFCCECEHDL Metabolism: Role of CETPFCFCKidneyKidneyLDLRLDLRCETGCETPCETPB BVLDL/LDLVLDL/LDLSlide SourceLipidsOnlinewww.lipidsonline.orgHDL Metabolism in CETP DeficiencyCEFCFCFCLCATLCATA-IABCA1ABCA1MacrophageMacrophageA-IA-ICECEFCFCCETGCETPCETPB BVLDL/LDLVLDL/LDLDelayedDelayedcatabolismcatabolismXSlide SourceLipidsOnlinewww.lipidsonline.orgOkamoto 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-705Slide SourceLipidsOnlinewww.lipidsonline.orgHDL Metabolism: Influence of CETP InhibitionLiverLiverCECECEFCFCFCLCATLCATFCFCBileBileSR-BISR-BIA-IABCA1ABCA1MacrophageMacrophageA-IA-IFCCECEFCFCLDLRLDLRCETGCETPCETPB BVLDL/LDLVLDL/LDLXSlide SourceLipidsOnlinewww.lipidsonline.orgnWeight 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.Slide SourceLipidsOnlinewww.lipidsonline.orgnTherapeutic lifestyle changesnSmoking cessationnRegular aerobic exercisenWeight lossnAlcohol use?Management of Low HDL-CSlide SourceLipidsOnlinewww.lipidsonline.orgnTherapeutic lifestyle changesnPharmacologic therapynStatinsManagement of Low HDL-CSlide SourceLipidsOnlinewww.lipidsonline.orgPatients 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=0.70Slide SourceLipidsOnlinewww.lipidsonline.orgPatients 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 0.001Slide SourceLipidsOnlinewww.lipidsonline.orgEvents (%)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% RRRRSlide SourceLipidsOnlinewww.lipidsonline.orgnTherapeutic lifestyle changesnPharmacologic therapynStatinsnFibratesManagement of Low HDL-CSlide SourceLipidsOnlinewww.lipidsonline.orgVA-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 = 0.006Slide SourceLipidsOnlinewww.lipidsonline.orgVA-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.Slide SourceLipidsOnlinewww.lipidsonline.orgVA-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.Slide SourceLipidsOnlinewww.lipidsonline.orgnTherapeutic lifestyle changesnPharmacologic therapynStatinsnFibratesnNiacinManagement of Low HDL-CSlide SourceLipidsOnlinewww.lipidsonline.orgEfficacy 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%Slide SourceLipidsOnlinewww.lipidsonline.orgnLifestyle changes and secondary causesnPharmacologic therapynIf LDL-C elevated: statinnIf TG elevated: fibratenIf isolated low HDL-C: niacinnCombination therapyManagement of Low HDL-CSlide SourceLipidsOnlinewww.lipidsonline.orgChange (%)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-CTGSlide SourceLipidsOnlinewww.lipidsonline.orgCV 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*Slide SourceLipidsOnlinewww.lipidsonline.orgnLDL-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 patientsSummarySlide SourceLipidsOnlinewww.lipidsonline.orgn48-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-C