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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment with Alirocumab, a PCSK9 Monoclonal Antibody
Circulation: Cardiovascular Genetics, Volume 8, No. 6, Year 2015
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Description
Background-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 4 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 with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). 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 of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824. © 2015 The Authors.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC5098466/bin/hcg-8-823-s001.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC5098466/bin/hcg-8-823-s002.doc
https://efashare.b-cdn.net/share/pmc/articles/PMC5098466/bin/hcg-8-823-s003.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC5098466/bin/hcg-8-823-s004.pdf
Authors & Co-Authors
Hopkins, Paul Nathan
United States, Salt Lake City
The University of Utah
Defesche, Joep C.
United States, Salt Lake City
The University of Utah
Fouchier, Sigrid W.
United States, Salt Lake City
The University of Utah
Bruckert, Éric
United States, Salt Lake City
The University of Utah
Luc, Gérald
United States, Salt Lake City
The University of Utah
Cariou, Bertrand
United States, Salt Lake City
The University of Utah
Sjouke, B.
United States, Salt Lake City
The University of Utah
Leren, Trond Paul
United States, Salt Lake City
The University of Utah
Harada-Shiba, Mariko
United States, Salt Lake City
The University of Utah
Mabuchi, Hiroshi
United States, Salt Lake City
The University of Utah
Rabès, Jean Pierre H.
United States, Salt Lake City
The University of Utah
Carrié, Alain
United States, Salt Lake City
The University of Utah
van Heyningen, Charles
United States, Salt Lake City
The University of Utah
Carreau, Valérie
United States, Salt Lake City
The University of Utah
Farnier, Michel
United States, Salt Lake City
The University of Utah
Bourbon, Mafalda
United States, Salt Lake City
The University of Utah
Kawashiri, Masaaki Aski
United States, Salt Lake City
The University of Utah
Nohara, Atsushi
United States, Salt Lake City
The University of Utah
Soran, Handrean
United States, Salt Lake City
The University of Utah
Marais, Adrian David
United States, Salt Lake City
The University of Utah
Tada, Hayato
United States, Salt Lake City
The University of Utah
Abifadel, Marianne S.
United States, Salt Lake City
The University of Utah
Boileau, Catherine R.
United States, Salt Lake City
The University of Utah
Chanu, Bernard
United States, Salt Lake City
The University of Utah
Lambert, Gilles
United States, Salt Lake City
The University of Utah
Miyamoto, Yoshihiro
United States, Salt Lake City
The University of Utah
Yamagishi, Masakazu
United States, Salt Lake City
The University of Utah
Zaïr, Yassine
United States, Salt Lake City
The University of Utah
Yancopoulos, George D.
United States, Salt Lake City
The University of Utah
Krempf, Michael A.
United States, Salt Lake City
The University of Utah
Statistics
Citations: 92
Authors: 30
Affiliations: 1
Identifiers
Doi:
10.1161/CIRCGENETICS.115.001129
ISSN:
1942325X
Research Areas
Cancer
Disability
Genetics And Genomics
Maternal And Child Health
Noncommunicable Diseases
Study Design
Randomised Control Trial
Cross Sectional Study
Cohort Study