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A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia

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Title: A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia
Authors: Brandts, J
Dharmayat, KI
Vallejo-Vaz, AJ
Azar Sharabiani, MT
Jones, R
Kastelein, JJP
Raal, FJ
Ray, KK
Item Type: Journal Article
Abstract: BACKGROUND AND AIMS: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. METHODS: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. RESULTS: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). CONCLUSIONS: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.
Issue Date: 1-May-2021
Date of Acceptance: 31-Mar-2021
URI: http://hdl.handle.net/10044/1/89241
DOI: 10.1016/j.atherosclerosis.2021.03.042
ISSN: 0021-9150
Publisher: Elsevier
Start Page: 46
End Page: 56
Journal / Book Title: Atherosclerosis
Volume: 325
Copyright Statement: © 2021 Elsevier B.V. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Familial hypercholesterolemia
PCSK9 lowering medication
Familial hypercholesterolemia
PCSK9 lowering medication
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Cardiovascular System & Hematology
Publication Status: Published
Conference Place: Ireland
Online Publication Date: 2021-04-20
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Central Services
Faculty of Medicine
School of Public Health

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