Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably Express the LDLR (Low-Density Lipoprotein Receptor): Implications for the Efficacy of Evolocumab
Open accessAbstract
Objective—: Evolocumab, a PCSK9 (proprotein convertase subtilisin kexin type 9)–neutralizing antibody, lowers low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemic (HoFH) patients with reduced LDLR (low-density lipoprotein receptor) function. However, their individual responses are highly variable, even among carriers of identical LDLR genetic defects. We aimed to elucidate why HoFH patients variably respond to PCSK9 inhibition. Approach and Results—: Lymphocytes were isolated from 22 HoFH patients enrolled in the TAUSSIG trial (Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders). Ten patients were true homozygotes (FH1/FH1) and 5 identical compound heterozygotes (FH1/FH2). Lymphocytes were plated with or without mevastatin, recombinant PCSK9 (rPCSK9), or a PCSK9-neutralizing antibody. Cell surface LDLR expression was analyzed by flow cytometry. All HoFH lymphocytes had reduced cell surface LDLR expression compared with non-FH lymphocytes, for each treatment modality. Lymphocytes from FH1/FH2 patients (LDLR defective/negative) displayed the lowest LDLR expression levels followed by lymphocytes from FH1/FH1 patients (defective/defective). Mevastatin increased, whereas rPCSK9 reduced LDLR expression. The PCSK9-neutralizing antibody restored LDLR expression. Lymphocytes displaying higher LDLR expression levels were those isolated from patients presenting with lowest levels of LDL-C and apolipoprotein B, before and after 24 weeks of evolocumab treatment. These negative correlations remained significant in FH1/FH1 patients and appeared more pronounced when patients with apolipoprotein E3/E3 genotypes were analyzed separately. Significant positive correlations were found between the levels of LDLR expression and the percentage reduction in LDL-C on evolocumab treatment. Conclusions—: Residual LDLR expression in HoFH is a major determinant of LDL-C levels and seems to drive their individual response to evolocumab.
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Genetic studies of NPC1L1 mutations support ezetimibe's benefit: naturally occurring inactivating mutations are associated with reduced plasma LDL-C and reduced coronary artery disease risk.
“The beneficial effect of ezetimibe is also supported by genetic studies of mutations in NPC1L1; naturally occurring mutations that inactivate the protein were found to be associated with reduced plasma LDL-C and reduced risk for CAD [55,269,270].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [269]
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References 18 · Cited by 105
- Authors
- Thedrez, A., Blom, D. J., Ramin-Mangata, S., Blanchard, V., Croyal, M., Chemello, K., Nativel, B., Pichelin, M., Cariou, B., Bourane, S., Tang, L., Farnier, M., Raal, F. J., & Lambert, G.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- From the CRNH Ouest, INRA UMR 1280 PhAN (A.T., V.B., M.C., G.L.) and L’institut du thorax, INSERM UMR 1087, CNRS UMR 6291 (A.T., M.P., B.C.), Université de Nantes, France; L’institut du thorax, CHU de Nantes, CIC Endocrino-Nutrition, France (A.T., M.P., B.C.); Lipidology Division of Internal Medicine, University of Cape Town, South Africa (D.J.B.); INSERM UMR 1188 DéTROI, Université de La Réunion, Sainte Clotilde, France (S.R.-M., V.B., K.C., B.N., S.B., G.L.); Amgen, Thousand Oaks, CA (L.T.); CHU...
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2018-03
- Volume
- 38
- Issue
- 3
- Pages
- 592-598
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC5823753
- OpenAlex
- W2778912952
- Cited by
- 105
- References
- 18
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 14 · 2023: 14 · 2022: 11 · 2021: 16 · 2020: 15 · 2019: 10 · 2018: 9
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-16-RHUS-0007)
- National Institutes of Health (NIH0010513932)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- homozygous familial hypercholesterolemia, LDL receptor, PCSK9 inhibition, evolocumab, mevastatin, LDL cholesterol, apolipoprotein E, compound heterozygosity, treatment response variability, lymphocytes
- MeSH terms
- Ezetimibe, Proprotein Convertase 9, PCSK9 Inhibitors, Adolescent, Adult, Antibodies, Monoclonal, Anticholesteremic Agents, Cells, Cultured, Drug Therapy, Combination, Female, Heterozygote, Homozygote, Humans, Hyperlipoproteinemia Type II, Cholesterol, LDL, Lovastatin, Lymphocytes, Male, Middle Aged, Mutation, Phenotype, Receptors, LDL, Serine Proteinase Inhibitors, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Genetic Predisposition to Disease, Apolipoprotein B-100, Young Adult, Antibodies, Monoclonal, Humanized
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