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Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and its Specific Treatment with Alirocumab, a PCSK9 Monoclonal Antibody

2015-09-15Journal article Restricted access
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dc.contributor.authorHopkins, P.N.
dc.contributor.authorDefesche, J.
dc.contributor.authorFouchier, S.W.
dc.contributor.authorBruckert, E.
dc.contributor.authorLuc, G.
dc.contributor.authorCariou, B.
dc.contributor.authorSjouke, B.
dc.contributor.authorLeren, T.P.
dc.contributor.authorHarada-Shiba, M.
dc.contributor.authorMabuchi, H.
dc.contributor.authorRabès, J.P.
dc.contributor.authorCarrié, A.
dc.contributor.authorvan Heyningen, C.
dc.contributor.authorCarreau, V.
dc.contributor.authorFarnier, M.
dc.contributor.authorTeoh, Y.P.
dc.contributor.authorBourbon, M.
dc.contributor.authorKawashiri, M.A.
dc.contributor.authorNohara, A.
dc.contributor.authorSoran, H.
dc.contributor.authorMarais, A.D.
dc.contributor.authorTada, H.
dc.contributor.authorAbifadel, M.
dc.contributor.authorBoileau, C.
dc.contributor.authorChanu, B.
dc.contributor.authorKatsuda, S.
dc.contributor.authorKishimoto, I.
dc.contributor.authorLambert, G.
dc.contributor.authorMakino, H.
dc.contributor.authorMiyamoto, Y.
dc.contributor.authorPichelin, M.
dc.contributor.authorYagi, K.
dc.contributor.authorYamagishi, M.
dc.contributor.authorZair, Y.
dc.contributor.authorMellis, S.
dc.contributor.authorYancopoulos, G.D.
dc.contributor.authorStahl, N.
dc.contributor.authorMendoza, J.
dc.contributor.authorDu, Y.
dc.contributor.authorHamon, S.
dc.contributor.authorKrempf, M.
dc.contributor.authorSwergold, G.D.
dc.date.accessioned2015-09-30T11:52:56Z
dc.date.available2015-09-30T11:52:56Z
dc.date.issued2015-09-15
dc.description.abstractBACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: -We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing four different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) >70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: Among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset 49.4 years) and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: In PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared to placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary endpoint). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: -PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk for premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and appears to be well tolerated in these patients. Clinical Trial Registration-www.clinicaltrials.gov; Unique Identifier: NCT01604824pt_PT
dc.description.sponsorshipThese studies were sponsored by Regeneron Pharmaceuticals Inc. and Sanofi.pt_PT
dc.identifier.citationCirc Cardiovasc Genet. 2015 Dec;8(6):823-31. doi: 10.1161/CIRCGENETICS.115.001129. Epub 2015 Sep 15.pt_PT
dc.identifier.doi10.1161/CIRCGENETICS.115.001129
dc.identifier.issn1942-325X
dc.identifier.urihttp://hdl.handle.net/10400.18/3173
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Heart Associationpt_PT
dc.relation.publisherversionhttp://circgenetics.ahajournals.org/content/early/2015/09/15/CIRCGENETICS.115.001129.full.pdfpt_PT
dc.subjectPCSK9pt_PT
dc.subjectAlirocumabpt_PT
dc.subjectCardiovascular Diseasept_PT
dc.subjectClinical Trialpt_PT
dc.subjectGeneticspt_PT
dc.subjectHypercapniapt_PT
dc.subjectHypercholesterolemiapt_PT
dc.subjectPCSK9pt_PT
dc.subjectDoenças Cardio e Cérebro-vascularespt_PT
dc.titleCharacterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and its Specific Treatment with Alirocumab, a PCSK9 Monoclonal Antibodypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage43pt_PT
oaire.citation.startPage1pt_PT
oaire.citation.titleCirculation: Cardiovascular Geneticspt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT

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