Use of fenofibrate on cardiovascular outcomes in statin users ...

In this propensity weighted cohort study, the addition of fenofibrate to statin treatment in adults with metabolic syndrome was associated with ... Skiptomaincontent Research Useoffenofibrateon... Useoffenofibrateoncardiovascularoutcomesinstatinuserswithmetabolicsyndrome:propensitymatchedcohortstudy CCBYNCOpenaccess Research Useoffenofibrateoncardiovascularoutcomesinstatinuserswithmetabolicsyndrome:propensitymatchedcohortstudy BMJ 2019; 366 doi:https://doi.org/10.1136/bmj.l5125 (Published27September2019) Citethisas:BMJ2019;366:l5125 Article Relatedcontent Metrics Responses Peerreview NamHoonKim,associateprofessor1,KiHoonHan,professor2,JimiChoi,statistician3,JuneyoungLee,professor3,SinGonKim,professor11DivisionofEndocrinologyandMetabolism,DepartmentofInternalMedicine,KoreaUniversityAnamHospital,KoreaUniversityCollegeofMedicine,126-1,Anam-dong5-ga,Seongbuk-gu,Seoul02841,RepublicofKorea2DepartmentofInternalMedicine,UlsanUniversity,Seoul,RepublicofKorea3DepartmentofBiostatistics,KoreaUniversityCollegeofMedicine,Seoul,RepublicofKoreaCorrespondenceto:SGKimk50367{at}korea.ac.krAccepted23July2019AbstractObjectiveToinvestigatewhetherfenofibrateasadd-ontostatintreatmentreducepersistentcardiovascularriskinadultswithmetabolicsyndromeinarealworldsetting.DesignPropensitymatchedcohortstudy.SettingPopulationbasedcohortinKorea.Participants29 771adultswithmetabolicsyndrome(≥40years)receivingstatintreatment.2156participantsreceivingcombinedtreatment(statinplusfenofibrate)wereweightedbasedonpropensityscoreina1:5ratiowith8549participantsusingstatinonlytreatment.MainoutcomemeasurePrimaryoutcomewascompositecardiovasculareventsincludingincidentcoronaryheartdisease,ischaemicstroke,anddeathfromcardiovascularcauses.ResultsTheincidencerateper1000personyearsofcompositecardiovasculareventswas17.7(95%confidenceinterval14.4to21.8)inthecombinedtreatmentgroupand22.0(20.1to24.1)inthestatingroup.Theriskofcompositecardiovasculareventswassignificantlyreducedinthecombinedtreatmentgroupcomparedwithstatingroup(adjustedhazardratio0.74,95%confidenceinterval0.58to0.93;P=0.01).Thesignificancewasmaintainedintheon-treatmentanalysis(hazardratio0.63,95%confidenceinterval0.44to0.92;P=0.02).Theriskofincidentcoronaryheartdisease,ischaemicstroke,andcardiovasculardeathwaslowerinthecombinedtreatmentgroupthanstatingroupbutwasnotsignificant.Participantcharacteristicsdidnotappeartobeassociatedwiththelowriskofcompositecardiovasculareventswithcombinedtreatment.ConclusionInthispropensityweightedcohortstudyofadultswithmetabolicsyndrome,theriskofmajorcardiovasculareventswassignificantlylowerwithfenofibrateasadd-ontostatintreatmentthanwithstatintreatmentalone.IntroductionMetabolicsyndromeisaclusterofinterrelatedriskfactorsthatleadstometabolicdysregulationandatheroscleroticcardiovasculardiseases.1Theincreasedriskofcardiovasculardiseaseinpeoplewithmetabolicsyndromehasbeenwellestablishedbyobservationalstudiesandmeta-analyses,234andconsideredtobepartlyattributabletotheaccompanyingatherogenicdyslipidaemia,whichischaracterisedbyincreasedtriglyceridelevels,smalldenselowdensitylipoproteinparticleswithlowlevelsofhighdensitylipoprotein(HDL)cholesterol.56Abundantevidenceshowsthatloweringlowdensitylipoprotein(LDL)cholesterolconcentrationswithstatinsistheprimarytreatmentoptionforminimisingcardiovasculardiseaseinpeopleatrisk,includingthosewithatherogenicdyslipidaemia.789Inmanyclinicaltrialsandobservationalstudies,substantialcardiovascularriskpersisted(residualcardiovascularrisk)despiteongoingstatintreatment.101112Fenofibrate,aperoxisomeproliferatoractivatedreceptor-αagonist,hasbeensuggestedasanimportanttreatmentoptioninthemanagementofdyslipidaemiaowingtoitseffectsonhypertriglyceridaemiaandlowHDLcholesterolconcentrations.13Althoughlargerandomisedclinicaltrialsoffenofibrate,includingtheFenofibrateInterventionandEventLoweringinDiabetes(FIELD)trialandtheActiontoControlCardiovascularRiskinDiabetes(ACCORD)-Lipidtrialfailedtoshowareductionintheprimaryoutcomeofmajorcardiovasculareventsinpopulationswithdiabetesbutastatisticallysignificantcardiovascularriskreductionwasobservedinsubgroupswithatherogenicdyslipidaemia.141516Twometa-analysesoffibratesalsoindicatedthattheassociatedreductionofcardiovasculareventswouldbenefitpeoplewithatherogenicdyslipidaemia.1718ThepreviousstudiesweremainlyconductedinWesternpopulationswithhighcardiovascularrisk,whichlimitsgeneralisabilityoftheresultstootherethnicpopulationsortopeoplewithabroaderrangeofcardiovascularrisk.GiventhatatherogenicdyslipidaemiaismoreprevalentinpeopleofEastAsianorigin,inwhomageneticsusceptibilitytopooreliminationofbloodtriglycerideshasbeenreported,19studybasedevidencetoevaluatefenofibrateefficacyincardiovascularriskreductioninthispopulationisnecessary.Weevaluatedtheeffectsoffenofibratetreatmentonmajorcardiovasculareventsinadultswithmetabolicsyndromeusingstatinsinarealworldsetting.Wealsoassessedthedegreeofbenefitfromcombinedtreatmentwithstatinandfenofibrateinresidualcardiovascularriskreduction.ThisstudywasconductedaspartoftheEffectivenessofFenofibrateTherapyinResidualCardiovascularRiskReductionintheRealWorldSetting(ECLIPSE-REAL)study.MethodsDatasourcesWeusedtheKoreanNationalHealthInsuranceService-HealthScreeningCohort(NHIS-HEALS),whichincluded514 866Koreans.Thiscohortrepresents10%ofarandomselectionofscreenedparticipantsaged40to79intheindexyears2002or2003andfollowed-upto2015.Thisdatabasecontainslongitudinalinformation,includingpersonaldata,medicalandpharmaceuticalrecords,diseasediagnoses(internationalclassificationofdiseases,10threvision),medicalprocedures,hospitaladmissions,prescribeddrugs,healthexaminationdata(eg,anthropometricmeasuresandlaboratorydata),anddeathrecords.Thecohortprotocolhasbeendescribedpreviously.20PatientselectionandpropensityscorematchingWeselectedadults(≥40years)fromtheoriginaldatabasewhohadusedstatinsforatleastthreemonthsfrom1January2007to31December2014,asthenationalhealthexaminationprogrammesincludedlipidprofilesfromJanuary2007.Adultswithoutdocumentedlipidprofilesbeforeinitiationofstatintreatmentwereexcluded.Potentiallyeligibleparticipantswerethenselectedwhometthemetabolicsyndromecriteria,asdefinedbytheAdultTreatmentPanelIIIguidelines,beforetheindexdate.21Waistcircumferencecut-offpointsformetabolicsyndromewereinaccordancewiththeAsianstandardsetbytheWorldHealthOrganization.22Thus,adultswithmetabolicsyndromewererequiredtomeetthreeormoreofthefollowingcriteria:waistcircumference≥90cminmenand≥80cminwomen,serumtriglyceridelevel≥1.7mmol/L,HDLcholesterollevel<1.0mmol/Linmenand<1.3mmol/Linwomen,fastingglucoselevel≥5.6mmol/Lorantidiabetestreatment,andbloodpressure≥130/85mmHgortreatmentforhypertension.Of24 857selectedadults,2457hadreceivedfenofibrateforatleastthreemonthsduringthefollow-upperiod.Propensityscorematching(maximum1:5)wasdoneforthosewhohadusedfenofibrate(combinedtreatmentwithstatinandfenofibrate)andthosewhohadnot(statintreatmentonly).Thepropensityscoreanalysisbalancescovariatesbetweenstudygroupsofobservationaldatausingapropensityscore,whichistheconditionalprobabilityofassignmenttoaparticulargroupgivenobservedcovariatesonly.23Theuseofapropensityscorewithtime-to-eventdatabyeitherweightingormatchingtechniquesiswellestablished.24Wederivedthepropensityscoremodelfromamultiplelogisticregressionthatincludedage,sex,waistcircumference;fastingglucoselevel;systolicbloodpressure;serumcreatininelevel;smokingstatus(current,former,ornever);alcoholconsumption(≥3times/week,≤2times/week,ornever);physicalactivity(≥3times/week,≤2times/week,ornever);pre-existingcardiovasculardisease,includingcoronaryheartdisease,ischaemicstroke,andheartfailure;antithromboticagents;antihypertensiveagents;statinintensitybasedontheaverageexpectedLDLcholesterolresponse8;anddurationofstatintreatmentbeforetheindexdate.BaselineLDLcholesterollevels(<2.59,2.59–3.36,3.36–4.14and≥4.14mmol/L),HDLcholesterollevels(<0.88,≥0.88mmol/L),andtriglyceridelevels(<2.3,≥2.3mmol/L)werealsousedasindependentvariablesinthepropensityscoremodel.Weusedagreedynearestneighbourmatchingonthelogitofpropensityscoreusingcalipersofwidth0.2ofthestandarddeviationofthelogitofthepropensityscore.Thecut-offpointsforHDLcholesterolandtriglycerideconcentrationwerederivedfromthesubgroupswhobenefitedfromfenofibratetreatmentoncardiovascularoutcomesinpreviousrandomisedcontrolledtrials,includingACCORD-LipidandFIELD.1525Overall,weselected2156adultsfromthecombinedtreatmentgroupand8549fromthestatinonlygroup.Supplementaryfigure1showsthedistributionofpropensityscores,indicatingthatthetwogroupswerewellmatched.OutcomemeasuresThecardiovascularoutcomesofinterestwereincidentcoronaryheartdisease(ICD-10codesI20-I25plusacoronaryarteryangiographyprocedure),ischaemicstroke(ICD-10codesI63-66withanexaminationofbrainimagingstudiesorprocedures),anddeathfromcardiovasculardisease(ICDcodesI00-I99).Compositecardiovasculardiseaseeventsincludedanyoftheprespecifiedcardiovascularevents.Eachparticipantwasfollowed-upfromtheindexdatetotheearliestoccurrenceofanystudyoutcome,death,orendofthestudyperiod(31December2015).Wedefinedtheindexdateasthreemonthsaftertheinitiationoftreatment.StatisticalanalysisDataarepresentedasmeans(standarddeviations)forcontinuousvariablesandnumbers(percentages)forcategoricalvariables.Ageneralisedestimatingequationformatcheddatawasusedtocomparepersonalandclinicalcharacteristicsbetweengroups.Wecalculatedincidenceratesper1000personyearswithcorresponding95%confidenceintervalsfortheindividualoutcomes.AstratifiedCoxproportionalhazardsregressionmodelformatcheddatawasusedtoevaluatetherelationbetweenthetreatmentsandstudyoutcomes.Inthematchedsampleallabsolutestandardiseddifferencesinbaselinecovariatesbetweenthetwogroupswerelessthan0.1exceptforβblockeruse,diureticsuse,andtriglyceridecategory,whichwerefurtheradjustedforthesubsequentanalyses.Characteristicsforsubgroupanalysisincludedage(≥65,<65years),sex(men,women),waistcircumference(≥90,<90cm),pre-existingcardiovasculardisease,hypertension,type2diabetes,pretreatmentHDLcholesterolconcentration(<0.88,≥0.88mmol/L),triglycerideconcentration(<2.3,≥2.3mmol/L),non-HDLcholesterolconcentrationcalculatedbytotalcholesterolminusHDLcholesterolconcentration(<3.36,≥3.36mmol/L),andon-treatmentLDLcholesterolconcentration(<2.59,≥2.59mmol/L).Toreducesurvivalbiasassociatedwithtimetofenofibrateinitiationafterstatintreatment,wesettheindexdateforpropensityscorematchingtobethesameasthedateofinitiationoffenofibratetreatmentinparticipantsandtheirmatchedcontrols.26Theindexdateforparticipantsinthestatingroupwastheindexdateofmatchedparticipantsinthecombinedtreatmentgroup.StatisticalanalyseswereperformedusingSASsoftware,version9.4(SASInstitute,Cary,NC).WeconsideredatwosidedPvalueof<0.05tobesignificant.PatientandpublicinvolvementPatientswerenotinvolvedinresearchdesignortheoutcomemeasures.Nopatientswereaskedtoadviseoninterpretationorwritingupofresults.Therearenoplanstodisseminatetheresultsoftheresearchtostudyparticipants.ResultsFigure1showstheflowofparticipantsthroughthestudy.Themeanageofparticipantswas62.5yearsandmeanbodymassindexwas25.8.Overall,985(9.2%)participantshadpre-existingcardiovasculardiseaseand4046(37.8%)hadtype2diabetes.Themeandurationofstatintreatmentwas30.2months.Afterpropensityweightedmatching,thebaselinecharacteristicsofthecombinedtreatmentgroupandstatingroupwerewellbalanced(table1),exceptforβblockeruse,diureticuse,andtriglyceridecategory—subsequentanalyseswerethereforeadjustedforthosevariables.HDLcholesterolandtriglyceridewerematchedbyprespecifiedcut-offs(0.88mmol/Landand2.3mmol/L,respectively)forlowerandhigherlevelsofeachvariable.Accordingtothecriteria,atbaseline891(8.3%)hadlowerHDLcholesterollevelsand5604(52.4%)hadhypertriglyceridaemia.Meandurationoffollow-upwas29.7(SD17.7)months.Fig1FlowdiagramofparticipantselectionDownloadfigure Openinnewtab Downloadpowerpoint Table1Baselinecharacteristicsofparticipants.Valuesarepercentages(numbers)unlessstatedotherwiseViewthistable:ViewpopupViewinlineChangesinserumlipidprofileswithtreatmentSupplementarytable1showschangesinlipidprofilesineachtreatmentgroup.Atbaseline,meanLDLandHDLcholesterolconcentrationswerewellbalancedbetweenthegroups,whereasthemeantriglycerideconcentrationswerehigherinthecombinedtreatmentgroup.On-treatmentLDLandHDLcholesterolconcentrationswerealsosimilarbetweenthegroups(meanLDLcholesterol2.56v2.48mmol/L,meanHDLcholesterol1.33v1.28mmol/L).Thecombinedtreatmentgroupshowedagreaterreductionintriglycerideconcentrationthanthestatingroupandtheachievedmeantriglycerideconcentrationwaslowerinthecombinedtreatmentgroup(1.64v1.85mmol/L).Meannon-HDLcholesterolconcentrationwassimilarbetweenthegroups(3.28v3.32mmol/L).RiskofmajorcardiovasculareventsTable2showsincidenceratesper1000personyearsandriskofcardiovascularoutcomesbetweenthegroups.Theriskofcoronaryheartdisease(hazardratio0.82,95%confidenceinterval0.62to1.09;P=0.2),ischaemicstroke(0.74,0.49to1.12;P=0.2),andcardiovasculardeath(0.48,0.18to1.23;P=0.1)wasnon-significantlylowerinthecombinedtreatmentcomparedwithstatingroup.Duringsixyearsoffollow-up,however,theriskofcompositeendpointswassignificantlyreducedinthecombinedtreatmentgroupcomparedwithstatingroup(0.74,0.58to0.93;P=0.01)(table2,fig2).Significancewasmaintainedintheon-treatmentanalysis(0.63,0.44to0.92;P=0.02).Table2CardiovascularoutcomesbytreatmentgroupViewthistable:ViewpopupViewinlineFig2Kaplan-Meiersurvivalcurvesforcompositecardiovascularoutcomesbetweentreatmentgroupsinallparticipants(top),participantswithhightriglycerideorlowhighdensitylipoproteincholesterolconcentrations(middle),andparticipantswithlowtriglycerideandhighhighdensitylipoproteincholesterolconcentrations(bottom)Downloadfigure Openinnewtab Downloadpowerpoint SubgroupanalysisforriskofcompositecardiovasculareventsInmostsubgroups,combinedtreatmentwasassociatedwithalowerriskofcompositecardiovasculareventscomparedwithstatintreatment(fig3).ThehazardratiosofcompositecardiovasculareventswerelowerinthosewithhightriglycerideorlowHDLcholesterollevelscomparedwiththosewithlowtriglycerideandhighHDLcholesterollevels(fig2),althoughtheresultswerenon-significant(Pforinteraction=0.2).Fig3Hazardratioofcompositecardiovasculareventsbysubgroups.CVD=cardiovasculardisease;LDL=lowdensitylipoprotein;HDL=highdensitylipoproteinDownloadfigure Openinnewtab Downloadpowerpoint SensitivityanalysesWeperformedasensitivityanalysiswithpropensityscorematchingbasedonnon-HDLcholesterolcategory(<3.36,3.36–4.14,4.14–4.92,≥4.92mmol/L).Thedirectionandstatisticalsignificanceofthissensitivityanalysiswascomparabletothoseoftheprimaryanalysis(supplementarytable2).Theriskofcompositecardiovasculareventswassignificantlylowerinthecombinedtreatmentgroupcomparedwithstatingroup(0.77,0.62to0.96;P=0.02)andintheon-treatmentanalysis(0.67,0.46to0.96;P=0.03).SafetyBetweenthegroupssimilarproportionsofparticipantshadliverenzyme(aspartateaminotransferaseandalanineaminotransferase)levelsmorethantwicetheupperlimitofthenormalrange(supplementarytable3).Withinsixmonthsaftertreatmentmeanserumcreatininelevelhadincreasedfrom88.9to91.0μmol/Linthecombinedtreatmentgroupbuthaddecreasedfrom88.0to85.3μmol/Linthestatingroup(supplementarytable4).Changeovertimewasnot,however,significantlydifferentbetweenthegroups(P=0.4).Inaddition,theproportionofparticipantswithserumcreatininelevelsmorethandoublethebaselinevaluewasslightly,butnotsignificantly,higherinthecombinedtreatmentgroupcomparedwithstatingroup(1.4%and0.8%)withinsixmonths.DiscussionInthispropensityweightedcohortstudy,theadditionoffenofibratetostatintreatmentinadultswithmetabolicsyndromewasassociatedwithasignificantlylowerriskofmajorcardiovasculareventscomparedwithstatintreatmentalone.InterpretationandimplicationsWiththeadoptionofstatintreatmenttomanagedyslipidaemiaandcardiovascularrisk,strategiesforresidualcardiovascularriskafterstatintreatmenthaveremainedimportant.1011Inrecentlargerandomisedclinicaltrials,certainoldandnoveldrugs,suchasezetimibeandproproteinconvertasesubtilisin/kexintype9inhibitors,haveshownsomepromisingresultsinresidualcardiovascularriskreduction;however,thosetrialsonlyincludedparticipantswithhighcardiovascularriskorestablishedcoronarydiseases.272829Evidencefavouringlipidmodifyingagentsoverstatinsforresidualcardiovascularriskreductionininpeoplewithabroadrangeofcardiovascularrisk,suchaspeoplewithmetabolicsyndrome,islimited.Fenofibrate,aperoxisomeproliferatoractivatedreceptor-α(PPAR-α)agonist,hasbeenproposedasapotentagentinthetreatmentofdyslipidaemia,especiallyinthecontextofhypertriglyceridaemiaandlowHDLcholesterollevels.Numerouspreclinicalandclinicalstudieshaveshownitsbenefitsonatherogenesis,whichincludefavourableeffectsonlipoproteinmetabolism,inflammation,andvasculardysfunction.133031Randomisedclinicaltrialshavenotprovidedevidenceforbeneficialeffectsonhardcardiovascularoutcomescomparedwithstatinshowever.IntheACCORD-Lipidtrial,therateofmajorcardiovascularoutcomeswasnotreducedbytheadditionoffenofibratetosimvastatincomparedwithsimvastatinalone.Onlyseveralsubpopulations,suchasmenandpeoplewithhightriglycerideandlowHDLcholesterolconcentrationsatbaselineseemedtobenefitfromfenofibrateadd-ontreatment.15Incontrast,ourstudyinarealworldsettingshowedthatfenofibratemightplayaroleinresidualcardiovascularriskreduction.Itisunclearwhythecardiovascularbenefitsoffenofibrateplusstatinthatweobservedinourcohortstudywasnotshowninearlierrandomisedcontrolledtrials.Althoughafundamentaldifferenceandaninferiorityintheevidencelevelexistbetweenourcohortstudyandtherandomisedclinicaltrials,westudiedagroupofpeoplewithmetabolicsyndromeandawiderangeofcardiovascularrisk,including9%withpre-existingcardiovasculardiseaseand38%withtype2diabetes.Thustherateofprimaryoutcomewaslowerinourstudy(5.5%duringsixyearsinthestatingroup)thanintheACCORD-Lipidtrial(annualrate2.4%inplacebogroup).Thesedifferencesinpopulationsandcardiovasculardiseaseriskmighthavemitigatedtheeffectsofstatinsinourstudysothatthebenefitsoffenofibrateonreductionofcardiovasculareventsbecamemoreapparent.Furthermore,intheFIELDandACCORD-Lipidtrialsandameta-analysiscomprisingotherfibrates,participantswithmetabolicsyndromeoritscomponents,suchashypertension,wereidentifiedandcategorisedintoarespondergroupforfenofibratetreatment,172532indicatingthatwerecruitedamoreappropriatetargetpopulationforfenofibratetreatmentinourstudy.Notably,mediantriglycerideconcentrationsatbaselineweresubstantiallyhigherinourstudy(2.35mmol/L)thanthoseintheFIELDandACCORD-Lipid(1.73mmol/Land1.83mmol/L,respectively)trials.AsonlyafewclinicaltrialsoffenofibrateorotherPPAR-αagonistshavebeendoneinAsianpopulations,wedidnothaveenoughdatatocomparetheeffectsoffenofibrateindifferentethnicgroups.Nevertheless,peopleofAsianoriginaremetabolicallymoresusceptibletohypertriglyceridaemiaandmetabolicsyndromethanotherethnicities.Forexample,morethan30%ofadultsinKorea,inwhombodymassindexisconsiderablylower,hadmetabolicsyndromeofasimilardegreetoadultsintheUSA.33Inaddition,aspecificAPOA5genepolymorphismpredisposingtohighfastingandpostprandialtriglyceridelevelswasreportedtobemoreprevalentinKoreans,eveninhealthy,non-obesepeople,19whichisconsistentwiththehighprevalenceofhypertriglyceridaemiainthispopulation.34Furthermore,triglycerideconcentrationasanindependentriskfactorofcardiovasculardisease,especiallycoronaryheartdisease,iswellestablishedinAsianpopulations.3536Consideringthattheantiatheroscleroticactionoffibratesprimarilyreducesthesecretionoftriglyceride-richverylowdensitylipoproteinparticlesbyenhancingfattyacidoxidationandreducinghepaticlipogenesis,37wesuggestthatourparticipantsweregoodcandidatesforshowingthecardiovascularbenefitsoffenofibratetreatment.Insubgroupanalyses,thehazardratiosforthecompositeoutcomeofincidentcoronaryheartdisease,ischaemicstroke,anddeathfromcardiovascularcauseswerelowerinparticipantsinthecombinedtreatmentgroupwithlowHDLcholesterolorhightriglycerideconcentrationsthaninthosewithoutthesecharacteristics,eventhoughthePvalueforinteractionwasnon-significantbetweenpairedgroupsinindividualsubgroupanalyses.Thetreatmenteffectsoffenofibratewerenoticeableonsignsofmetabolicsyndromesuchashypertension,indicatingthatindividualsymptomsmightprovideinformationrelatedtothebeneficialtreatmenteffectsoffenofibrate,whichhasalreadybeensupportedbyotherpreviousstudies.161718Afewsafetyconcernshavebeenraisedaboutusingfenofibratecombinedwithstatins.1438Theseincludeanincreaseofserumcreatininelevelsaswellasanincreasedriskofmyopathyormyalgia.Inourstudy,meanserumcreatininelevelwasincreasedwithinsixmonthsaftercombinedtreatmentandgraduallydecreased.Themeanchangeinserumcreatininelevelfrombaselineinthecombinedtreatmentgroupwasonly2.4%,however,andnostatisticallysignificantdifferencewasfoundinchangesovertimecomparedwiththestatingroup.Wewerenotabletodeterminetheeffectsonmyopathyormyalgiaowingtoalackofinformationinthedatabase.Instead,weidentifiedchangesintransaminaselevelsandfoundthatmeanlevelsweresimilarbetweenthegroupsduringfollow-up,aswastheproportionofparticipantswithtransaminaselevelsmorethantwicetheupperlimitofthenormalrange.StrengthsandweaknessesofthisstudyImmortalandtimelagbiaseshavebeenproblematicinpharmacoepidemiologicalstudies.3940Toexcludesuchbiases,wesettheindexdateforpropensityscorematchingtobethesameasthedateforstartingfenofibratetreatmentinparticipantsandtheirmatchedcontrols.Inaddition,wealsoanalysedtheoutcomesonlyduringthefenofibratetreatmentperiodinparticipantsandmatchedcontrolsandfoundthatthestatisticallysignificantreductionincardiovasculareventswithcombinedtreatmentwasmaintained.Theotherpossiblebiasisthatsomevariables(βblockeruse,diureticuse,andtriglyerideconcentrations)werenotbalancedatbaselineevenaftermatching.Wethereforeadjustedforthosevariablesinfurtheranalyses.ConclusionWefoundabeneficialroleofadd-onfenofibratetostatintreatmentincardiovascularriskreductioninadultswithmetabolicsyndrome.WhatisalreadyknownonthistopicRandomisedclinicaltrialsoffenofibratetreatmenthavefailedtoshowareductioninriskofmajorcardiovasculareventsinpeoplewithdiabetes,butastatisticallysignificantcardiovascularriskreductionwasobservedinsubgroupswithatherogenicdyslipidaemiaMeta-analysesoffibratesalsoindicatedthatpeoplewithatherogenicdyslipidaemiawouldbenefitfromfibratesoncardiovasculareventsreductionRealworldevidencewasinsufficienttoprovetheefficacyoffenofibrateincardiovascularriskreductionespeciallyinpeopleofEastAsianoriginwhoarereportedtobegeneticallysusceptibletopooreliminationofbloodtriglycerideWhatthisstudyaddsTheriskofmajorcardiovasculareventswasreducedinadultswithmetabolicsyndromeusingfenofibrateasadd-ontostatintreatmentAcknowledgmentsWethanktheparticipantsoftheKoreanHealthInsuranceCohortstudyandtheNationalHealthInsuranceServicewhodevelopedtheNHIS-HEALS(2002-15)database(NHIS-2017-2-592).TheviewsexpressedinthisarticlearethoseoftheauthorsanddonotnecessarilyrepresenttheofficialpositionofthedepartmentoftheKoreanNationalHealthInsuranceService.FootnotesContributors:SGKandKHHconceivedanddesignedthestudy.JCanalysedthedata.JLsupervisedthedataanalysis.NHKwrotethemanuscript.SGKsupervisedthestudyandistheguarantor.Allauthorscontributedtothereviewandrevisionofthemanuscript.Thecorrespondingauthoratteststhatalllistedauthorsmeetauthorshipcriteriaandthatnoothersmeetingthecriteriahavebeenomitted.Funding:ThisstudywassupportedbytheAbbottLaboratoriesKorea.Thefundershadnoroleinthedesignandconductofthestudy;analysis,preparation,review,andapprovalofthemanuscript.Competinginterests:AllauthorshavecompletedtheICMJEuniformdisclosureformatwww.icmje.org/coi_disclosure.pdfanddeclare:supportfromAbbottLaboratoriesKorea;nofinancialrelationshipswithanyorganisationsthatmighthaveaninterestinthesubmittedworkinthepreviousthreeyears;andnootherrelationshipsoractivitiesthatcouldappeartohaveinfluencedthesubmittedwork.Ethicalapproval:ThisstudywasapprovedbytheinstitutionalreviewboardofKoreaUniversityAnamHospital(IRBNoED17181).DatafromtheNHIScohortdonotinvolveanypersonallyidentifiabledata.ThustheNHISapprovedthecohortstudywithoutinformedconsentfromparticipants.Datasharing:AdditionaldataareavailablethroughapprovalandoversightbytheKoreanNationalHealthInsuranceService.Theleadauthors(NHK,SGK)affirmthatthemanuscriptisanhonest,accurateandtransparentaccountofthestudybeingreported;thatnoimportantaspectsofthestudyhavebeenomitted;andthatanydiscrepanciesfromthestudyasplanned(and,ifrelevant,registered)havebeenexplained.ThisisanOpenAccessarticledistributedinaccordancewiththeCreativeCommonsAttributionNonCommercial(CCBY-NC4.0)license,whichpermitsotherstodistribute,remix,adapt,builduponthisworknon-commercially,andlicensetheirderivativeworksondifferentterms,providedtheoriginalworkisproperlycitedandtheuseisnon-commercial.See:http://creativecommons.org/licenses/by-nc/4.0/.References↵ReavenGM.Bantinglecture1988.Roleofinsulinresistanceinhumandisease.Diabetes1988;37:1595-607.doi:10.2337/diab.37.12.1595. pmid:3056758OpenUrlAbstract/FREEFullText↵IsomaaB,AlmgrenP,TuomiT,etal.Cardiovascularmorbidityandmortalityassociatedwiththemetabolicsyndrome.DiabetesCare2001;24:683-9.doi:10.2337/diacare.24.4.683. pmid:11315831OpenUrlAbstract/FREEFullText↵LakkaHM,LaaksonenDE,LakkaTA,etal.Themetabolicsyndromeandtotalandcardiovasculardiseasemortalityinmiddle-agedmen.JAMA2002;288:2709-2716.dio:doi:10.1001/jama.288.21.2709OpenUrlCrossRefPubMedWebofScience↵GamiAS,WittBJ,HowardDE,etal.Metabolicsyndromeandriskofincidentcardiovasculareventsanddeath:asystematicreviewandmeta-analysisoflongitudinalstudies.JAmCollCardiol2007;49:403-14.doi:10.1016/j.jacc.2006.09.032. pmid:17258085OpenUrlFREEFullText↵TenenbaumA,FismanEZ,MotroM,AdlerY.Atherogenicdyslipidemiainmetabolicsyndromeandtype2diabetes:therapeuticoptionsbeyondstatins.CardiovascDiabetol2006;5:20.doi:10.1186/1475-2840-5-20. pmid:17002798OpenUrlCrossRefPubMed↵GrundySM.Hypertriglyceridemia,atherogenicdyslipidemia,andthemetabolicsyndrome.AmJCardiol1998;81(4A):18B-25B.doi:10.1016/S0002-9149(98)00033-2. pmid:9526809OpenUrlCrossRefPubMedWebofScience↵LaRosaJC,HeJ,VupputuriS.Effectofstatinsonriskofcoronarydisease:ameta-analysisofrandomizedcontrolledtrials.JAMA1999;282:2340-6.doi:10.1001/jama.282.24.2340. pmid:10612322OpenUrlCrossRefPubMedWebofScience↵StoneNJ,RobinsonJG,LichtensteinAH,etal.,AmericanCollegeofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines.2013ACC/AHAguidelineonthetreatmentofbloodcholesteroltoreduceatheroscleroticcardiovascularriskinadults:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines.Circulation2014;129(Suppl2):S1-45.doi:10.1161/01.cir.0000437738.63853.7a. pmid:24222016OpenUrlFREEFullText↵CatapanoAL,GrahamI,DeBackerG,etal.,ESCScientificDocumentGroup.2016ESC/EASGuidelinesfortheManagementofDyslipidaemias.EurHeartJ2016;37:2999-3058.doi:10.1093/eurheartj/ehw272. pmid:27567407OpenUrlCrossRefPubMed↵FruchartJC,SacksF,HermansMP,etal.TheResidualRiskReductionInitiative:acalltoactiontoreduceresidualvascularriskinpatientswithdyslipidemia.AmJCardiol2008;102(Suppl):1K-34K.doi:10.1016/j.amjcard.2008.10.002. pmid:19068318OpenUrlCrossRefPubMedWebofScience↵SampsonUK,FazioS,LintonMF.ResidualcardiovascularriskdespiteoptimalLDLcholesterolreductionwithstatins:theevidence,etiology,andtherapeuticchallenges.CurrAtherosclerRep2012;14:1-10.doi:10.1007/s11883-011-0219-7. pmid:22102062OpenUrlCrossRefPubMed↵RidkerPM,GenestJ,BoekholdtSM,etal.,JUPITERTrialStudyGroup.HDLcholesterolandresidualriskoffirstcardiovasculareventsaftertreatmentwithpotentstatintherapy:ananalysisfromtheJUPITERtrial.Lancet2010;376:333-9.doi:10.1016/S0140-6736(10)60713-1. pmid:20655105OpenUrlCrossRefPubMedWebofScience↵TenenbaumA,FismanEZ.Fibratesareanessentialpartofmodernanti-dyslipidemicarsenal:spotlightonatherogenicdyslipidemiaandresidualriskreduction.CardiovascDiabetol2012;11:125.doi:10.1186/1475-2840-11-125. pmid:23057687OpenUrlCrossRefPubMed↵KeechA,SimesRJ,BarterP,etal.,FIELDstudyinvestigators.Effectsoflong-termfenofibratetherapyoncardiovasculareventsin9795peoplewithtype2diabetesmellitus(theFIELDstudy):randomisedcontrolledtrial.Lancet2005;366:1849-61.doi:10.1016/S0140-6736(05)67667-2. pmid:16310551OpenUrlCrossRefPubMedWebofScience↵GinsbergHN,ElamMB,LovatoLC,etal.,ACCORDStudyGroup.Effectsofcombinationlipidtherapyintype2diabetesmellitus.NEnglJMed2010;362:1563-74.doi:10.1056/NEJMoa1001282. pmid:20228404OpenUrlCrossRefPubMedWebofScience↵HermansMP.Impactoffenofibrateontype2diabetespatientswithfeaturesofthemetabolicsyndrome:subgroupanalysisfromFIELD.CurrCardiolRev2010;6:112-8.doi:10.2174/157340310791162686. pmid:21532777OpenUrlCrossRefPubMed↵JunM,FooteC,LvJ,etal.Effectsoffibratesoncardiovascularoutcomes:asystematicreviewandmeta-analysis.Lancet2010;375:1875-84.doi:10.1016/S0140-6736(10)60656-3. pmid:20462635OpenUrlCrossRefPubMedWebofScience↵BruckertE,LabreucheJ,DeplanqueD,TouboulPJ,AmarencoP.Fibrateseffectoncardiovascularriskisgreaterinpatientswithhightriglyceridelevelsoratherogenicdyslipidemiaprofile:asystematicreviewandmeta-analysis.JCardiovascPharmacol2011;57:267-72.doi:10.1097/FJC.0b013e318202709f. pmid:21052016OpenUrlCrossRefPubMed↵JangY,KimJY,KimOY,etal.The-1131T-->CpolymorphismintheapolipoproteinA5geneisassociatedwithpostprandialhypertriacylglycerolemia;elevatedsmall,denseLDLconcentrations;andoxidativestressinnonobeseKoreanmen.AmJClinNutr2004;80:832-40.doi:10.1093/ajcn/80.4.832. pmid:15447887OpenUrlAbstract/FREEFullText↵SeongSC,KimYY,ParkSK,etal.Cohortprofile:theNationalHealthInsuranceService-NationalHealthScreeningCohort(NHIS-HEALS)inKorea.BMJOpen2017;7:e016640.doi:10.1136/bmjopen-2017-016640. pmid:28947447OpenUrlAbstract/FREEFullText↵ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.ExecutiveSummaryofTheThirdReportofTheNationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection,Evaluation,AndTreatmentofHighBloodCholesterolInAdults(AdultTreatmentPanelIII).JAMA2001;285:2486-97.doi:10.1001/jama.285.19.2486. pmid:11368702OpenUrlCrossRefPubMedWebofScience↵AlbertiKG,EckelRH,GrundySM,etal.,InternationalDiabetesFederationTaskForceonEpidemiologyandPrevention,HationalHeart,Lung,andBloodInstitute,AmericanHeartAssociation,WorldHeartFederation,InternationalAtherosclerosisSociety,InternationalAssociationfortheStudyofObesity.Harmonizingthemetabolicsyndrome:ajointinterimstatementoftheInternationalDiabetesFederationTaskForceonEpidemiologyandPrevention;NationalHeart,Lung,andBloodInstitute;AmericanHeartAssociation;WorldHeartFederation;InternationalAtherosclerosisSociety;andInternationalAssociationfortheStudyofObesity.Circulation2009;120:1640-5.doi:10.1161/CIRCULATIONAHA.109.192644. pmid:19805654OpenUrlAbstract/FREEFullText↵RosenbaumPR,RubinDB.Thecentralroleofthepropensityscoreinobservationalstudiesforcausaleffects.Biometrika1983;70:41-55.doi:10.1093/biomet/70.1.41.OpenUrlCrossRefWebofScience↵AustinPC.Theuseofpropensityscoremethodswithsurvivalortime-to-eventoutcomes:reportingmeasuresofeffectsimilartothoseusedinrandomizedexperiments.StatMed2014;33:1242-58.doi:10.1002/sim.5984. pmid:24122911OpenUrlCrossRefPubMed↵ScottR,O’BrienR,FulcherG,etal.,FenofibrateInterventionandEventLoweringinDiabetes(FIELD)StudyInvestigators.Effectsoffenofibratetreatmentoncardiovasculardiseaseriskin9,795individualswithtype2diabetesandvariouscomponentsofthemetabolicsyndrome:theFenofibrateInterventionandEventLoweringinDiabetes(FIELD)study.DiabetesCare2009;32:493-8.doi:10.2337/dc08-1543. pmid:18984774OpenUrlAbstract/FREEFullText↵ZhouZ,RahmeE,AbrahamowiczM,PiloteL.Survivalbiasassociatedwithtime-to-treatmentinitiationindrugeffectivenessevaluation:acomparisonofmethods.AmJEpidemiol2005;162:1016-23.doi:10.1093/aje/kwi307. pmid:16192344OpenUrlCrossRefPubMedWebofScience↵CannonCP,BlazingMA,GiuglianoRP,etal.,IMPROVE-ITInvestigators.Ezetimibeaddedtostatintherapyafteracutecoronarysyndromes.NEnglJMed2015;372:2387-97.doi:10.1056/NEJMoa1410489. pmid:26039521OpenUrlCrossRefPubMed↵SabatineMS,GiuglianoRP,KeechAC,etal.,FOURIERSteeringCommitteeandInvestigators.Evolocumabandclinicaloutcomesinpatientswithcardiovasculardisease.NEnglJMed2017;376:1713-22.doi:10.1056/NEJMoa1615664. pmid:28304224OpenUrlCrossRefPubMed↵SchwartzGG,StegPG,SzarekM,etal.,ODYSSEYOUTCOMESCommitteesandInvestigators.Alirocumabandcardiovascularoutcomesafteracutecoronarysyndrome.NEnglJMed2018;379:2097-107.doi:10.1056/NEJMoa1801174. pmid:30403574OpenUrlCrossRefPubMed↵FruchartJC.Peroxisomeproliferator-activatedreceptor-alpha(PPARalpha):atthecrossroadsofobesity,diabetesandcardiovasculardisease.Atherosclerosis2009;205:1-8.doi:10.1016/j.atherosclerosis.2009.03.008. pmid:19386311OpenUrlCrossRefPubMedWebofScience↵LeeJM.Nuclearreceptorsresolveendoplasmicreticulumstresstoimprovehepaticinsulinresistance.DiabetesMetabJ2017;41:10-9.doi:10.4093/dmj.2017.41.1.10. pmid:28236381OpenUrlCrossRefPubMed↵KoopalC,VisserenFLJ,WesterinkJ,vanderGraafY,GinsbergHN,KeechAC.Predictingtheeffectoffenofibrateoncardiovascularriskforindividualpatientswithtype2diabetes.DiabetesCare2018;41:1244-50.doi:10.2337/dc17-0968. pmid:29472432OpenUrlAbstract/FREEFullText↵LimS,ShinH,SongJH,etal.IncreasingprevalenceofmetabolicsyndromeinKorea:theKoreanNationalHealthandNutritionExaminationSurveyfor1998-2007.DiabetesCare2011;34:1323-8.doi:10.2337/dc10-2109. pmid:21505206OpenUrlAbstract/FREEFullText↵JeongJS,KwonHS.PrevalenceandclinicalcharacteristicsofdyslipidemiainKoreans.EndocrinolMetab(Seoul)2017;32:30-5.doi:10.3803/EnM.2017.32.1.30. pmid:28345314OpenUrlCrossRefPubMed↵ChenAH,TsengCH.Theroleoftriglycerideincardiovasculardiseaseinasianpatientswithtype2diabetes--asystematicreview.RevDiabetStud2013;10:101-9.doi:10.1900/RDS.2013.10.101. pmid:24380086OpenUrlCrossRefPubMed↵KimEH,LeeJB,KimSH,etal.SerumtriglyceridelevelsandcardiovasculardiseaseeventsinKoreans.Cardiology2015;131:228-35.doi:10.1159/000380941. pmid:25968991OpenUrlCrossRefPubMed↵SchoonjansK,Peinado-OnsurbeJ,LefebvreAM,etal.PPARalphaandPPARgammaactivatorsdirectadistincttissue-specifictranscriptionalresponseviaaPPREinthelipoproteinlipasegene.EMBOJ1996;15:5336-48.doi:10.1002/j.1460-2075.1996.tb00918.x. pmid:8895578OpenUrlCrossRefPubMedWebofScience↵GenestJ,FrohlichJ,SteinerG.Effectoffenofibrate-mediatedincreaseinplasmahomocysteineontheprogressionofcoronaryarterydiseaseintype2diabetesmellitus.AmJCardiol2004;93:848-53.doi:10.1016/j.amjcard.2003.12.022. pmid:15050487OpenUrlCrossRefPubMedWebofScience↵LévesqueLE,HanleyJA,KezouhA,SuissaS.Problemofimmortaltimebiasincohortstudies:exampleusingstatinsforpreventingprogressionofdiabetes.BMJ2010;340:b5087.doi:10.1136/bmj.b5087. pmid:20228141OpenUrlFREEFullText↵SuissaS.LowerriskofdeathwithSGLT2inhibitorsinobservationalstudies:realorbias?DiabetesCare2018;41:6-10.doi:10.2337/dc17-1223. pmid:29263192OpenUrlAbstract/FREEFullTextViewAbstract 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