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

Julia Brandts; Kanika I Dharmayat; Antonio J Vallejo-Vaz; Mansour Taghavi Azar Sharabiani; Rebecca Jones; John J P Kastelein; Frederick J Raal; Kausik K Ray

doi:10.1016/j.atherosclerosis.2021.03.042

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

Atherosclerosis. 2021 May;325:46-56. doi: 10.1016/j.atherosclerosis.2021.03.042. Epub 2021 Apr 20.

Authors

Julia Brandts¹, Kanika I Dharmayat², Antonio J Vallejo-Vaz², Mansour Taghavi Azar Sharabiani², Rebecca Jones³, John J P Kastelein⁴, Frederick J Raal⁵, Kausik K Ray⁶

Affiliations

¹ Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom; Department of Medicine I, University Hospital RWTH Aachen, Aachen, Germany.
² Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.
³ Imperial College Library, Imperial College London, London, United Kingdom.
⁴ Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁵ Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁶ Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom. Electronic address: k.ray@imperial.ac.uk.

PMID: 33901739
DOI: 10.1016/j.atherosclerosis.2021.03.042

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 (Q_M = 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) (Q_M = 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.

Keywords: Familial hypercholesterolemia; Genotype; LDL-Cholesterol; Meta-analysis; PCSK9 lowering medication.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Anticholesteremic Agents* / therapeutic use
Cholesterol, LDL
Humans
Hyperlipoproteinemia Type II* / diagnosis
Hyperlipoproteinemia Type II* / drug therapy
Hyperlipoproteinemia Type II* / genetics
Pharmaceutical Preparations*
Proprotein Convertase 9 / genetics

Substances

Anticholesteremic Agents
Cholesterol, LDL
Pharmaceutical Preparations
PCSK9 protein, human
Proprotein Convertase 9