LE DISLIPIDEMIE VECCHIE E NUOVE TERAPIE DISLIPIDEMIE VECCHIE E NUOVE TERAPIE ... A receptor mediated...
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LEDISLIPIDEMIEVECCHIEENUOVETERAPIE
Un’avventuraa:raversotregenerazioni
AnnaNelvaAslBI-Biella
LEDISLIPIDEMIEVECCHIEENUOVETERAPIE
Un’avventuraa:raversotregenerazioni
AnnaNelvaAslBI-Biella
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DAL1960AL1985
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Anni’60• SidiffondonosKlidivitachefannoesploderelapatologiacardiovascolare.• VieneassegnatoilPremioNobelinPhysiologyorMedicineaKonradBlocheFeodorLynen“fortheirdiscoveriesconcerningthemechanismandregulaKonofthecholesterolandfa:yacidmetabolism”(1964)• Sonodisponibiliniacina,clofibrato,colesKramina
Konrad Bloch Feodor Lynen
Endo A. A gift from nature: the birth of the statins. Nat. Med. 2008; 14:1050-1052. doi: 10.1038/nm 1008-1050 Brown MS, Goldstei JL. A receptor mediated pathway for cholesterol homeostasis. Science 1986; 232:34-47 Lipid Research Clinics Program. The Lipid Research Clinics coronary primary prevention trial results, 1: reduction in the incidence of coronary artery disease. Jama. 1984; 251-:351-364 Lipid Research Clinics Program. The Lipid Research Clinics coronary primary prevention trial results, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984; 251: 365-374
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Anni’70• Nel 1973 Joseph L. Goldstein e Michael S. BrownidenKficanoilrece:oredelleLDL• Nel 1973 anno Akira Endo isola la compacKna(mevastaKna) prodo:a da Penicillium citrinum Pen-51,dopoaveretestato6000ceppidimicrorganismi• Nel 1978 viene isolata la lovastaKna da AspergillusterreusAnni’80• Nel1984ilCoronaryPrimaryPrevenKonTrialdimostraper laprimavolta che la riduzionedella colesterolemia(con la colesKramina) riduce in modo significaKvo glievenK da coronaropaKa,in misura proporzionale alladiminuzionedelcolesteroloLDL• Nel1985vienecara:erizzatoilgenedelrece:oredelleLDLdaBrowneGoldstein.NellostessoannoricevonoilpremioNobelper la scoperta del rece:ore delle LDL edelsuoruolonellaseveraipercolesterolemiafamiliare.
Endo A. A gift from nature: the birth of the statins. Nat. Med. 2008; 14:1050-1052. doi: 10.1038/nm 1008-1050 Brown MS, Goldstei JL. A receptor mediated pathway for cholesterol homeostasis. Science 1986; 232:34-47 Lipid Research Clinics Program. The Lipid Research Clinics coronary primary prevention trial results, 1: reduction in the incidence of coronary artery disease. Jama. 1984; 251-:351-364 Lipid Research Clinics Program. The Lipid Research Clinics coronary primary prevention trial results, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984; 251: 365-374
MicrografiadiPenicilliumcitrinumPen-51
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DAL1985AL2010
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1987laFDAapprovalalovastaKna,primastaKnacommercializzata.E’seguitadasimvastaKna,eda5KpidistaKnesinteKche(fluvastaKna,cerivastaKna,atorvastaKna,rosuvastaKna,pitavastaKna).LacerivastaKnasaràtoltadalcommerciopersegnalazionidigravemiopaKaAnni’90Trialemetanalisiconfermanounariduzionedose-dipendentedipatologiacardiovascolareconl’abbassamentodelcolesteroloLDL:ogni40mg/dldiriduzionedelcolesteroloLDLsiassociaaunacorrispondenteriduzionedel22%dimortalitàemorbiditàcardiovascolareDimostranoanchechelestaKneriduconoinmodosostanzialemorbiditàemortalitàcardiovascolaresiainprevenzioneprimariachesecondariaLestaKnesidimostranoingradodirallentarelaprogressioneoanchedipromuoverelaregressionedell’aterosclerosicoronaricaDiventanoifarmacidiprimasceltainpazienIconipercolesterolemiaoiperlipidemiacombinata
Endo A. A gift from nature: the birth of the statins. Nat. Med. 2008; 14:1050-1052. doi: 10.1038/nm 1008-1050 European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818 Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012; 33: 1635-701
Ada2atodaCTTCollaborators.Lancet.2005;366:1267-78
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Lancet 2010; 376:1670–81
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! RiduconolasintesiepaKcadicolesterolo,inquantopotenKinibitoricompeKKvidiHMGCoAredu:asi,enzimachiavedellabiosintesidelcolesterolo.
! Lariduzionedellaconcentrazionedicolesterolointracellulareinducel’espressionedelrece:oreperleLDLsullasuperficiedegliepatociK.
! Questoportaaunaumentodell’estrazionedicolesteroloLDLdalsangueeaunarido:aconcentrazionedicolesteroloLDLcircolanteedialtrelipoproteinecontenenKapoB,compreseleparKcellericcheditrigliceridi
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818
ComefunzionanolestaKne?
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• Differisconofraloroinassorbimento,biodisponibilità,legamealleproteineplasmaKche,escrezioneesolubilità
• LovastaKnaesimvastaKnasonoprofarmaci,mentrelealtrestaKnesonosomministrateinformaajva
• Tassidiassorbimentofrail20eil98%
• SonometabolizzatealivelloepaKcocongliisoenzimicitocromoP450(CYPs),trannepravastaKna,rosuvastaKna,pitavastaKna
ComefunzionanolestaKne?
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818
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Nel2005AkiraEndoriceveilpremioLasker-DeBakeyClinicalResearchPrizedalPremioNobelJosephGoldstein
perlascopertadellestaKne
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EvenIavversi
Esisteunavariabilitàinterindividuale(comeanchenellarisposta),maglievenKavversisonocomunquerari.PiùfrequenKconetàavanzata,corporaturaminuta,generefemminile,disfunzionerenaleeepaKca,periodiperioperatori,ipoKroidismo,pluripatologia,abusodialcool
• MiopaKa:<1/1000,puòprogredireversolarabdomiolisi
• Mialgie,senzaaumentoCK:5-10%
• Aumentotransaminasi,dose-dipendente:0,5-2%
• Diabete,malariduzionedirischiodievenKCVneipzadaltorischiosuperal’aumentomoltopiccolodiincidenzadidiabete
• Disturboacutoereversibiledimemoria(confermatoancheconaltreterapieipolipemizzanK)
C’èunrovesciodellamedaglia?
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818 Strom BL, Schinnar R, Karlawish J, et al. Statin therapy and risk of acute memory impairment. JAMA Intern Med 2015, 175:1399-405
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ResinesequestranKgliacidibiliari(colesKramina)
Comeagiscono:
• NonvengonoassorbiKincircolo,néalteraKdeglienzimidigesKvi
• Leganogliacidibiliaririducendoneilricircoloentero-epaKco
• Ilfegato,depletodiacidibiliari,nesinteKzzamaggiormenteusandoleriserveepaKchedicolesterolo
• L'aumentatocatabolismoepaKcodelcolesteroloinacidibiliariportaaunaumentocompensatoriodell'ajvitàdelrece:oreperLDLalivelloepaKco,conaumentatosequestrodiLDL-Cdalcircolo
• Riduconoilivellidiglucosioneipz.iperglicemici
Efficaciaclinica:
• Con24gdicolesKraminaosservatariduzionediLDL-Cdel18-25%.
EvenIavversieinterazioni
• PossonoaumentareitrigliceridiinalcunipzpredisposK
• CausanoeffejcollateralidiKpointesKnale(flatulenza,sKpsi,dispepsiaenausea)
• Possonoridurrel'assorbimentodivitamineliposolubili
• ImportanKinterazioniconmolKaltrifarmaci
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818 Hegele RA, et. al. Nonstatin low-density Lipoprotein.Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council. Arterioscl Thromb Vasc Biol. 2015;35:2269-2280. DOI:10,1161/ATVBAHA.115.306442.
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EzeKmibeComeagisce:
• Inibiscel'assorbimentodicolesteroloesogenoalivellodellamucosaintesKnale(interferendoconNiemannPickC1-likereceptor1)
• Inrispostaalrido:oapportodicolesteroloilfegatoreagisceaumentandol'espressionediLDL-R,aumentandolaclearancediLDLdalsangue
Efficaciaclinica:
• InaggiuntaaunastaKnariduceilcolesteroloLDLdiunulteriore15-20%
• Nel2015iltrialIMPROVE-IThadimostratocherispe:oallasolastaKnaezeKmibe+simvastaKnariducevanoinmodosignificaKvoglievenKcardiovascolarimaggioridel7%,quandoiniziaKentro10giornidaSCA,conunamaggiorediminuzionediLDL-Cdicirca16mg/dl
• Semprenel2015iltrialPRECISE-IVUShadimostratounamaggioreregressionedelvolumedellaplaccacoronaricaconezeKmibe+atorvastaKnarispe:oallasolaatorvastaKna
EvenIavversieinterazioni
• NonriportaKeffejcollateralimaggiori,solomoderatoincrementodienzimiepaKciemialgie
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818 Hegele RA, et. al. Nonstatin low-density Lipoprotein.Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council. Arterioscl Thromb Vasc Biol. 2015;35:2269-2280. DOI:10,1161/ATVBAHA.115.306442.
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Omega-3Comeagiscono:
• Meccanismiancorapocochiari,almenoinpartelegaKainterazioneconPPARserido:asecrezionediapoB
• Efficaciaclinica:
• Riduzionedeitriglicerididel30%circa(dosi2-4g/die)
• InassociazioneconsimvastaKnadimostratamaggiorediminuzionedeitrigliceridiconunpiccoloaumentodiHDL-C
• InassociazioneapravastaKnaefenofibratoindiabeKcidislipidemicidimostratamaggiorediminuzionedellatrigliceridemiaediminuzionediomocisteinemia
• AssociaKabassedosidipravastaKnaosimvastaKnarispe:oallasolastaKnahannorido:oglievenKcoronaricimaggiorisenzamodificareitassidimorteimprovvisadioriginecardiaca
EvenIavversieinterazioni:
• Sicurieprividiinterazionicliniche
• PereffejanKtromboKcipossonoaumentareirischidisanguinamentoinassociazioneaaspirina/clopidogrel
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818
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FibraKComeagiscono:
• AgonisKdiperoxisomeproliferator-acKvatedreceptor(PPAR-alfa),cheregolavaripassaggidelmetabolismodilipidielipoproteineagendoa:raversofa:oriditrascrizione;reclutanodifferenKcofa:orieregolanol'espressionegenica
Efficaciaclinica:
• Abbassanoilivelliditrigliceridisiaadigiunochepost-prandialidel30-50%eiremnantricchiditrigliceridi
• Modestoeffe:odiaumentodiHDL-C
• Sembranoessercibeneficisulrischiocardiovascolaresopra:u:oinpzconTG>200mg/dl
EvenIavversieinterazioni:
• Sintomigastroenterici5%
• rashcutanei2%
• MiopaKa(specieseinsuffrenalecronicaecongemfibrozil,cheinibisceilmetabolismodellastaKnea:raversoglucuronidazione;moltominoreconfenofibrato).
• AumenKdelletransaminasi,coleliKasi,lieveaumentodiincidenzadipancreaKteeemboliapolmonare
• AumenKdicreaKninaeomocisteina
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818 Hegele RA, et. al. Nonstatin low-density Lipoprotein.Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council. Arterioscl Thromb Vasc Biol. 2015;35:2269-2280. DOI:10,1161/ATVBAHA.115.306442.
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LomitapideComeagisce:
• Inibitoredellaproteinamicrosomialeditrasportodeitrigliceridi,chefacilital’incorporazionediestericolesterilicietrigliceridinelleVLDLa:raversol’interazioneconapoB-100eapoB-48Somministrazioneorale
Efficaciaclinica:
• riduzionediLDL-Cdel35-50%.Effe:oindipendentedalrece:oreLDL
EvenIavversi:
• aumenKdelletransaminasiesteatosiepaKca
ErogabileatotalecaricodelSSNperiltra:amentodell’ipercolesterolemiafamiliareomozigote(età>18anni),inassociazioneadietaabassotenoredigrassi,altrifarmaciipolipemizzanK,sianeipzcheeffe:uanoLDLaferesicheneglialtri
Hegele RA, et. al. Nonstatin low-density Lipoprotein.Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council. Arterioscl Thromb Vasc Biol. 2015;35:2269-2280. DOI:10,1161/ATVBAHA.115.306442.
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Aferesidellelipoproteineabassadensità
• RimozionesejmanaleoogniduesejmanediLDLeLp(a)dalplasmaincorsodicircolazioneextracorporea
• Tecnicacostosamaefficace
• Indicataperraripzconseveraiperlipidemia,sopra:u:oconFHomozigoteeeterozigotegrave
• EseguitasoloincentrimoltospecializzaK
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818
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IntegratorialimentariealimenKfunzionali
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818
Fitosteroli PresenKnaturalmenteinvarialimenKvegetaliCompetonoconilcolesteroloperl’assorbimentointesKnaleVengonoaggiunKavarialimenK2g/diepossonodeterminareunabbassamentocolesterolototeLDLdel7-10%NondaKsuprevenzionediCVDPossibileminoreassorbimentodicarotenoidievitamineliposolubili
Proteinedellasoia Modestoeffe:odiriduzionedelcolesteroloLDL(3-5%)
Fibrealimentariidrosolubilidacruscad’avena,beta-glucani,Psyllium
5-15g/diepossonoridurreilcolesteroloLDL
Omega-3 2-3g/diedioliodipesceriduconoitriglicerididel25-30%SupplemenKdiomega3acatenalungapossonoaumentareilcolesteroloLDLdel5%circaneipzcongraveipertrigliceridemia
Risorossofermentato MeccanismostaKno-simile(monacolina)
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SKledivita!
Tipodigrassi
• 1%dienergiainpiùdaigrassisaturi:1,6mg/dlinpiùdiLDL-C• 1%dienergiainpiùdagrassimonoinsaturi:1,6mg/dlinmenodiLDL-C• Unadietariccadimonoinsaturirispe:oaunadietariccadigrassisaturiaumentala
sensibilitàall'insulinaeriduceitrigliceridi,specienelperiodopost-prandiale• Gliomega3nonriduconoilcolesterolo,mailconsumodipesceriduceilrischio
cardiovascolare• Adosifarmacologichegliomega-3riduconoitrigliceridiconeffe:oneutrooconlieve
aumentodiLDL
TipodicarboidraI
• CarboidraKadaltoindiceglicemicodeterminanounaumentodeitrigliceridi,comeancheilfru:osioeunconsumoelevatosiassociaaunadiminuzionesignificaKvadiHDL-C
Fibre
• Lefibreriduconolacolesterolemia
Peso
• IlcalodipesoinfluenzaCol.ToteLDL:8mg/dldiLDL-Cinmenoogni10Kgdicaloneigrandiobesi
• Ilcalodipesodeterminaunariduzionedeitriglicerididel20-30%;inoltreunaumentodiHDL-Cdi0,4mg/dlperogniKginmenoquandolariduzionesièstabilizzata
AUvitàfisica: • UnaumentodiHDL-Cconeffe:ominoresull'LDL-Cèindo:odaajvitàfisicaregolare
Fumo:
• Sme:eredifumarepuòcontribuireall'aumentodiHDL-C
CasiparIcolari
• Nellesevereipertrigliceridemieconpresenzadichilomicroni,ancheadigiuno,èappropriatoridurreilpiùpossibileigrassidelladieta(considerarel'usodiTGacatenamedia)
European Assoociation for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-818
1,1%energiadaigrassisaturi=1,6mg/dldiLDL-C
-8mg/dldiLDL-Cogni10Kgpersi
Diminuzionedeitriglicerididel20-30%concalodipeso
AumentodiHDL-Cdi0,4mg/dlperogniKginmeno
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SimvastaKnaRosuvastaKnaPravastaKnaLovastaKnaFluvastaKnaAtorvastaKna
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NOTA13Checosaprescrivere:ipercolesterolemiaeipercolesterolemia
poligenica• SIledivita:atuUesempre
• Prescriveredieta,poiseinsufficientestaKne,poiezeKmibe+staKne(IIlivelloancherosuvastaKna)
• MalaterapiadovrebbeessereintrapresacontemporaneamenteallamodificadellosKledivitaneipz.arischiomoltoaltoconC-LDL>70mg/dleinquelliarischioaltoconC-LDL>100mg/dl
• SesdcoronaricheacuteoPTCA:atorvastaKnaadosaggioelevato
• SeintolleranzaastaKne:ezeKmibeinmonoterapia(neipzconrischioperCVDmoltoalto:rosuvastaKna)
• SeincorsodistaKneHDLbasse(M<40,F<50)e/oTG>200:fibraK
• TargetterapeuKco
• Pzconrischiomedio:colesteroloLDL<130mg/dl
• Pzconrischiomoderato:colesteroloLDL<115mg/dl
• Pzconrischioalto:colesteroloLDL<100mg/dl
• Pzconrischiomoltoalto:colesteroloLDL<70mg/dl
• Neipzarischiobasso(score0-1%)indicatasololamodificaallosKledivita
• RimborsabilitàsenzalimiKdietàinprevenzionesecondaria;inprevenzioneprimariaèprevistafinoagli80anni,masenzalimiKdietàincasodimalajacoronarica,vascolare,odiabetemellito(pzdaconsiderareinprevenzionesecondaria)
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NOTA13Checosaprescrivere:dislipidemiefamiliari
• Ipercolesterolemiafamiliaremonogenica
StaKneezeKmibe+staKneaggiungereresinesequestranKgliac.biliari
• Iperlipidemiafamiliarecombinata
StaKnediIlivellorosuvastaKna/PUFA-N3/ezeKmibe+staKne
• Disbetalipoproteinemia
StaKne/fibraKrosuvastaKna/ezeKmibe+staKneaggiungereresinesequestranKac.biliari
• Iperchilomicronemieegraviipertrigliceridemie
FibraK/PUFA-N3fibraK+PUFA-N3
EzeKmiberimborsatoinmonoterapiaseintolleranzaastaKne
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NOTA13Checosaprescrivere:situazioniparKcolari
• Insufficienzarenalecronicamoderataegrave:
• Setrigliceridi>500mg/dl:PUFA-N3
• SeLDL-D>=130mg/dl:1°sceltasimvastaKna+ezeKmibe,2°sceltaaltrestaKneaminimaescrezionerenale
• NeidiabeKci:
• dovrebbeessereconsideratoancheildosaggiodiApoB(TT<=80mg/dl)perchéleLDLsonoimpoveriteincolesteroloearricchiteintrigliceridi),inalternaKvavalutareilcolesterolononHDL.ApoBpuòessereuKleancheinpresenzadisd.metabolicaoinsuff.renalecronica
• IncorsidianKretrovirali:
• controindicataSimvastaKna(usarestaKnedisecondolivello)
Einfine:
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EDAADESSOINPOI?
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2003 2004 2007 2009 2010
Gain-of-funcKonmutaKonsinproproteinconvertasesubKlisin/kexintype9(PCSK9)associatedwithautosomal-dominanthypercholesterolemia1
OverexpressionofPCSK9inmiceshowntoresultinLDLreceptorknockoutphenotype2
ScienIstsreportcrystalstructureofPCSK93
ResearchersreportthatananIbodyagainstPCSK9canlowercholesterolinmiceandnonhumanprimates4
ThefirstexampleofaPCSK9neutralizinganKbodyreducingLDL-Cinvivo
mAbsagainstPCSK9enterhumantesIng5
1.AbifadelM,etal.NatGenet.2003;34:154-156.2.MaxwellKN,etal.ProcNatlAcadSciUSA.2004;101:7100-7105.3.PiperDE,etal.Structure.2007;15:545-552.4.ChanJCY,etal.ProcNatlAcadSciUSA.2009;106:9820-9825.5.DiasC,etal.CirculaUon.2011;124:Abstract10701.
ReprintedfromStructure,vol15,PiperDE,etal.ThecrystalstructureofPCSK9:aregulatorofplasmaLDL-cholesterol,pp545-552,Copyright(2007),withpermissionfromElsevier.
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EvoluzionedegliAnKcorpiMonoclonali
1.FoltzIetal.CirculaUon2013Jun4;127(22):2222-30;2.NelsonALetal.NatureReviewsDrugDiscovery2010Oct;9(10):767-74
28
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FunzioneeCicloBiologicodelRece:oreLDL
ForillustraKonpurposesonly
29
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IlRuolodiPCSK9nellaRegolazionedell’EspressionedelRece:oreperleLDL
X
ForillustraKonpurposesonly
30
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DownregulatesPCSK9
LaregolazionediPCSK9èdinamicaPCSK9isproducedprimarilybythe
liver,kidney,andintesInes1
• Dietaryandcellularcholesterol4
• Long-termfasKng1
• Bileacids3,4
PlasmaPCSK9level
UpregulatesPCSK9
• CholesteroldepleKon2,3• Cholestyramine2
• Sterolregulatoryelement-bindingprotein21,3,4
• StaIns3,4
1. HortonJD,etal.JLipidRes.2009;50:S172-S177.2. LopezD.BiochemBiophysActa.2008;1781:184-191.3. AbifadelM,etal.HumMutat.2009;30:supplementaryinformaUon.4. AbifadelM,etal.In:TothPP.TheYearinLipidDisorders.Vol.2.
Oxford,UK:AtlasMedicalPublishingLtd.2010:3-23.31
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Impa:odell’AnKcorpocontroPCSK9sull’EspressionedelRece:oredelleLDL
ForillustraKonpurposesonly
32
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Cara:erisKchedegliinibitoridiPCSK9(risultaKdeitrial)
• DeterminanounariduzionedicolesterolodelLDL40-65%,conriduzioneanchedicolesterolotot.eLp(a)eunaumentodiHDLdel6%
• EffejindesideraKlievierelaKvamentenonfrequenK
• EfficacianchenelleipercolesterolemiefamiliariomozigoK(evolucumab420mg/4sejmane)inmisuralegataalgradodiresiduaajvitàdiLDL-R
• NonsonostaKdeterminaKcomeoutcomeprimaripre-specificaKgliesiKcardiovascolarichesonoinveceogge:odistudioditriala:ualmenteincorso
• DaKpreliminarisuggerisconotu:aviaefficacianelridurreglievenKcardiovascolaria1-1,5anni
• Estremamentecostosi
WhiteCM,PharmD,FCP,FCCP.TherapeuUcPotenUalandCriUcalAnalysisofthePCSK9MonoclonalAnUbodiesEvolucumabandAliroocumab.Ann.Pharmac2015;49(12):1327-1335
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34
PazienIconIntolleranzaalleStaIne
IpercolesterolemiainpazienIarichioCVmoltoalto(noncontrollaKconmaxdosetolleratadistaKna
±Eze)
Evolocumab,Alirocumab,Bococizumab
AbanK-PCSK9PERILTRATTAMENTO
DELL’IPERCOLESTEROLEMIA«DIFFICILE»FarmaciBiologici:inibitoriPCSK9
InibitoriPCSK9comeAdd-onamassimadosetolleratastaIne(±
altriLLT)
PazienIconIpercolesterolemiaFamiliare(i.eHeFH)
Ulterioreriduzionedel55-60%diLDL-CrispeeoaterapiamaxconstaIne.
65-80%dipazienIHeFHatargetdiLDL-C<70mg/dL
InibitoriPCSK9comeAdd-onamassimadosetolleratastaIne(±
altriLLT)
Ulterioreriduzionedel60-70%rispeeoaterapiamaxconstaIne
85-90%dipazienIatargetperLDL-C<70mg/dL
PCSK9InibitoriMONOTERAPIA(oAdd-ontoaltriipolipemizzanI?)
50-55%diriduzionediLDL-Cinmonoterapia
Buonprofilodisicurezza
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TAKEHOMEMESSAGES
Itra:amenKdisponibilihannoefficaciaesicurezzaindiscuKbili
VannousaKsecondoleindicazionidellelineeguida,inparKcolareperquantoriguardaKpo,dosi,controlli,sullabasedellecara:erisKchedelsingolopaziente,peraverneilmassimobeneficio
GliinibitoridiPCSK9rappresentanoun’opzioneperpazienKchepotrebberobeneficiarediunaulterioreriduzionedel50-60%dicolesteroloLDL
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