Statin-Fibrate Combination for the Treatment of Dyslipidaemia

The additive effects of statin–fibrate combinations on lipid profiles have been documented. The atorvastatin–fenofibrate combination has been shown to have ... Skiptomaincontent AER CFR ECR ICR3 JAPSC USC ECRistheofficialjournalofthe AboutECR EditorialBoard ForAuthors Topics CurrentVolume SpecialCollections PreviousVolumes Videos Podcasts SubmitArticle Authors ArticleInfo Cite Metrics ArticleText Figures&Tables References Article Statin-FibrateCombinationfortheTreatmentofDyslipidaemia EwaDembowski , MichaelHDavidson , RegisterorLogintoViewPDF Permissions Views:7434 Likes:0 Downloads:9 Share: Citation: EuropeanCardiology2008;4(1):10–1 Citation× Selectformat .ris(Mendeley,Papers,Zotero) .enw(EndNote) .bibtex(BibTex) .txt(Medlars,RefWorks) Downloadcitation DOI:https://doi.org/10.15420/ecr.2008.4.1.10 Openaccess:ThecopyrightinthisworkbelongstoRadcliffeMedicalMedia.OnlyarticlesclearlymarkedwiththeCCBY-NClogoarepublishedwiththeCreativeCommonsbyAttributionLicence.TheCCBY-NCoptionwasnotavailableforRadcliffejournalsbefore1January2019.Articlesmarked‘OpenAccess’butnotmarked‘CCBY-NC’aremadefreelyaccessibleatthetimeofpublicationbutaresubjecttostandardcopyrightlawregardingreproductionanddistribution.Permissionisrequiredforreuseofthiscontent. Pharmacologicalregulationoflipidmetabolisminpatientswithdyslipidaemiaisundeniablyassociatedwithsignificantreductionsinriskofcardiovascular(CV)morbidityandmortality.Therearestrongclinicaltrialdatatosupporttheuseoflipid-loweringtherapiesinthesettingsofbothprimaryandsecondaryprevention.StatinsandfibratesaretwoclassesofdrugthathavedemonstratedsignificantlyreducedCVeventratesinprospective,placebo-controlledclinicaltrials.However,monotherapywitheitherofthesedrugsdoesnotalwaysachievelipidgoalsinthedyslipidaemicpatient.Furthermore,eveninthosepatientswhodoachievelipidgoalswithmonotherapythereoftenremainsahighresidualriskofCVevents,warrantingevenfurthertherapy.Aneffectivetherapeuticapproachformanyofthesepatientsiscombinationtherapywithstatinsandfibrates. Thereisahighprevalenceofmixeddyslipidaemiaamongpatientswithmetabolicsyndromeordiabetesmellitus.1Thishighlyatherogenicphenotype,characterisedbyincreasedlow-densitylipoproteincholesterol(LDL-C),elevatedtriglyceridesandlowhigh-densitylipoproteincholesterol(HDL-C),isassociatedwithanincreasedriskofcoronaryarterydisease(CAD).2,3Inaddition,thepredominanceofsmalldenseLDL(dLDL)particlesfurtherincreasestheatherogenicriskinthesepatients.4PatientswithelevatedLDL-CwhoalsohavelowHDL-CandelevatedtriglyceridesareatgreaterriskofCADthanthosewithelevatedLDL-Calone.5Recognisingthisresidualrisk,theNationalCholesterolEducationProgramAdultTreatmentPanel(NCEPATPIII)guidelinesrecommendbothLDL-Candnon-HDL-Cgoalsforhigh-riskpatients.6 ThemajorityofpatientscanachievetheNCEPATPIIIgoalswithstatintherapyalone.7Statinsarestructuralinhibitorsof3-hydroxy-3-methylglutarylcoenzymeAreductase,therate-limitingenzymeforhepaticcholesterolbiosynthesisthatresultsintheupregulationoftheLDLreceptorandtheloweringofLDL-Cintheblood.OutcometrialsofstatinshaveprovedconclusivelythatthisclassofdrugslowersLDL-Clevels,resultinginasignificantreductionofCVeventsinmanyhigh-riskpatients.8,9StatinshavealsobeenshowntoincreaseHDLandlowertriglyceridelevels.Inaddition,althoughofunknownclinicalsignificance,statinshavebeenreportedtohaveeffectsindependentoflipid-levelalterations.These‘pleiotropic’effectsinclude,amongothers,vasodilation,plaquestabilisationandantioxidant,anti-inflammatoryandantithromboticeffects.10 TherelationbetweenLDL-CandCADeventsappearstobelinear,supportingthe‘lowerisbetter’hypothesis.11However,manypatientshaveinitialorrecurrentcoronaryheartdiseaseeventsdespiteaggressivereductionsinLDL-Cbystatins.12EvenwithLDL-ClevelsatNCEPATPIIIgoals,thereremainsaresidualriskforsubsetsofhigh-riskpatients.Forexample,intheTreatingtoNewTarget(TNT)trial,patientstakingatorvastatin80mg(meanLDL-Clevel77mg/dl)hada28%CVeventratecomparedwitha33%eventrateforpatientstakingatorvastatin10mg(meanLDL-Clevel101mg/dl),whichisa22%relativeriskreduction.9Therefore,approximately70%oftheeventswerenotavoidedevenwithsignificantLDL-Creduction.13AnimportantclinicalchallengeistofurtherreducetheresidualCADriskinpatientstakingoptimalstatintherapywithoutadverselyaffectingpatientsafety. Fibratetherapy,whichsignificantlydecreasestriglyceridelevelsandincreasesHDL-CwithoutreducingLDL-C,isalsoassociatedwithareductioninCVevents.14Fibratesreducetheproductionoftriglyceride-richlipoproteinsandincreasethecatabolismoftriglyceridesbytheinductionoflipoproteinlipase(LPL)andreducedexpressionofapolipoproteinC-III(apoCIII)viaactivationofperoxisomeproliferatoractivatedreceptor(PPAR)-alpha.ThebenefitoffibratetherapyonlipidprofileinatherogenicdyslipidaemiawasdemonstratedintheTriglycerideReductioninMetabolicSyndrome(TRIMS)15study.Aftereightweeksoftreatmentwithfenofibrate,favourablechangeswerenotedintermsofdecreasedlevelsofnon-HDLaswellasincreasedlevelsofHDL.Inaddition,treatmentwithfenofibrateproducedashifttowardslargerLDLparticlesize. FibratesalsochangetherelativeproportionsofLDLsubfractions,markedlyshiftingtheprofiletowardsalessdenseLDL.Studiescomparinglipid-loweringtherapieshaveshownthatwhileatorvastatinreducesallLDLsubfractions,fenofibratereducesLDLdensity.16ThisisduetoamorepronouncedreductionofthemostdenseLDLfraction(LDL-6)byfenofibratecomparedwithatorvastatin.17IntheDiabetesAtherosclerosisInterventionStudy(DAIS),18fenofibratereducedtherateofCADprogressioninsubjectswithtype2diabetes.MultivariateanalysisdemonstratedthatLDLparticlesizewasanindependentpredictorofthedegreeofdiseaseprogressioninmodelscontainingLDL-CandapoB. Recognisingthatstatinandfibratetherapiesaffectdifferentaspectsoflipoproteinmetabolism,combinationtherapywiththesetwoclassesofdrugisemergingasapossibletherapeuticapproachformanyhigh-riskpatients,especiallythosewithatherogenicdyslipidaemia.Theadditiveeffectsofstatin–fibratecombinationsonlipidprofileshavebeendocumented.Theatorvastatin–fenofibratecombinationhasbeenshowntohaveahighlybeneficialeffectonlipidparametersinpatientswithtype2diabetesandcombinedhyperlipidaemia(CHL).19Atotalof120diabetesandCHLpatientswhowerefreeofCADwererandomlyassignedtoatorvastatin20mg/day,micronisedfenofibrate200mg/dayoracombinationofboth.Theatorvastatin–fenofibratecombinationreducedtotalcholesterolby37%,LDL-Cby46%andtriglyceridesby50%,andincreasedHDL-Cby22%.Thesechangesweresignificantlybetterthanthoseofbothmonotherapies.TheadditiveeffectsofsimvastatinandfenofibrateonlipidparametershavebeendocumentedintheSimvastatinPlusFenofibrateforCombinedHyperlipidemia(SAFARI)trial.20Simvastatinmonotherapy(20mg/day)wascomparedwithcombinationtherapy(simvastatin20mg/dayplusfenofibrate160mg/day)inpatientswithCHL.ThemeanLDLlevelsweresignificantlydecreasedwithcombinationtherapycomparedwithmonotherapy(31.2and25.8%,respectively;p<0.001).Inaddition,meanHDL-Clevelssignificantlyincreasedwithcombinationtherapycomparedwithmonotherapy(18.6and9.7%,respectively;p<0.001). Historically,however,fibrate–statincombinationtherapyhasbeenasourceofsafetyconcerns.IntheNEPTUNEsurvey,2125%ofpatientsreceivingtreatmentfordyslipidaemiahadtriglyceridelevels>200mg/dl.Only27%ofpatientswithhypertriglyceridaemiaandCADhadachievedtheirnon-HDLtreatmentgoals.Inaddition,only5%ofthosesurveyedwerereceivingcombinationantilipidaemictherapy.Themajorreasonthatcombinationtherapywithfibratesisseldomclinicallyusedistheperceptionofadversesafetyassociatedwithcombiningastatinandafibrate.Althoughthereisanincreaseinreportsofrhabdomyolysiswithstatin–fibratecombinedtherapy,thisriskappearstobeabout15timeshigherforgemfibrozilthanforfenofibratewhenusedwithstatins.13Datafromtheseveralrecenttrialssuggestthatcombiningfenofibratewithstatinsdoesnotsignificantlyincreasetheriskofmyopathy.19,20 Asevidenceforthesafetyandefficacyofstatin–fibratecombinationtherapycontinuestoemerge,combinationtabletsarebeingdevelopedasafixed-dosesinglepillthatwilltargethighLDL,lowHDLandhightriglycerides.Afixed-dosetabletcombiningatorvastatin40mgwithlow-dosefenofibrate100mg(LCP-AtorFen)iscurrentlyinclinicaldevelopment.22ThephaseIstudyhasalreadydemonstratedsafety,andrecentlythephaseIIstudywasannounced,althoughithasnotyetbeenpublished.ThephaseIItrialcomparedLCP-AtorFenwithatorvastatin40mgandfenofibrate145mginapproximately200patientswithmixeddyslipidaemiaover12weeks.LCP-AtorFenwasfoundtobesignificantlymoreeffectivethanatorvastatininloweringtriglyceridesandraisingHDL.Inaddition,LCP-AtorFenwassignificantlymoreeffectivethanfenofibrateinloweringtriglyceridesandLDL.Anothercombinationoffenofibricacidandrosuvastatinisinclinicaldevelopmentforthetreatmentofdyslipidaemia.Fenofibricacid(ABT-335)135mghaspreviouslybeenstudiedincombinationwithsimvastatin,atorvastatinandrosuvastatin.Thesetrialshavebeensubmittedforregulatoryapprovaltoreceiveanindicationforcombinationofafibratewithstatintreatment. Anoutcometrialwithstatin–fibratetherapyhasyettobecompleted.TheActiontoControlCardiovascularRiskinDiabetes(ACCORD)trial23iscomparingtheefficacyofstatinmonotherapywiththatofafibrate–statincombinationtherapyin5,800patientswithdiabetesmellitus.Thistrialisexpectedtobecompletedby2009andwillestablishwhetherornottherapywiththiscombinationleadstoagreaterreductionintheriskofCVmorbidityandmortalitythantherapywithastatinalone. References FarnierM,Diabetes:statins,fibrates,orboth?,CurrAtherosclerRep,2001;3:10. ManninenV,TenkanenL,KoskinenP,etal.,JointeffectsofserumtriglycerideandLDLcholesterolandHDLcholesterolconcentrationsoncoronaryheartdiseaseriskintheHelsinkiHeartStudy.Implicationsfortreatment,Circulation,1992;85(1):37–45. Crossref|PubMed StanekEJ,SarawateC,WilleyVJ,etal.,Riskofcardiovasculareventsinpatientsatoptimalvaluesforcombinedlipidparameters,CurrMedResOpin,2007;23(3):553–63. 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