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ClinicalTrialsandGuidelinesforLipidManagementintheDiabeticPatient

StevenHaffner,MDClinicalTrialsandGuidelinesUKPDSDesignAimTodeterminewhetherintensifiedbloodglucosecontrol,witheithersulphonylureaorinsulin,reducestheriskofmacrovascularormicrovascularcomplicationsintype2diabetesPatients3867newlydiagnosedtype2diabeticpatientswhowereasymptomaticafter3monthsofdiet;fastingglucose6.1-15mmol/L(110-270mg/dl);treatfor10yearsAdaptedfromUKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:837-853;

TurnerRetal.AnnInternMed1996;124:136-145.UKPDSDesignAimAdaptedfromUKUKPDSGroup.Lancet1998;352:837-853.UKPDS10-YearFollow-upResults:

GlycemicControl,Weight,andPlasmaInsulinYearsfromRandomization01234567891011120123456789101112YearsfromRandomizationConventionalConventionalIntensiveIntensiveConventionalIntensiveIntensiveConventionalFastingplasmaglucoseMedian(mmol/L)HemoglobinA1cWeightPlasmainsulin111098760Median(%)987607.552.50-2.5Baseline=75kgMeanChange(kg)403020100-10-20MedianChange(pmol/L)Baseline=89pmol/LUKPDSGroup.Lancet1998;352:8UKPDS:ProportionofPatientsTakingDifferentTherapiesintheConventional-TherapyGroupCourtesyofDr.AmandaAdler%ofpatients10080604020Dietalone1357911YearsfromrandomizationAdditional

pharmacologic

therapyUKPDS:ProportionofPatientsUKPDS:CausesofDeathbyGlucoseTreatmentGroupRate/1000

patient-yearsMI

Stroke

Suddendeath

PVDAllmacrovascularRenaldiseaseCancer

Otherspecified

UnknownTotalUKPDSGroup.Lancet1998;352:837-853.%Rate/1000

patient-years%7.6

1.6

0.9

0.110.20.34.4

2.4

0.517.8Cause43

9

5

158225

13

31008.0

1.3

1.6

0.311.20.24.4

2.7

0.218.743

7

8

260124

14

1100ConventionalIntensiveUKPDS:CausesofDeathbyGlucUKPDS:EndpointsbyGlucose

TreatmentGroupRate/1000

Patient-YearsAnydiabetes-related*MIStrokePVD**MicrovascularUKPDSGroup.Lancet1998;352:837-853.Rate/1000

Patient-YearsPCause40.914.75.61.18.6*Combinedmicrovascularandmacrovascularevents

**AmputationordeathfromPVD%Risk

Reduction46.017.45.01.611.40.0290.0520.520.150.00991216––25ConventionalIntensiveUKPDS:EndpointsbyGlucose

TUKPDS:ImpactofGlucose-LoweringAgentsonMIandStrokeSulphonylureaorexogenousinsulin(n=2729)MI16%reduction(P=0.052)Stroke11%increase(P=0.52)Metformininoverweightsubjects(n=342)MI39%reduction(P=0.01)Stroke41%reduction(P=0.13)AdaptedfromUKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:837-853;

UKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:854-865.UKPDS:ImpactofGlucose-LowerUKPDSResults:IntensiveBloodPressureControlAnydiabetes-relatedendpointDeathsrelatedtodiabetesMyocardialinfarctionStrokeMicrovasculardiseaseIntensiveBlood

PressureControl24322144370.00460.019NS0.0130.092AdaptedfromUKProspectiveDiabetesStudyGroup.BMJ1998;317:703-713.Reduction

(%)PValueUKPDSResults:IntensiveBlooComparisonofCaptoprilvs.Atenolol

inUKPDS

PrimaryAnydiabetes-relatedendpointDeathrelatedtodiabetesAll-causemortality

SecondaryMyocardialinfarctionStrokePeripheralvasculardiseaseMicrovasculardiseaseClinicalEndpointAdaptedfromUKProspectiveDiabetesStudyGroup.BMJ1998;317:713-720.RRfor

CaptoprilPValue

1.10(0.86–1.41)1.27(0.82–1.97)1.14(0.81–1.61)

1.20(0.82–1.76)1.12(0.59–2.12)1.48(0.35–6.19)1.29(0.80–2.10)

0.430.280.44

0.350.740.590.30ComparisonofCaptoprilvs.AtComparisonofGlucoseLoweringandBloodPressureLoweringinUKPDSAnydiabetes-related

endpointMyocardialinfarctionStrokeMicrovasculardisease

12161125Reduction

%

=IncreaseinriskAdaptedfromUKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:837-853;

UKProspectiveDiabetesStudyGroup.BMJ1998;317:703-713.P

ValueReduction

%P

ValueIntensiveBlood

GlucoseControl(n=2729)IntensiveBlood

PressureControl(n=758)

0.0290.052NS0.0099

24214437

0.0046NS0.0130.092ComparisonofGlucoseLoweringTreatmentStrategiesforDiabeticDyslipidemiaPrimaryStrategy-LowerLDLcholesterolSecondaryStrategy-RaiseHDLcholesterol-LowertriglyceridesOtherApproaches-Non-HDLcholesterol-ApoB-RemnantsAdaptedfromAmericanDiabetesAssociation.DiabetesCare.2000;23(suppl1):S57-S60;ChaitA,BrunzellJD.

DiabetesMellitus.AFundamentalandClinicalText.Philadelphia:LippincottRaven,1996;772-779;

EuropeanDiabetesPolicyGroup1999.DiabetMed.1999;16:716-730.TreatmentStrategiesforDiabeCHDPreventionTrialswithStatinsinDiabeticSubjects:SubgroupAnalysesPrimaryPreventionAFCAPS/TexCAPSSecondaryPreventionCARE4SLIPIDBaseline

LDL-C,

mg/dl

(mmol/L)*ValuesforoverallgroupAdaptedfromDownsJRetal.JAMA1998;279:1615-1622;GoldbergRBetal.Circulation1998;98:2513-2519;

Py?r?l?Ketal.DiabetesCare1997;20:614-620;HaffnerSMetal.ArchInternMed1999;159:2661-2667;TheLong-TermInterventionwithPravastatininIschaemicDisease(LIPID)StudyGroup.NEnglJMed1998;339:1349-1357.DrugNo.LDL-C

LoweringLovastatinPravastatinSimvastatinPravastatin25%28%36%25%*150(3.9)136(3.6)186(4.8)150*(3.9)239586202782StudyCHDPreventionTrialswithStaCHDPreventionTrialswithStatinsinDiabeticSubjects:SubgroupAnalyses(cont’d)PrimaryPreventionAFCAPS/TexCAPSSecondaryPreventionCARE4SLIPID4S-ExtendedCHDRisk

Reduction

(overall)DrugNo.LovastatinPravastatinSimvastatinPravastatinSimvastatin43%25%(p=0.05)55%(p=0.002)19%42%(p=0.001)37%23%32%25%32%239586202782483CHDRisk

Reduction

(diabetes)StudyAdaptedfromDownsJRetal.JAMA1998;279:1615-1622;GoldbergRBetal.Circulation1998;98:2513-2519;Py?r?l?Ketal.DiabetesCare1997;20:614-620;TheLong-TermInterventionwithPravastatininIschaemicDisease(LIPID)StudyGroup.NEnglJMed1998;339:1349-1357;HaffnerSMetal.ArchInternMed1999;159:2661-2667.CHDPreventionTrialswithStaAdaptedfromPy?r?l?etal.Diabetes

Care1997;20:614-620.Diabeticvs.NondiabeticPatientsin4S00.20.40.81.4RelativeRiskwith95%ConfidenceIntervalsTotalmortality0.61.01.2ReducedIncreasedCHDmortalitySimvastatinBetterPlacebo

BetterMajorCHDeventCerebrovasculareventAnyatheroscleroticeventP=0.001

P=0.087P<0.0001

P=0.242P<0.0001

P=0.002P=0.097

P=0.071P<0.0001

P=0.018NodiabetesDiabetesAdaptedfromPy?r?l?etal.Di1.00.90.80.70.60.50ProportionwithoutMajorCHDEventYearsSinceRandomization0123456AdaptedfromPy?r?l?etal.DiabetesCare1997;20:614-620.DiabetesbyHx,simvastatin

DiabetesbyHx,placeboNodiabetesbyHx,simvastatin

NodiabetesbyHx,placeboP=0.002P=0.0001MajorCoronaryEventsin4SPatientswithorwithoutDiabetesbyHistory(n=202)1.0ProportionwithoutMajorCHAdaptedfromHaffnerSMetal.Arch

Intern

Med1999;159:2661-26674S:ExtendedDiabeticSubgroupAnalysis:

Diabetes(n=483;251onSimvastatin)—FastingGlucose>7mmol/L(126mg/dl)0.00.20.40.81.4RelativeRiskCHDmortality

(P=0.26)Totalmortality

(P=0.34)Revascularizations(P=0.005)Majorcoronaryevents(P=0.001)0.61.01.20.720.790.520.58AdaptedfromHaffnerSMetal.AdaptedfromHaffnerSMetal.Arch

Intern

Med1999;159:2661-26674S:ExtendedDiabeticSubgroupAnalysis:

ImpairedFastingGlucose(n=678;343onSimvastatin)—FastingGlucose6.0-6.9mmol/L(110-125mg/dl)0.00.20.40.81.4RelativeRiskCHDmortality

(P=0.007)Totalmortality

(P=0.02)Revascularizations(P=0.01)Majorcoronaryevents(P=0.003)0.61.01.20.450.570.570.62AdaptedfromHaffnerSMetal.SimvastatinNormalfasting

glucoseBedDays(per100Pts)4S:EffectofStatinTherapyonHospitalStayAdaptedfromHermanWHetal.Diabetes

Care1999;22:1771-1778.55%

(p<0.001)PlaceboSimvastatinImpairedfasting

glucosePlaceboSimvastatinPlaceboDiabetes

mellitus38%

(p=0.005)28%

(p<0.001)SimvastatinNormalfasting

glucCARE:MajorCoronaryEventsin

DiabeticSubgroupsAdaptedfromGoldbergRBetal.Circulation1998;98:2513-2519.4535302520151050PercentwithEventNoDiabetesbyHistoryDiabetesbyHistoryFollow-upTime(years)PercentwithEvent4535302520151050Follow-upTime(years)01234650123465PlaceboPravastatinPravastatinPlaceboRelativerisk=0.75

P=0.05Relativerisk=0.77

P<0.001CARE:MajorCoronaryEventsi%RiskReductionAFCAPS/TexCAPS:SubgroupAnalysisDownsJRetal.JAMA1998;279:1615-1622.MenWomenOlderSmokersHTNDiabetes-37-46-31-58-38-42LovastatinReducedtheRiskofAcuteMCE%RiskReductionAFCAPS/TexCAPSCARE:MajorCoronaryEventsin

DiabeticSubgroupsAdaptedfromGoldbergRBetal.Circulation1998;98:2513-2519.454035302520151050PercentwithEventNoDiabetesbyHistoryDiabetesbyHistoryFollow-upTime(years)PercentwithEventFollow-upTime(years)01234650123465PlaceboPravastatinPravastatinPlaceboRelativerisk=0.75

P=0.05Relativerisk=0.77

P<0.001454035302520151050CARE:MajorCoronaryEventsiPer-Patient%ofGraftsPOST-CABG:EffectofAggressiveLipidLoweringonProgressioninaDiabeticSubgroupHoogwerfBJetal.Diabetes.1999;48:1289-1294.Aggressive

RxModerate

RxAggressive

RxModerate

RxDiabetes(n=116)NoDiabetes(n=1235)99%CI

(0.20-1.19)99%CI

(0.46-0.79)51%40%Per-Patient%ofGraftsPOST-CACHDPreventionTrialswithFibratesinDiabeticSubjects:SubgroupAnalysesPrimaryPreventionHelsinki

HeartStudySecondaryPreventionVA-HITBaseline

LDL-C,

mg/dl

(mmol/L)No.LDL-C

LoweringAdaptedfromKoskinenPetal.DiabetesCare1992;15:820-825;

RubinsHBetal.NEnglJMed1999;341:410-418.Drug

DoseStudyCHD

ReductionGemfibrozil

(1200mg/d)Gemfibrozil

(1200mg/d)135

627

203

(5.2)112

(2.9)

68%

NS24%p=0.05

6%

–

CHDPreventionTrialswithFibPrimaryCHD*PreventioninType2DiabeticPatients:TheHelsinkiHeartStudy5-YearIncidenceofCHD(%)Type2

(n=135)*MyocardialinfarctionorcardiacdeathAdaptedfromKoskinenPetal.DiabetesCare1992;15:820-825.Others

(n=3946)Type2onPlacebo

(n=76)Type2on

Gemfibrozil

(n=59)P<0.027.43.310.53.4P=0.19PrimaryCHD*PreventioninTypYearCumulativeIncidence(%)VA-HIT:IncidenceofDeathfromCHD

andNonfatalMIPlaceboAdaptedfromRubinsHBetal.NEnglJMed1999;341:410-418.GemfibrozilYearCumulativeIncidence(%)VAVA-HIT:DeathDuetoCHD,NonfatalMI,andConfirmedStrokeinDiabeticPatientsDiabetes

Nodiabetes

Placebo**Valuesarenumberswithevents/totalnumbers(%)AdaptedfromRubinsHBetal.NEnglJMed1999;341:410-418.Risk

ReductionGemfibrozil*PValue116/318

(36)214/949

(23)88/309

(28)170/955

(18)24%

24%

0.05

0.009

VA-HIT:DeathDuetoCHD,NonFutureDirectionsOngoingTrialswith

Lipid-LoweringFocusDrugSimvastatinAtorvastatinAtorvastatinCerivastatin+

fenofibratemicronizedFenofibratemicronizedFenofibratemicronizedHPS=HeartProtectionStudy;ASPEN=AtorvastatinStudyinPreventingEndpointsinNIDDM;

CARDS=CollaborativeAtorvastatinDiabetesStudy;LDS=LipidsinDiabetesStudy;

DAIS=DiabetesAtherosclerosisInterventionStudy;FIELD=FenofibrateIntervention

andEventLoweringinDiabetesHPSASPENCARDSLDS

DAISFIELDFutureDirectionsOngoingTrialHeartProtectionStudyPrimarypreventionwithriskfactors

(hypertension,diabetes,andCVA)2x2factorialdesign

simvastatin40mg/day,antioxidantcocktail

(600mgvitaminE,250mgvitaminC,20mgbetacarotene)N=20,000;subgroupsinclude:

Women(n~5,000)

Elderly(>65,n~10,000)

Diabetics(n~6,000)

Stroke(n~3,000)

Hypertension(n~8,000)

Noncoronaryvasculardisease(n~7,000)

Lowtoaveragebloodcholesterol(n~8,000)FPI–1996,fullyenrolled,results2001MedicalResearchCouncil.August1994HeartProtectionStudyPrimaryEndpointStudies:TreatingtoNewTargets(TNT):

StudyDesignSiteSelection

November1997Investigator

Meeting

March1998Recruitment

Complete

June1999StudyEnd

Dec2004Atorvastatin

10mgLDL

75mg/dLLDL

100mg/dL5YearsAtorvastatin

80mg10,000CADPatientsEndpointStudies:TreatingtoStudyoftheEffectivenessofAdditionalReductionsinCholesterolandHomocysteinewithSimvastatinandFolicAcid/VitaminB12(SEARCH):StudyDesignPrimaryobjective:Todeterminewhetherthegreatercholesterolreductionsachievedwithsimvastatin80mgproducegreaterCHDreductionsinpost-MIpatientsthanachievedwithsimvastatin20mgSecondaryprevention2x2factorialdesign:

simvastatin20or80mg;2mgfolicacid/1mgVitaminB12N=12,000FPI–12/97,results2003StudyoftheEffectivenessofCerivastatinArmFenofibrateArmCerivastatin

Fenofibrate

(n=1,250)Placebo

Fenofibrate

(n=1,250)Cerivastatin

Placebo

(n=1,250)Placebo

Placebo

(n=1,250)2,500

active

fenofibrate2,500

placebo

fenofibraten=2,500active

cerivastatinn=2,500placebo

cerivastatin5,000pts

intotalLipidsinDiabetesStudy(LDS):

Two-by-TwoFactorialRandomizationCerivastatinArmFenofibrateArConclusionsCHDriskisextremelyhighindiabeticsubjectsBenefitsofrisk-factormodificationininterventiontrialsalsoapplytosubgroupswithdiabetesResultsofstrictglycemiccontrolonmacrovasculardiseaseareinconclusiveConclusionsCHDriskisextreme糖尿病脂代謝紊亂的治療與臨床指南-課件ClinicalTrialsandGuidelinesforLipidManagementintheDiabeticPatient

StevenHaffner,MDClinicalTrialsandGuidelinesUKPDSDesignAimTodeterminewhetherintensifiedbloodglucosecontrol,witheithersulphonylureaorinsulin,reducestheriskofmacrovascularormicrovascularcomplicationsintype2diabetesPatients3867newlydiagnosedtype2diabeticpatientswhowereasymptomaticafter3monthsofdiet;fastingglucose6.1-15mmol/L(110-270mg/dl);treatfor10yearsAdaptedfromUKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:837-853;

TurnerRetal.AnnInternMed1996;124:136-145.UKPDSDesignAimAdaptedfromUKUKPDSGroup.Lancet1998;352:837-853.UKPDS10-YearFollow-upResults:

GlycemicControl,Weight,andPlasmaInsulinYearsfromRandomization01234567891011120123456789101112YearsfromRandomizationConventionalConventionalIntensiveIntensiveConventionalIntensiveIntensiveConventionalFastingplasmaglucoseMedian(mmol/L)HemoglobinA1cWeightPlasmainsulin111098760Median(%)987607.552.50-2.5Baseline=75kgMeanChange(kg)403020100-10-20MedianChange(pmol/L)Baseline=89pmol/LUKPDSGroup.Lancet1998;352:8UKPDS:ProportionofPatientsTakingDifferentTherapiesintheConventional-TherapyGroupCourtesyofDr.AmandaAdler%ofpatients10080604020Dietalone1357911YearsfromrandomizationAdditional

pharmacologic

therapyUKPDS:ProportionofPatientsUKPDS:CausesofDeathbyGlucoseTreatmentGroupRate/1000

patient-yearsMI

Stroke

Suddendeath

PVDAllmacrovascularRenaldiseaseCancer

Otherspecified

UnknownTotalUKPDSGroup.Lancet1998;352:837-853.%Rate/1000

patient-years%7.6

1.6

0.9

0.110.20.34.4

2.4

0.517.8Cause43

9

5

158225

13

31008.0

1.3

1.6

0.311.20.24.4

2.7

0.218.743

7

8

260124

14

1100ConventionalIntensiveUKPDS:CausesofDeathbyGlucUKPDS:EndpointsbyGlucose

TreatmentGroupRate/1000

Patient-YearsAnydiabetes-related*MIStrokePVD**MicrovascularUKPDSGroup.Lancet1998;352:837-853.Rate/1000

Patient-YearsPCause40.914.75.61.18.6*Combinedmicrovascularandmacrovascularevents

**AmputationordeathfromPVD%Risk

Reduction46.017.45.01.611.40.0290.0520.520.150.00991216––25ConventionalIntensiveUKPDS:EndpointsbyGlucose

TUKPDS:ImpactofGlucose-LoweringAgentsonMIandStrokeSulphonylureaorexogenousinsulin(n=2729)MI16%reduction(P=0.052)Stroke11%increase(P=0.52)Metformininoverweightsubjects(n=342)MI39%reduction(P=0.01)Stroke41%reduction(P=0.13)AdaptedfromUKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:837-853;

UKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:854-865.UKPDS:ImpactofGlucose-LowerUKPDSResults:IntensiveBloodPressureControlAnydiabetes-relatedendpointDeathsrelatedtodiabetesMyocardialinfarctionStrokeMicrovasculardiseaseIntensiveBlood

PressureControl24322144370.00460.019NS0.0130.092AdaptedfromUKProspectiveDiabetesStudyGroup.BMJ1998;317:703-713.Reduction

(%)PValueUKPDSResults:IntensiveBlooComparisonofCaptoprilvs.Atenolol

inUKPDS

PrimaryAnydiabetes-relatedendpointDeathrelatedtodiabetesAll-causemortality

SecondaryMyocardialinfarctionStrokePeripheralvasculardiseaseMicrovasculardiseaseClinicalEndpointAdaptedfromUKProspectiveDiabetesStudyGroup.BMJ1998;317:713-720.RRfor

CaptoprilPValue

1.10(0.86–1.41)1.27(0.82–1.97)1.14(0.81–1.61)

1.20(0.82–1.76)1.12(0.59–2.12)1.48(0.35–6.19)1.29(0.80–2.10)

0.430.280.44

0.350.740.590.30ComparisonofCaptoprilvs.AtComparisonofGlucoseLoweringandBloodPressureLoweringinUKPDSAnydiabetes-related

endpointMyocardialinfarctionStrokeMicrovasculardisease

12161125Reduction

%

=IncreaseinriskAdaptedfromUKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998;352:837-853;

UKProspectiveDiabetesStudyGroup.BMJ1998;317:703-713.P

ValueReduction

%P

ValueIntensiveBlood

GlucoseControl(n=2729)IntensiveBlood

PressureControl(n=758)

0.0290.052NS0.0099

24214437

0.0046NS0.0130.092ComparisonofGlucoseLoweringTreatmentStrategiesforDiabeticDyslipidemiaPrimaryStrategy-LowerLDLcholesterolSecondaryStrategy-RaiseHDLcholesterol-LowertriglyceridesOtherApproaches-Non-HDLcholesterol-ApoB-RemnantsAdaptedfromAmericanDiabetesAssociation.DiabetesCare.2000;23(suppl1):S57-S60;ChaitA,BrunzellJD.

DiabetesMellitus.AFundamentalandClinicalText.Philadelphia:LippincottRaven,1996;772-779;

EuropeanDiabetesPolicyGroup1999.DiabetMed.1999;16:716-730.TreatmentStrategiesforDiabeCHDPreventionTrialswithStatinsinDiabeticSubjects:SubgroupAnalysesPrimaryPreventionAFCAPS/TexCAPSSecondaryPreventionCARE4SLIPIDBaseline

LDL-C,

mg/dl

(mmol/L)*ValuesforoverallgroupAdaptedfromDownsJRetal.JAMA1998;279:1615-1622;GoldbergRBetal.Circulation1998;98:2513-2519;

Py?r?l?Ketal.DiabetesCare1997;20:614-620;HaffnerSMetal.ArchInternMed1999;159:2661-2667;TheLong-TermInterventionwithPravastatininIschaemicDisease(LIPID)StudyGroup.NEnglJMed1998;339:1349-1357.DrugNo.LDL-C

LoweringLovastatinPravastatinSimvastatinPravastatin25%28%36%25%*150(3.9)136(3.6)186(4.8)150*(3.9)239586202782StudyCHDPreventionTrialswithStaCHDPreventionTrialswithStatinsinDiabeticSubjects:SubgroupAnalyses(cont’d)PrimaryPreventionAFCAPS/TexCAPSSecondaryPreventionCARE4SLIPID4S-ExtendedCHDRisk

Reduction

(overall)DrugNo.LovastatinPravastatinSimvastatinPravastatinSimvastatin43%25%(p=0.05)55%(p=0.002)19%42%(p=0.001)37%23%32%25%32%239586202782483CHDRisk

Reduction

(diabetes)StudyAdaptedfromDownsJRetal.JAMA1998;279:1615-1622;GoldbergRBetal.Circulation1998;98:2513-2519;Py?r?l?Ketal.DiabetesCare1997;20:614-620;TheLong-TermInterventionwithPravastatininIschaemicDisease(LIPID)StudyGroup.NEnglJMed1998;339:1349-1357;HaffnerSMetal.ArchInternMed1999;159:2661-2667.CHDPreventionTrialswithStaAdaptedfromPy?r?l?etal.Diabetes

Care1997;20:614-620.Diabeticvs.NondiabeticPatientsin4S00.20.40.81.4RelativeRiskwith95%ConfidenceIntervalsTotalmortality0.61.01.2ReducedIncreasedCHDmortalitySimvastatinBetterPlacebo

BetterMajorCHDeventCerebrovasculareventAnyatheroscleroticeventP=0.001

P=0.087P<0.0001

P=0.242P<0.0001

P=0.002P=0.097

P=0.071P<0.0001

P=0.018NodiabetesDiabetesAdaptedfromPy?r?l?etal.Di1.00.90.80.70.60.50ProportionwithoutMajorCHDEventYearsSinceRandomization0123456AdaptedfromPy?r?l?etal.DiabetesCare1997;20:614-620.DiabetesbyHx,simvastatin

DiabetesbyHx,placeboNodiabetesbyHx,simvastatin

NodiabetesbyHx,placeboP=0.002P=0.0001MajorCoronaryEventsin4SPatientswithorwithoutDiabetesbyHistory(n=202)1.0ProportionwithoutMajorCHAdaptedfromHaffnerSMetal.Arch

Intern

Med1999;159:2661-26674S:ExtendedDiabeticSubgroupAnalysis:

Diabetes(n=483;251onSimvastatin)—FastingGlucose>7mmol/L(126mg/dl)0.00.20.40.81.4RelativeRiskCHDmortality

(P=0.26)Totalmortality

(P=0.34)Revascularizations(P=0.005)Majorcoronaryevents(P=0.001)0.61.01.20.720.790.520.58AdaptedfromHaffnerSMetal.AdaptedfromHaffnerSMetal.Arch

Intern

Med1999;159:2661-26674S:ExtendedDiabeticSubgroupAnalysis:

ImpairedFastingGlucose(n=678;343onSimvastatin)—FastingGlucose6.0-6.9mmol/L(110-125mg/dl)0.00.20.40.81.4RelativeRiskCHDmortality

(P=0.007)Totalmortality

(P=0.02)Revascularizations(P=0.01)Majorcoronaryevents(P=0.003)0.61.01.20.450.570.570.62AdaptedfromHaffnerSMetal.SimvastatinNormalfasting

glucoseBedDays(per100Pts)4S:EffectofStatinTherapyonHospitalStayAdaptedfromHermanWHetal.Diabetes

Care1999;22:1771-1778.55%

(p<0.001)PlaceboSimvastatinImpairedfasting

glucosePlaceboSimvastatinPlaceboDiabetes

mellitus38%

(p=0.005)28%

(p<0.001)SimvastatinNormalfasting

glucCARE:MajorCoronaryEventsin

DiabeticSubgroupsAdaptedfromGoldbergRBetal.Circulation1998;98:2513-2519.4535302520151050PercentwithEventNoDiabetesbyHistoryDiabetesbyHistoryFollow-upTime(years)PercentwithEvent4535302520151050Follow-upTime(years)01234650123465PlaceboPravastatinPravastatinPlaceboRelativerisk=0.75

P=0.05Relativerisk=0.77

P<0.001CARE:MajorCoronaryEventsi%RiskReductionAFCAPS/TexCAPS:SubgroupAnalysisDownsJRetal.JAMA1998;279:1615-1622.MenWomenOlderSmokersHTNDiabetes-37-46-31-58-38-42LovastatinReducedtheRiskofAcuteMCE%RiskReductionAFCAPS/TexCAPSCARE:MajorCoronaryEventsin

DiabeticSubgroupsAdaptedfromGoldbergRBetal.Circulation1998;98:2513-2519.454035302520151050PercentwithEventNoDiabetesbyHistoryDiabetesbyHistoryFollow-upTime(years)PercentwithEventFollow-upTime(years)01234650123465PlaceboPravastatinPravastatinPlaceboRelativerisk=0.75

P=0.05Relativerisk=0.77

P<0.001454035302520151050CARE:MajorCoronaryEventsiPer-Patient%ofGraftsPOST-CABG:EffectofAggressiveLipidLoweringonProgressioninaDiabeticSubgroupHoogwerfBJetal.Diabetes.1999;48:1289-1294.Aggressive

RxModerate

RxAggressive

RxModerate

RxDiabetes(n=116)NoDiabetes(n=1235)99%CI

(0.20-1.19)99%CI

(0.46-0.79)51%40%Per-Patient%ofGraftsPOST-CACHDPreventionTrialswithFibratesinDiabeticSubjects:SubgroupAnalysesPrimaryPreventionHelsinki

HeartStudySecondaryPreventionVA-HITBaseline

LDL-C,

mg/dl

(mmol/L)No.LDL-C

LoweringAdaptedfromKoskinenPetal.DiabetesCare1992;15:820-825;

RubinsHBetal.NEnglJMed1999;341:410-418.Drug

DoseStudyCHD

ReductionGemfibrozil

(1200mg/d)Gemfibrozil

(1200mg/d)135

627

203

(5.2)112

(2.9)

68%

NS24%p=0.05

6%

–

CHDPreventionTrialswithFibPrimaryCHD*PreventioninType2DiabeticPatients:TheHelsinkiHeartStudy5-YearIncidenceofCHD(%)Type2

(n=135)*MyocardialinfarctionorcardiacdeathAdaptedfromKoskinenPetal.DiabetesCare1992;15:820-825.Others

(n=3946)Type2onPlacebo

(n=76)Type2on

Gemfibrozil

(n=59)P<0.027.43.310.53.4P=0.19PrimaryCHD*PreventioninTypYearCumulativeIncidence(%)VA-HIT:IncidenceofDeathfromCHD

andNonfatalMIPlaceboAdaptedfromRubinsHBetal.NEnglJMed1999;341:410-418.GemfibrozilYearCumulativeIncidence(%)VAVA-HIT:DeathDuetoCHD,NonfatalMI,andConfirmedStrokeinDiabeticPatientsDiabetes

Nodiabetes

Placebo**Valuesarenumberswithevents/totalnumbers(%)AdaptedfromRubinsHBetal.NEnglJMed1999;341:410-418.Risk

ReductionGemfibrozil*PValue116/318

(36)214/949

(23)88/309

(28)170/

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