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现代脂质三联治疗现代脂质三联治疗IntroductionPartIIntroductionPartIEfficacy-ThePowertoReachTargetKeyFactor:

+

Differentiators:LDLReduction TG HDL LDL/HDLRatio TheLipidTriad

Efficacy-ThePowertoReachTheLDL/HDLRatio-OurStrength,OurStory!!ClearpositioningforLipobayAnewperceptionofefficacyDifferentiationtoAtorvastatinFitwithourproductprofileTheLDL/HDLRatio-OurStrengLDLHDLAdditionalriskfactor,especiallyindiabeticsTheLipidTriad-OverviewTGTheLipidTriadTheRatioLDLHDLAdditionalriskfactor,TTheLipidTriadandStrategicRationalePartIITheLipidTriadPartII

NoscientificevidenceEvidencecontradictingthisstatementAmarketinghypothesistobuildtheirLDLstoryCreatingtheperceptionofthestatinwiththestrongestefficacyThelower..............thebetter???NoscientificevidenceThelo

It’slogicalIt’smeasurableIt’spracticableTheLipidTriad-TheGP’sPerspectiveIt’slogicalIt’smeasurablHDLLDLHDLLDLSupportingDatafromLandmarkStudiesPartIIISupportingDataPartIII121086420%MortalityPlacebo Q1 Q2 Q3 Q4 (lowHDL-increase) (highHDL-increase)4S-StudyCADMortalityperQuartilesofIncreasesinHDL-CholesterolKJEKSHUSJ&PEDERSENT(unpublished)12%MortalityPlaceboHDLInterventionTrial(VA-HIT)RUBINSHBetal.NewEnglJMed1999;341:41006-31-4-35-30-25-20-15-10-50510CholesterolLDL-CHDL-CTriglyceridesPercentchangecomparedtoplaceboat1yearSecondaryPreventionin2531men

withlowHDL-C&LDL-Cshoweda

22%reductionincombinedfatal

andnon-fatalMIHDLInterventionTrial(VA-HITHDL-CholesterolasRiskFactorforCHDLRC-CPPT(Placebo)MRFIT(usualcare)IncidencerateofCHDIncidencerateofCHD121086420100130160190GORDONDJetal.Circulation1989;79:8-15.HDL-C[mg/dl]65554535LDL-Cholesterolmg/dlLDL-Cholesterolmg/dl121086420100130160190HDL-CholesterolasRiskFact00.511.522.53FraminghamHeartStudyCADriskasafunctionofLDL-CandHDL-Cinmen(50to70y)CASTELLIWP.AmJCardiol1998;82:60-6522016010085654525HDL-Cholesterol(mg/dl)LDLCholesterol(mg/dL)00.511.522.53FraminghamHeart0246810121416LDL<=5LDL>5HDL>=1.08HDL<1.08LDL/HDL<=5LDL/HDL>5Incidenceofcardiacevents(per1000person-years)GemfibrozilPlaceboLDL-CTertiles(mmol/L)HDL-CTertiles(mmol/L)LDL-C/HDL-CTertiles244632363445223938531829IncidenceforcardiaceventsvslipidparameterHelsinkiHeartStudyMANNINENV,LeenaT,KoskinenPetal.Circulation1992;85:37-450246810121416LDL<=5LDL>5HDL>=1AFCAPS/TEXCAPSApoB/A1TertilesLDL-C/HDL-CTertiles1.6

1.4

1.210.8

0.6

0.4

0.2

0

1.6

1.4

1.210.8

0.6

0.4

0.2

0

EventRateper100Patient-YearsofRiskEventRateper100Patient-YearsofRisk£0.88890.8898-1.0205³1.0252£3.77423.7744-4.4096³4.4101GOTTOAetal.Circulation2000;101:477-484LDL/HDLRatioasTherapeuticSuccessPlaceboStatinAFCAPS/TEXCAPSApoB/A1Tertil2411631245050100150200250300<=5>5LDL/HDL-RatioTriglycerides<200mg/dlTriglycerides>=200mg/dlCADcasesper1,000subjectsin6yearsASSMANNGandSCHULTEH;AmJCardiol1992;70:733-737IncidenceofCADvsLDL/HDLratiobyTGlevel(n=4559)PROCAMHeartStudy2411631245050100150200250300<=050100150200250300<3<4<5>5>6>7LDL/HDLratioCHDIncidence/1000in6yearsCHDriskaccordingtoLDL/HDLratioatbaselineASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:43>5HighCHDriskMediumCHDriskLowCHDrisk3-5<3PROCAMHeartStudy050100150200250300<3<4<5>5MeanvaluesfordevelopingatheroscleroticCHDwithin6yearsVariable CHDDevelopment NoCHDDevelopment (n=186) (n=4221)TC(mg/dl) 251.8 222.9HDL-C(mg/dl) 39.5 45.2LDL-C(mg/dl) 176.2 147.1LDL/HDLratio 4.72 3.4

TG(mg/dl) 163.0 134.5ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:41PROCAMHeartStudyMeanvaluesfordevelopingathPredictivevalueofriskfactorsfordevelopingatheroscleroticCHDwithin6yearsVariable RiskRatio PredictivePower% TG200mg/dl 2.3 7.5 TC250(mg/dl) 2.8 8.3LDL-C195(mg/dl) 3.7 12.0LDL-C155(mg/dl) 3.3 7.1 HDL-C35(mg/dl) 3.9 11.0LDL/HDLratio5 6.4 16.5

ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:43PROCAMHeartStudyPredictivevalueofriskfactoHDLasCHDriskfactorshowed186events,inmenaged40-60years(n=4407)CHDIncidenceper1,000in6years020406080100120140160

35 35-5555HDL-C(mg/dL)1103021ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:59PROCAMHeartStudyHDLasCHDriskfactorshowedLDLasCHDriskfactorshowed177eventsinmenaged40-60years,(n=4263)CHDIncidenceper1,000in6years020406080100120140

135 135-154155-195 195LDL-C(mg/dL)54301631120ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:60PROCAMHeartStudyLDLasCHDriskfactorshowedExpertOpinionsPartIVExpertOpinionsPartIVTheLipidTriad-ExpertCommentsAHA,November1999“EvaluatingtheriskonthebasesofLDLalone,isnaive”

ValentinFuster,MountSinaiMedicalCenter,NewYork“TheLDL/HDLratioisamuchstrongerpredictorfortheCHDriskthanLDLalone”PaulRidker,BrighamInstituteforWomen’sHospital,BostonTheLipidTriad-ExpertCommeACCP,March2000“LowHDLisabetterindicatorofCHDthanhighLDLasseeninepidemiologicalstudiessuchastheFraminghamStudyandrecentlytheVA-HITStudy.”SanderRobins,UniversityMedicalCenter,Boston“LandmarkstatintrialshaveshownconsistentbenefitsonCHDreductionafterraisingHDLby5-10%irrespectiveofLDLlevels”ChristieBallantyne,BaylorCollegeofMedicine,Houston

TheLipidTriad-ExpertCommentsACCP,March2000TheLipidTriaHelsinkiHeartStudy“TheLDL/HDLratiowasthebestsinglepredictorofcardiac events”ManninenV,LeenaT,KoskinenPetal.Circulation1992;85,1:37“Patientsintheplacebogroupwithtriglyceridelevelsof200mg/dlandanLDL/HDLratioof5.0hadbyfarthehighestincidenceofcardiacevents”GerdAssmann,LipidMetabolismDisordersandCoronaryHeartDisease,MMVMedizinVerlag,1993TheLipidTriad-ExpertCommentsHelsinkiHeartStudyTheLipidPROCAM“Thegreatestdifference,inrelativeterms,betweenthegroupswithandwithoutmajorcoronaryeventswasseenintheLDL/HDL-ratio”AssmannG,CullenPandSchulteH;EurHeartJournal1998,19A2-A11“ForpracticalpurposesitappearsadvisabletobasepredictionsforatheroscleroticCADandtreatmentdecisiononafulllipidprofile,(cholesterol,triglycerides,LDLandHDLcholesterol)ratherthancholesterolorLDLcholesteroldeterminantsalone”GerdAssmann,LipidMetabolismDisordersandCoronaryHeartDisease,MMVMedizinVerlag,1993TheLipidTriad-ExpertCommentsPROCAMTheLipidTriad-ExpertStateoftheArtConference,BerlinApril2000“TheLipidTriadshouldformthebasesofdiagnosticandtherapeuticdecisionsinlipidtherapy”MarkolfHanefeld,InstituteforMetabolismDisordersandResearch,Dresden“ByjustusinghighLDLasacriterionforprescription,somepatientsarereceivingstatintreatmentwhodonotneedit,andthosewithlowHDLandhighLDLwhodoneedthetreatmentarenotgettingit!”GerdAssmann,InstituteofClinicalChemistryandLabMedicine,Münster,GermanyTheLipidTriad-ExpertCommentsStateoftheArtConference,BTheImpactofGuidelinesPartVTheImpactPartVTheLipidTriad-WhattheNCEP*GuidelinesSayHDLCholesterol35mg/dl(0.9mmol/l)LDLCholesterol100mg/dl(2.6mmol/l)TG200mg/dl(2.3mmol/l)*NationalCholesterolEducationProgramtargetsforsecondarypreventionTheLipidTriad-WhattheNCETheLDL/HDLRatio-WhattheGuidelinessaySecondaryPreventionGuidelinesNCEP(USA) LDL/HDL<2.8AssociationofCardiology(Germany) LDL/HDL<2.5SocietyofLipidTherapy(Germany) LDL/HDL<3TheLDL/HDLRatio-WhattheGCerivastatinClinicalDataPartVICerivastatinPartVIChangeinLDL/HDLRatioDatapoolanalysis,8weeks00.511.522.533.544.55Baseline0.1mg0.2mg0.3mg0.4mg0.8mgn=459n=636n=645n=1072n=732LDL/HDLRatioDataonfileChangeinLDL/HDLRatioDatapoo5045403530252015105025.60.746.240.235.532.0%ChangeinLDL/HDLRatioDatapoolanalysis,8weeks

%ChangeinLDL/HDLRatioPlacebo0.1mg0.2mg0.3mg0.4mg0.8mgDataonfile5045403530252015105025.60.746.BaselineLDL/HDLratio After8weeks%ofrespondents

5

5 12.3

3 69.9

=3 18.13-=5

5 0.2

3 11.4

=3

88.5=3

3 0.5

=3 99.5LDL/HDLResponderRates0.4mgresponderrateat8weeks(n=941)DataonfileBaselineLDL/HDLResponderRatBaselineafter8weeks>5HighCHDriskMediumCHDriskLowCHDrisk8%60%32%90%9%1%3-5<3LDL/HDLMovingpatientsintothesafetyareaafter8weeks(n=187)ReachingTargetwithLDL/HDLRatioReductionOSEetal.CurrMedRes&Opinion2000;16(2):80-87Baselineafter8weeks>5HighMedLDL-C(mean%changefrombaselineafter24weeks)

10-40-30-20-100-50-44.4%Men(n=200)Women(n=102)-37.0%LDLCholesterolReductionFromBaselineOSEetal.CurrMedRes&Opinion1999;15(3):231-43LDLReductionwith0.4mgofCerivastatinLDL-C(mean%change10-40-30-908070605040302010029.787.470.749.530354045Cumulative%ofrespondentsLDLResponderRateswith0.4mgLDL%reductionratesinpatientsaged60to65years(n=156)Dataonfile908070605040302010029.787.470.0,02,04,06,08,010,012,014,016,018,0<50<40<30HDLbaselineHDLResponderRates>50%HDLincreaseDataonfile0.4mgresponderrateat8weeks6.510.317.98.20,02,04,06,08,010,012,014,016,90807060504030201001023.39.381.465.155.820304050TGresponderratesfor0.4mgTG%reductionratesfrombaseline300mg/dlat8weeks(n=43)

Cumulative%ofrespondentsDataonfile90807060504030201001023.39.3Triglyceridemean%changefrombaselineafter8weeks-20-100-30-405placebo0.3mg0.4mgBaselinetriglycerides<150mg/dl150-250mg/dl>250mg/dl0.1mg0.2mg10-35-25-155TGReductionSTEINEetal.Atherosclerosis1999;144(S1):A37Triglyceridemean%changefroApoB/ApoA1(LS-Means%Changewithminimum8weekstreatment)-20,0-10,00,0-30,0-40,05Placebo-35,0-25,0-15,05,0ApoB/ApoA1CerivastatinPooledDataDataonfile0.1mg0.2mg0.3mg0.4mg0.8mgn=588n=259n=265n=573n=658n=5992,0-18.5-22.4-26.8-29.1-36.0ApoB/ApoA1(LS-Means%ChangPatientGroupCerivastatinPlacebo100mg200mg300mg400mg800mg-18.5-16.9-21.0-19.6-17.2-21.9

-20.5-22.8-22.4-20.6-24.9-23.0-21.2-26.0-24.9-26.6-26.8-25.9-28.3-25.5-26.0-29.5-28.7-30.3-29.1-28.0-30.6-23.2-29.1-30.7-27.5-33.2-36.0-35.3-37.1-32.3-35.9-37.1-36.0-38.5AllMaleFemale£40Years>40-<65Years³65Years

Elderlypatients-male-female2.02.21.7-0.52.71.11.21.0CerivastatinStudies8WeeksMinimumTreatmentApoB/ApoA1(%changeatweek8)DataonfilePatientGroupCerivastatinPlaceSalessupportingactivitiesActivelycreatingdataandinformationGainingconsensusfromOLLeadinginsteadofFollowingSalessupportingActivelycrea现代脂质三联治疗现代脂质三联治疗IntroductionPartIIntroductionPartIEfficacy-ThePowertoReachTargetKeyFactor:

+

Differentiators:LDLReduction TG HDL LDL/HDLRatio TheLipidTriad

Efficacy-ThePowertoReachTheLDL/HDLRatio-OurStrength,OurStory!!ClearpositioningforLipobayAnewperceptionofefficacyDifferentiationtoAtorvastatinFitwithourproductprofileTheLDL/HDLRatio-OurStrengLDLHDLAdditionalriskfactor,especiallyindiabeticsTheLipidTriad-OverviewTGTheLipidTriadTheRatioLDLHDLAdditionalriskfactor,TTheLipidTriadandStrategicRationalePartIITheLipidTriadPartII

NoscientificevidenceEvidencecontradictingthisstatementAmarketinghypothesistobuildtheirLDLstoryCreatingtheperceptionofthestatinwiththestrongestefficacyThelower..............thebetter???NoscientificevidenceThelo

It’slogicalIt’smeasurableIt’spracticableTheLipidTriad-TheGP’sPerspectiveIt’slogicalIt’smeasurablHDLLDLHDLLDLSupportingDatafromLandmarkStudiesPartIIISupportingDataPartIII121086420%MortalityPlacebo Q1 Q2 Q3 Q4 (lowHDL-increase) (highHDL-increase)4S-StudyCADMortalityperQuartilesofIncreasesinHDL-CholesterolKJEKSHUSJ&PEDERSENT(unpublished)12%MortalityPlaceboHDLInterventionTrial(VA-HIT)RUBINSHBetal.NewEnglJMed1999;341:41006-31-4-35-30-25-20-15-10-50510CholesterolLDL-CHDL-CTriglyceridesPercentchangecomparedtoplaceboat1yearSecondaryPreventionin2531men

withlowHDL-C&LDL-Cshoweda

22%reductionincombinedfatal

andnon-fatalMIHDLInterventionTrial(VA-HITHDL-CholesterolasRiskFactorforCHDLRC-CPPT(Placebo)MRFIT(usualcare)IncidencerateofCHDIncidencerateofCHD121086420100130160190GORDONDJetal.Circulation1989;79:8-15.HDL-C[mg/dl]65554535LDL-Cholesterolmg/dlLDL-Cholesterolmg/dl121086420100130160190HDL-CholesterolasRiskFact00.511.522.53FraminghamHeartStudyCADriskasafunctionofLDL-CandHDL-Cinmen(50to70y)CASTELLIWP.AmJCardiol1998;82:60-6522016010085654525HDL-Cholesterol(mg/dl)LDLCholesterol(mg/dL)00.511.522.53FraminghamHeart0246810121416LDL<=5LDL>5HDL>=1.08HDL<1.08LDL/HDL<=5LDL/HDL>5Incidenceofcardiacevents(per1000person-years)GemfibrozilPlaceboLDL-CTertiles(mmol/L)HDL-CTertiles(mmol/L)LDL-C/HDL-CTertiles244632363445223938531829IncidenceforcardiaceventsvslipidparameterHelsinkiHeartStudyMANNINENV,LeenaT,KoskinenPetal.Circulation1992;85:37-450246810121416LDL<=5LDL>5HDL>=1AFCAPS/TEXCAPSApoB/A1TertilesLDL-C/HDL-CTertiles1.6

1.4

1.210.8

0.6

0.4

0.2

0

1.6

1.4

1.210.8

0.6

0.4

0.2

0

EventRateper100Patient-YearsofRiskEventRateper100Patient-YearsofRisk£0.88890.8898-1.0205³1.0252£3.77423.7744-4.4096³4.4101GOTTOAetal.Circulation2000;101:477-484LDL/HDLRatioasTherapeuticSuccessPlaceboStatinAFCAPS/TEXCAPSApoB/A1Tertil2411631245050100150200250300<=5>5LDL/HDL-RatioTriglycerides<200mg/dlTriglycerides>=200mg/dlCADcasesper1,000subjectsin6yearsASSMANNGandSCHULTEH;AmJCardiol1992;70:733-737IncidenceofCADvsLDL/HDLratiobyTGlevel(n=4559)PROCAMHeartStudy2411631245050100150200250300<=050100150200250300<3<4<5>5>6>7LDL/HDLratioCHDIncidence/1000in6yearsCHDriskaccordingtoLDL/HDLratioatbaselineASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:43>5HighCHDriskMediumCHDriskLowCHDrisk3-5<3PROCAMHeartStudy050100150200250300<3<4<5>5MeanvaluesfordevelopingatheroscleroticCHDwithin6yearsVariable CHDDevelopment NoCHDDevelopment (n=186) (n=4221)TC(mg/dl) 251.8 222.9HDL-C(mg/dl) 39.5 45.2LDL-C(mg/dl) 176.2 147.1LDL/HDLratio 4.72 3.4

TG(mg/dl) 163.0 134.5ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:41PROCAMHeartStudyMeanvaluesfordevelopingathPredictivevalueofriskfactorsfordevelopingatheroscleroticCHDwithin6yearsVariable RiskRatio PredictivePower% TG200mg/dl 2.3 7.5 TC250(mg/dl) 2.8 8.3LDL-C195(mg/dl) 3.7 12.0LDL-C155(mg/dl) 3.3 7.1 HDL-C35(mg/dl) 3.9 11.0LDL/HDLratio5 6.4 16.5

ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:43PROCAMHeartStudyPredictivevalueofriskfactoHDLasCHDriskfactorshowed186events,inmenaged40-60years(n=4407)CHDIncidenceper1,000in6years020406080100120140160

35 35-5555HDL-C(mg/dL)1103021ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:59PROCAMHeartStudyHDLasCHDriskfactorshowedLDLasCHDriskfactorshowed177eventsinmenaged40-60years,(n=4263)CHDIncidenceper1,000in6years020406080100120140

135 135-154155-195 195LDL-C(mg/dL)54301631120ASSMANNG;LipidMetabolismDisordersandCHD;MMVMedizinVerlag,1993:60PROCAMHeartStudyLDLasCHDriskfactorshowedExpertOpinionsPartIVExpertOpinionsPartIVTheLipidTriad-ExpertCommentsAHA,November1999“EvaluatingtheriskonthebasesofLDLalone,isnaive”

ValentinFuster,MountSinaiMedicalCenter,NewYork“TheLDL/HDLratioisamuchstrongerpredictorfortheCHDriskthanLDLalone”PaulRidker,BrighamInstituteforWomen’sHospital,BostonTheLipidTriad-ExpertCommeACCP,March2000“LowHDLisabetterindicatorofCHDthanhighLDLasseeninepidemiologicalstudiessuchastheFraminghamStudyandrecentlytheVA-HITStudy.”SanderRobins,UniversityMedicalCenter,Boston“LandmarkstatintrialshaveshownconsistentbenefitsonCHDreductionafterraisingHDLby5-10%irrespectiveofLDLlevels”ChristieBallantyne,BaylorCollegeofMedicine,Houston

TheLipidTriad-ExpertCommentsACCP,March2000TheLipidTriaHelsinkiHeartStudy“TheLDL/HDLratiowasthebestsinglepredictorofcardiac events”ManninenV,LeenaT,KoskinenPetal.Circulation1992;85,1:37“Patientsintheplacebogroupwithtriglyceridelevelsof200mg/dlandanLDL/HDLratioof5.0hadbyfarthehighestincidenceofcardiacevents”GerdAssmann,LipidMetabolismDisordersandCoronaryHeartDisease,MMVMedizinVerlag,1993TheLipidTriad-ExpertCommentsHelsinkiHeartStudyTheLipidPROCAM“Thegreatestdifference,inrelativeterms,betweenthegroupswithandwithoutmajorcoronaryeventswasseenintheLDL/HDL-ratio”AssmannG,CullenPandSchulteH;EurHeartJournal1998,19A2-A11“ForpracticalpurposesitappearsadvisabletobasepredictionsforatheroscleroticCADandtreatmentdecisiononafulllipidprofile,(cholesterol,triglycerides,LDLandHDLcholesterol)ratherthancholesterolorLDLcholesteroldeterminantsalone”GerdAssmann,LipidMetabolismDisordersandCoronaryHeartDisease,MMVMedizinVerlag,1993TheLipidTriad-ExpertCommentsPROCAMTheLipidTriad-ExpertStateoftheArtConference,BerlinApril2000“TheLipidTriadshouldformthebasesofdiagnosticandtherapeuticdecisionsinlipidtherapy”MarkolfHanefeld,InstituteforMetabolismDisordersandResearch,Dresden“ByjustusinghighLDLasacriterionforprescription,somepatientsarereceivingstatintreatmentwhodonotneedit,andthosewithlowHDLandhighLDLwhodoneedthetreatmentarenotgettingit!”GerdAssmann,InstituteofClinicalChemistryandLabMedicine,Münster,GermanyTheLipidTriad-ExpertCommentsStateoftheArtConference,BTheImpactofGuidelinesPartVTheImpactPartVTheLipidTriad-WhattheNCEP*GuidelinesSayHDLCholesterol35mg/dl(0.9mmol/l)LDLCholesterol100mg/dl(2.6mmol/l)TG200mg/dl(2.3mmol/l)*NationalCholesterolEducationProgramtargetsforsecondarypreventionTheLipidTriad-WhattheNCETheLDL/HDLRatio-WhattheGuidelinessaySecondaryPreventionGuidelinesNCEP(USA) LDL/HDL<2.8AssociationofCardiology(Germany) LDL/HDL<2.5SocietyofLipidTherapy(Germany) LDL/HDL<3TheLDL/HDLRatio-WhattheGCerivastatinClinicalDataPartVICerivastatinPartVIChangeinLDL/HDLRatioDatapoolanalysis,8weeks00.511.522.533.544.55Baseline0.1mg0.2mg0.3mg0.4mg0.8mgn=459n=636n=645n=1072n=732LDL/HDLRatioDataonfileChangeinLDL/HDLRatioDatapoo5045403530252015105025.60.746.240.235.532.0%ChangeinLDL/HDLRatioDatapoolanalysis,8weeks

%ChangeinLDL/HDLRatioPlacebo0.1mg0.2mg0.3mg0.4mg0.8mgDataonfile5045403530252015105025.60.746.BaselineLDL/HDLratio After8weeks%ofrespondents

5

5 12.3

3 69.9

=3 18.13-=5

5 0.2

3 11.4

=3

88.5=3

3 0.5

=3 99.5LDL/HDLResponderRates0.4mgresponderrateat8weeks(n=941)DataonfileBaselineLDL/HDLResponderRatBaselineafter8weeks>5HighCHDriskMediumCHDriskLowCHDrisk8%60%32%90%9%1%3-5<3LDL/HDLMovingpatientsintothesafetyareaafter8weeks(n=187)ReachingTargetwi

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