Legacy effect of fibrate add-on therapy in diabetic patients with ...

The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study found no evidence of a beneficial effect of statin-fibrate ... Skiptomaincontent Advertisement SearchallBMCarticles Search Legacyeffectoffibrateadd-ontherapyindiabeticpatientswithdyslipidemia:asecondaryanalysisoftheACCORDIONstudy DownloadPDF DownloadePub DownloadPDF DownloadePub Originalinvestigation OpenAccess Published:05March2020 Legacyeffectoffibrateadd-ontherapyindiabeticpatientswithdyslipidemia:asecondaryanalysisoftheACCORDIONstudy LinZhu  ORCID:orcid.org/0000-0001-6883-51761,AndrewHayen1&KatyJ.L.Bell2  CardiovascularDiabetology volume 19,Article number: 28(2020) Citethisarticle 4570Accesses 15Citations 10Altmetric Metricsdetails AbstractBackgroundTheActiontoControlCardiovascularRiskinDiabetes(ACCORD)-Lipidstudyfoundnoevidenceofabeneficialeffectofstatin-fibratecombinedtreatment,comparedtostatinsalone,oncardiovascularoutcomesandmortalityintype2diabetesmellitusafter5 yearsofactivetreatment.However,abeneficialreductioninmajorCVDeventswasshowninapre-specifiedsub-groupofparticipantswithdyslipidemia.Theextendedfollow-upofthistrialprovidestheopportunitytofurtherinvestigatepossiblebeneficialeffectsoffibratesinthisgroupofpatients.Weaimedtoevaluatepossible“legacyeffects”offibrateadd-ontherapyonmortalityandmajorcardiovascularoutcomesinpatientswithdyslipidemia.MethodsTheACCORD-lipidstudywasarandomizedcontrolledtrialof5518participantsassignedtoreceivesimvastatinplusfenofibratevssimvastatinplusplacebo.Afterrandomizedtreatmentallocationhadfinishedattheendofthetrial,allsurvivingparticipantswereinvitedtoattendanextendedfollow-upstudy(ACCORDION)tocontinueprospectivecollectionofclinicaloutcomes.Weundertookasecondaryanalysisoftrialandpost-trialdatainpatientswhohaddyslipidemia.Theprimaryoutcomewasall-causeandcardiovascularmortality,andsecondaryoutcomeswerenonfatalmyocardialinfarction,stroke,congestiveheartfailureandmajorcoronaryheartdisease.Weusedanintention-to-treatapproachtoanalysistomakecomparisonsbetweentheoriginalrandomizedtreatmentgroups.Results853participantswithdyslipidemiahadsurvivedattheendofthetrial.Mostparticipantscontinuedtousestatins,butfewusedfibratesineithergroupduringthepost-trialperiod.Theincidenceratesinthefenofibrategroupwerelowerwithrespecttoall-causemortality,CVDmortality,nonfatalmyocardialinfarction,congestiveheartfailureandmajorcoronaryheartdiseasethanthoseintheplacebogroupoverapost-trialfollow-up.Allocationtothecombinedfibrate-statintreatmentarmduringthetrialperiodhadabeneficiallegacyeffectonall-causemortality(adjustedHR = 0.65,95%CI0.45–0.94;P = 0.02).ConclusionsFibratetreatmentduringtheinitialtrialperiodwasassociatedwithalegacybenefitofimprovedsurvivaloverapost-trialfollow-up.Thesefindingssupportre-evaluationoffibratesasanadd-onstrategytostatinsinordertoreducecardiovascularriskindiabeticpatientswithdyslipidemia.Trialregistrationclinicaltrials.gov,Identifier:NCT00000620 BackgroundDyslipidemiaisamajorcontributortotheincreasedriskofcardiovasculardisease(CVD)amongpatientswithtype2diabetesmellitus(T2DM).Whileothertypesoflipidabnormalitiescanbefoundinpeoplewithdiabetes,thetypicaldiabeticdyslipidemia(alsocalledatherogenicdyslipidemia)ischaracterizedbyelevatedtriglycerides,smalldenselow-densitylipoproteins(LDL)particles,andlowlevelsofhigh-densitylipoproteins(HDL)cholesterol[1].RecommendedfirstlinemeasuresforCVDpreventioninpeoplewithdiabeteswhohavedyslipidemiaincludenon-druginterventions(dietaryregulation,exercise,moderationofalcoholintakeandweightloss)andLDL-cholesterolloweringwithstatindrugtherapy[2,3].Theuseofstatinsastheprimarydrugtreatmentoptionissupportedbyalargebodyofevidence.Forexample,ameta-analysisof14randomizedtrialswhichincludedmorethan18,000peoplewithdiabetes,foundthatforeverymmol/LreductioninLDLcholesteroltherewasa21%proportionalreductionintheriskofamajorvascularevent[4].Thisproportionalriskreductionissimilartothatobservedinpeoplewithoutdiabetes[5],butbecausethebaselineabsoluteriskisonaveragehigherinpeoplewithdiabetes,theabsolutebenefitsaregreater.However,thetrialdataalsoshowsubstantial“residualrisk”inpeoplewithT2DMwhoareonstatintreatment[6,7,8],andoftentheabsoluteriskisstillhigherthanthatinpeoplewithoutdiabeteswhoarenotonstatintreatment[9,10,11].ThisindicatesthatpreventativetreatmentwithstatinsalonemaynotbeenoughinpeoplewithT2DMandadditionaltherapiesmayneedtobeconsidered.ThereisalsoevidencefromMendelianrandomizationstudiesthathightriglyceridesarecausallyrelatedtoCVD,andsodrugtherapytargetingthislipidabnormalitycouldhelptofurtherreduceCVDriskinpeoplewithT2DM[12,13,14].Fibratesareanexampleofsuchadrugtherapy,astheybothdecreasetriglyceridelevelsandincreaseHDL-C[15].ToinvestigateiftheseeffectsonlipidbiomarkerstranslatesintoareductioninCVD,theActiontoControlCardiovascularRiskinDiabetes(ACCORD)-Lipidstudyrandomized5518peoplewithT2DMtocombinedstatin-fibratetherapyvsstatintherapyalone.AlthoughtheACCORD-Lipidstudyfoundnobenefitbetweenrandomizedgroupsoverall,abeneficialreductioninmajorCVDeventswasfoundinapre-specifiedsub-groupanalysisofstudyparticipantswithdyslipidemia(triglyceridegreaterthan204 mg/dlandhigh-densitylipoproteinless34 mg/dl)[16,17].Theauthorshypothesizedthatfibratetherapy,offeredasanadd-ontostatintherapy,maybebeneficialforpeoplewithdiabeteswhoarefoundhavehypertriglyceridemiaand/orreducedHDL-C.ThishypothesisissupportedbythefindingsofseveralsystematicreviewsofRCTsoffibratetherapy[18,19,20,21].AttheendoftheACCORD-Lipidtrial,participantswereunblindedfromtheirrandomizedgroups,andpassivelyfollowedupforanadditional5 yearsthroughfollow-upclinicsandroutinedatacollectionmethods.Thepost-trialfollow-updataprovideauniqueopportunitytoevaluatetheeffectofadd-onfibratetherapyinthelonger-term,andthepossibilityoftheemergenceof“legacyeffects”.Legacyeffectsdescribeinterventioneffectsobservedinthepost-trialperiodwhicharenotduetothedirecteffectsobservedduringthetrialperiod[22].Thefindingofalegacyeffectwouldhaveimportantclinicalimplications,includingthepotentialbenefitsofearlyinitiationoffibratetreatmentinthesettingofdiabeticdyslipidemia.Althoughpotentiallegacyeffectsforstatintreatmenthavebeeninvestigatedinanumberofpost-trialfollowupstudies[23],thoseforcombinedstatin-fibratetreatmentremainunexplored[24,25].Post-trialdataafterastatin-fibrateRCTprovidetheopportunitytoinvestigatepotentiallegacyeffectsinpeoplewithT2DManddyslipidemia.Therefore,weconductedasecondaryanalysisofdatafromtheACCORD-LipidtrialandtheACCORDIONpost-trialfollow-upstudy,inordertodeterminewhetherornotthereisevidenceforlegacyeffectsforfibrateadd-onstrategytostatinsindiabeticpatientswithdyslipidemia.MethodsStudyparticipantsandsettingTheActiontoControlCardiovascularRiskinDiabetes(ACCORD)Trialwasarandomized,double2 × 2factorialdesignstudy,whichevaluatedtheeffectsofintensiveglycemiccontrol,intensivebloodpressurecontrol,andcombinedfibratestatintreatment,onthepreventionofcardiovasculardiseaseinpeoplewithT2DM[26].Itenrolled10,251people(meanage62 years),whohadahistoryofT2DMforamediandurationof10 years,withmeanglycatedhemoglobin(HbA1c)levelof8.3%.Participantshadeitherahistoryofpreviouscardiovasculardiseaseorhadelevatedriskfactorslevels.Thelipidsub-studywasconductedin5518ofthetrialparticipants.InadditiontofulfillingtheoverarchingACCORDentrycriteria,theLIPIDparticipantsneededtomeetallofthefollowingadditionalcriteria:(1)60 mg/dl