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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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