ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia—Brief Report
Open accessAbstract
Objective: The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. Approach and Results: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5- 2 H 3 )-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59±2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616±504% and 113±14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. Conclusions: In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04722068.
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ANGPTL3 blockade increases fractional catabolic rates of IDL and LDL apoB, supporting a clearance-driven mechanism of LDL reduction.
“The resulting increase in fractional catabolic rates of IDL and LDL apoB supports a clearance-driven mechanism of LDL reduction under ANGPTL3 blockade [58].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [58]
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“…with the ability to target ANGPTL3 has developed, and it has been demonstrated that this drug can reduce lipid levels through several mechanisms [68,70], suggesting that targeting ANGPTL3 may be a compelling therapeutic option for the management of HoFH patients [71] and has an effect on LDL-C…”
BackgroundRNA interference-based therapies for the control of atherosclerosis risk factors
Kettunen, S., Ruotsalainen, A., & Ylä‐Herttuala, S. (2022) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000972 · Cited by 10 · see citing works
Proof-of-concept study for liver-directed miQURE technology in a dyslipidemic mouse model
Zancanella, V., Vallès, A., Liefhebber, J. M. P., Paerels, L., Vendrell‐Tornero, C., Wattimury, H., van der Zon, T., van Rooijen, K., Golinska, M. A., Grevelink, T., et al. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.04.004 · Cited by 5 · see citing works
“Consequently, loss-of-function ANGPTL3 variants and inhibition of ANGPTL3 using evinacumab are associated with low levels of plasma TGs and VLDL-C/LDL-C, moderately low levels of HDL-C and reduced cardiovascular risk.(34,35,52,53) As expected, mean plasma levels of TG and TCwere significantly reduced in dyslipidemic m…”
BackgroundWhite, R. T., Sankey, K. H., & Nawarskas, J. J. (2023) · Cardiology in Review · doi:10.1097/crd.0000000000000522 · Cited by 6 · see citing works
Ginsberg, H. N., & Goldberg, I. J. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.317966 · Cited by 83 · see citing works
ANGPTL3 and residual atherosclerotic risk: from lipid metabolism to therapeutic targeting
Weng, S., Ding, C., Lin, J., & Chai, D. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1706091 · Cited by 5 · see citing works
Innovative Lipid-Lowering Strategies: RNA-Based, Small Molecule, and Protein-Based Therapies
Jang, Y., Rhee, E., & Choi, S.-H. (2025) · Endocrinology and Metabolism · doi:10.3803/enm.2025.2691 · Cited by 5
“In pivotal trials, evinacumab demonstrated robust reductions in LDL-C (up to 50%), TRLs, and apoB-containing particles, with notable increases in the clearance of IDL and LDL [58].”
Angiopoietin-like Protein 3 (ANGPTL3) Targeting in the Management of Dyslipidemias
Kosmas, C. E., Rallidis, L., Hoursalas, I., Papakonstantinou, E. J., & Kostara, C. E. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020921 · Cited by 4
“…that the evinacumab-mediated inhibition of ANGPTL3 was associated with an increase in the fractional catabolic rate of IDL-apoB and LDL-apoB, suggesting that evinacumab lowers LDL-cholesterol levels primarily by increasing the clearance of apoB-containing lipoprotein from the circulation [32].”
Evinacumab Therapy for Homozygous Familial Hypercholesterolemia
Toth, P. P. (2023) · JACC Advances · doi:10.1016/j.jacadv.2023.100646 · Cited by 2 · see citing works
Chan, D. C., Ying, Q., & Watts, G. F. (2021) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000795 · Cited by 6 · see citing works
Alam, U., Mathai, S. V., Filtz, A., Kuno, T., Badimon, J. J., Sniderman, A. D., Virani, S. S., Toth, P. P., Shapiro, M. D., Lavie, C. J., et al. (2026) · Current Cardiology Reports · doi:10.1007/s11886-025-02337-1 · Cited by 4 · see citing works
“While the risk of pancreatitis increases substantially with severe and LDL apoB supports a clearance-driven mechanism of LDL reduction under ANGPTL3 blockade [ 58 ].”
Olatunji, G., Kokori, E., Moradeyo, A., Lema, K., Ayo, O., Obasanjo, O. M., Mustapha, M., Stanley, A. C., & Aderinto, N. (2024) · The Egyptian Journal of Internal Medicine · doi:10.1186/s43162-024-00335-3 · Cited by 3 · see citing works
“Reeskamp et al. (2021) reported no adverse reactions during their study, indicating a favorable safety profile [18].”
BackgroundHomozygous Familial Hypercholesterolemia
Young, L., Brown, E. E., & Martin, S. (2022) · JACC Case Reports · doi:10.1016/j.jaccas.2022.10.005 · Cited by 3
“Genetic testing, and PCSK9 and angiopoietin-like 3 inhibitors, have emerged as promising diagnostic tools and therapies, respectively.(3,4) HoFH, an autosomal codominant disorder, involves defective LDL receptor structure or function because of loss-offunction variants in LDLR, APOB, or LDLRAP genes or gain-of-functio…”
McIntosh, C. S., Watts, G., Wilton, S., & Aung-Htut, M. (2021) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000793 · Cited by 3 · see citing works
Angiopoietin-like protein 3 inhibitors and contemporary unmet needs in lipid management
Ying, Q., Chan, D. C., & Watts, G. F. (2021) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000747 · Cited by 4 · see citing works
Are we underestimating the benefits of lipid-lowering therapies?
Pirillo, A., Casula, M., Olmastroni, E., Scotti, S., Corsini, A., & Catapano, A. L. (2026) · Pharmacological Reviews · doi:10.1016/j.pharmr.2026.100140 · Cited by 2 · see citing works
Promise of ANGPTL3 as a therapeutic target for controlling cholesterol levels
Hegele, R. A. (2026) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2026.2671686 · Cited by 1 · see citing works
Bakour, H. A., Timraz, J. H., Saddiq, B. W. B., Alghamdi, N. A., Thalib, H. I., Alyarimi, M., & Algarni, I. A. (2025) · Cureus · doi:10.7759/cureus.78032
“While the drug is generally well-tolerated, these side effects, along with potential concerns about glucose metabolism and adipose tissue function, require further investigation [13].”
Arca, M., Björnson, E., D’Erasmo, L., Costanzo, A. D., Bini, S., Minicocci, I., Tramontano, D., Covino, S., Ciarlo, G., Lombardi, M., et al. (2026) · Journal of Internal Medicine · doi:10.1111/joim.70124 · Cited by 2 · see citing works
Biolo, M., Lupo, M., Marodin, G., Portinari, C., Zambon, A., Bertocco, S., Previato, L., Simioni, P., Ferri, N., & Zambon, S. (2026) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2026.03.014 · Cited by 1 · see citing works
Breaking barriers: Innovative therapies for managing homozygous familial hypercholesterolemia
Huang, S.-J., Huang, P. H., Song, N.-N., Jia, X.-H., Gao, H., Lu, Z., & Wen, X. (2025) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2025.105003 · Cited by 1 · see citing works
Evinacumab Improved the Homozygous Familial Hypercholesterolemia Lipid Metabolism: A Case Report
Matsuda, T., Osaki, Y., Matsumoto, N., Nakajima, R., Murayama, Y., Sugano, Y., IWASAKI, H. O., Mathis, B. J., Sekiya, M., & Shimano, H. (2025) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.65925 · Cited by 1 · see citing works
“HPLC showed reductions across multiple cholesterol fractions, which is consistent with previous reports 9, 58) .”
InfluentialThe Role of Genetics in Managing Peripheral Arterial Disease
Biagetti, G. M., Thompson, E. W., O’Brien, C., & Damrauer, S. M. (2024) · Annals of Vascular Surgery · doi:10.1016/j.avsg.2024.04.022 · Cited by 2 · see citing works
Tracing the lipidome in inborn errors of metabolism
Zandl‐Lang, M. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2024.159491 · Cited by 2 · see citing works
El-Bawab, E.-S. M. E.-S., Alomairi, M., Kabeer, A. M. E., & Abd-Allah, S. (2023) · Al-Azhar Assiut Medical Journal · doi:10.4103/azmj.azmj_22_24 · Cited by 1 · see citing works
Valle, C. D., Zuin, M., & Bilato, C. (2026) · European Journal of Clinical Investigation · doi:10.1111/eci.70267
“ANGPTL3 inhibition enhances lipoprotein lipase and endothelial lipase activity and promotes the clearance of atherogenic lipoproteins through mechanisms that do not depend on LDL-receptor function [65].”
A Nutrient-Dependent ANGPTL3–PCSK9-Containing Complex in HepG2 Cells and Human Plasma
Bini, S., Pecce, V., Grimaldos, A. P., Costanzo, A. D., Minicocci, I., Covino, S., Tramontano, D., Piconese, S., D’Erasmo, L., & Arca, M. (2026) · Biomolecules · doi:10.3390/biom16101531
“Additionally, studies in individuals with ANGPTL3 activity inhibited by monoclonal antibodies suggested that this protein may also contribute to the LDLR-dependent clearance of ApoB-containing lipoproteins [17].”
Shahid, R. S., Habib, S. M., Awan, M., Usman, M. A., & Mushtaq, M. (2026) · Journal of clinical lipidology · doi:10.1016/j.jacl.2026.10.011
Ruotolo, G., Harris, C., Lin, Y., Wilson, J. M., Pirro, V., Duffin, K. L., Thomas, M. K., Hartman, M. L., Neill, C. O., Coşkun, T., et al. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.71200
“In a subgroup of these patients, adjunctive selective approaches targeting apoC-III, ANGPTL3, ANGPTL3/8 or ANGPTL4 might be considered [32, 35–38].”
From discovery to therapeutic development of monoclonal antibodies
Rojekar, S. V., Gholap, A. D., Pallapati, A., Latif, R., Angsantikul, P., Kommineni, N., Sultana, F., Macdonald, A., Vasilyeva, D., Sims, S. L., et al. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115034
Schonck, W. A. M., Crosti, C., Marchesin, A., Gallo, A., Kayikcioglu, M., Banach, M., Cuchel, M., Jones, R., Kainth, P., Catapano, A., et al. (2025) · European Atherosclerosis Journal · doi:10.56095/eaj.v4i3.115
“Clinical studies have demonstrated that Evinacumab can reduce LDL-C levels by approximately 50% in patients with HoFH, representing a substantial improvement compared to conventional LLTs [4-6].”
Self-citationDoes siRNA therapy against ANGPTL3 bring new hope in homozygous familial hypercholesterolaemia?
Santos, R. D. (2025) · The Lancet Diabetes and Endocrinology · doi:10.1016/s2213-8587(25)00330-4
Antibody-Based Therapeutics for Hypercholesterolemia
Tomlinson, B., & Chan, P. (2025) · Biologics · doi:10.2147/btt.s500456 · Cited by 1 · see citing works
Pro-Inflammatory and Lipid Metabolism Dysregulating Effects of ANGPTL3 in THP-1 Macrophages
Milani, I., Rossi, I., Marodin, G., Lupo, M. G., Adorni, M. P., Zimetti, F., & Ferri, N. (2025) · Lipidology · doi:10.3390/lipidology2030014
“This finding supports the hypothesis that evinacumab primarily lowers LDL cholesterol by enhancing the clearance of apoB-containing lipoproteins from circulation [11].”
Zhang, P., Wang, K., Hu, T., Xu, M., You, X., Chen, M., Tang, X. L., Hu, H., Jiang, Y., Zhao, W., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202301564rr · Cited by 1 · see citing works
“17,78,79 In our study, it was observed that treatment with F1519-D95aA for 8 weeks not only potently reduced the serum TG and LDL-C levels, but also more effectively lowered the level of ApoB in serum than its parent F1519 and Evinacumab.”
BackgroundClinical and Therapeutic Applications of Individual-level Tissue-Specific Imputed Transcriptomes
Wang, X., Selvaggi, C., Weng, L.-C., Jurgens, S., Choi, S., Jha, A., Cao, T., Koyama, S., Ramo, J., Kany, S., et al. (2022) · medRxiv · doi:10.1101/2022.11.23.22282644
“Indeed, ANGPTL3 is the target of a group of new medications that inhibit its expression in the liver to treat hypercholesterolemia.(19) Another interesting .”
Background
- Authors
- Reeskamp, L. F., Millar, J. S., Wu, L., Jansen, H., van Harskamp, D., Schierbeek, H., Gipe, D. A., Rader, D. J., Dallinga-Thie, G. M., Hovingh, G. K., & Cuchel, M.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Pennsylvania (US)
- Division of Translational Medicine and Human Genetics, Department of Medicine (J.S.M., L.W., D.J.R., M.C.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
- Stable Isotope Research Laboratory, Endocrinology, Vrije Universiteit (D.v.H., H.S.), Amsterdam UMC, location AMC, University of Amsterdam, The Netherlands.
- Regeneron (United States) (US)
- Corresponding author
- Cuchel, Marina
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2021-05-05
- Volume
- 41
- Issue
- 5
- Pages
- 1753-1759
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC8057526
- OpenAlex
- W3135251972
- Cited by
- 109
- References
- 22
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 25 · 2023: 17 · 2022: 22 · 2021: 17 · 2020: 1
- FWCI
- 19.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Regeneron Pharmaceuticals
- National Institutes of Health (UL1TR001878)
- National Heart, Lung, and Blood Institute (R01HL148769)
- National Center for Advancing Translational Sciences
- 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
- evinacumab, homozygous familial hypercholesterolemia, apolipoprotein B, intermediate density lipoprotein, LDL cholesterol, fractional catabolic rate, lipoprotein clearance, monoclonal antibody therapy
- MeSH terms
- Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Adult, Antibodies, Monoclonal, Anticholesteremic Agents, Female, Homozygote, Humans, Hyperlipoproteinemia Type II, Lipoproteins, LDL, Cholesterol, LDL, Liver, Male, Mutation, Netherlands, Pennsylvania, Phenotype, Receptors, LDL, Time Factors, Biomarkers, Treatment Outcome, Genetic Predisposition to Disease, Apolipoprotein B-100, Lipoproteins, IDL
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