{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:16:26Z","timestamp":1790957786326,"version":"4.1.0"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:00:00Z","timestamp":1735862400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:00:00Z","timestamp":1735862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University of Cape Town"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Curr Atheroscler Rep"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Purpose of review<\/jats:title>\n            <jats:p>Homozygous familial hypercholesterolaemia (HoFH) is characterized by marked elevation of low-density lipoprotein cholesterol (LDLC) and premature atherosclerotic cardiovascular disease. This is a review of novel pharmacological therapies to lower LDLC in patients with HoFH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Recent findings<\/jats:title>\n            <jats:p>Novel therapies can be broadly divided by whether their efficacy is dependent or independent of residual low-density lipoprotein receptor (LDLR) function. Novel LDLR dependent therapies that reduce proprotein subtilisin kexin type 9 levels include monoclonal antibodies (alirocumab and evolocumab) and a small inhibitory RNA (inclisiran). LDLC reductions are highly variable and depend on residual LDLR function. Microsomal triglyceride inhibitors (lomitapide) and therapies that reduce angiopoietin like factor 3 (evinacumab and zodasiran) both reduce LDLC by approximately 50%, irrespective of residual LDLR function. <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Summary\n<\/jats:title>\n            <jats:p>Most patients with HoFH require multiple therapies to achieve LDLC targets. Better LDLC control with LDLR independent therapies is likely to improve the outlook for patients with HoFH while at the same time reducing the need for other therapies such as apheresis or hepatic transplantation. <\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s11883-024-01269-5","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T01:57:14Z","timestamp":1735869434000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Homozygous Familial Hypercholesterolemia Treatment: New Developments"],"prefix":"10.1007","volume":"27","author":[{"given":"Dirk J.","family":"Blom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. David","family":"Marais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick J.","family":"Raal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,3]]},"reference":[{"issue":"25","key":"1269_CR1","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1093\/eurheartj\/ehad197","volume":"44","author":"M Cuchel","year":"2023","unstructured":"Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on homozygous familial hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023;44(25):2277\u201391. https:\/\/doi.org\/10.1093\/eurheartj\/ehad197. Most recent consensus statement on the management of HoFH.","journal-title":"Eur Heart J"},{"issue":"9","key":"1269_CR2","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1093\/eurheartj\/ehu058","volume":"36","author":"B Sjouke","year":"2015","unstructured":"Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJ, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2015;36(9):560\u20135. https:\/\/doi.org\/10.1093\/eurheartj\/ehu058.","journal-title":"Eur Heart J"},{"issue":"2","key":"1269_CR3","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1097\/MOL.0000000000000664","volume":"31","author":"L D\u2019Erasmo","year":"2020","unstructured":"D\u2019Erasmo L, Di Costanzo A, Arca M. Autosomal recessive hypercholesterolemia: update for 2020. Curr Opin Lipidol. 2020;31(2):56\u201361. https:\/\/doi.org\/10.1097\/MOL.0000000000000664.","journal-title":"Curr Opin Lipidol"},{"issue":"4","key":"1269_CR4","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.jacl.2020.04.011","volume":"14","author":"EE Brown","year":"2020","unstructured":"Brown EE, Sturm AC, Cuchel M, Braun LT, Duell PB, Underberg JA, et al. Genetic testing in dyslipidemia: a scientific statement from the National Lipid Association. J Clin Lipidol. 2020;14(4):398\u2013413. https:\/\/doi.org\/10.1016\/j.jacl.2020.04.011.","journal-title":"J Clin Lipidol"},{"key":"1269_CR5","unstructured":"Tromp TR, Hartgers ML, Hovingh GK, Vallejo-Vaz AJ, Ray KK, Soran H et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet. 2022. doi: 10.1016\/S0140-6736(21)02001-8. The largest and most recent worldwide cohort study of patients with HoFH."},{"issue":"20","key":"1269_CR6","doi-asserted-by":"publisher","first-page":"2202","DOI":"10.1161\/CIRCULATIONAHA.111.042523","volume":"124","author":"FJ Raal","year":"2011","unstructured":"Raal FJ, Pilcher GJ, Panz VR, van Deventer HE, Brice BC, Blom DJ, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124(20):2202\u20137. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.111.042523. The first study to show that statin therapy was associated with improved outcomes in patients with HoFH.","journal-title":"Circulation"},{"issue":"14","key":"1269_CR7","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1093\/eurheartj\/ehx317","volume":"39","author":"GR Thompson","year":"2018","unstructured":"Thompson GR, Blom DJ, Marais AD, Seed M, Pilcher GJ, Raal FJ. Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol. Eur Heart J. 2018;39(14):1162\u20138. https:\/\/doi.org\/10.1093\/eurheartj\/ehx317. This study showed that survival was best in patients with the lowest LDLC.","journal-title":"Eur Heart J"},{"issue":"6","key":"1269_CR8","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/0002-9149(87)91199-4","volume":"59","author":"JM Hoeg","year":"1987","unstructured":"Hoeg JM, Starzl TE, Brewer HB. Jr. Liver transplantation for treatment of cardiovascular disease: comparison with medication and plasma exchange in homozygous familial hypercholesterolemia. Am J Cardiol. 1987;59(6):705\u20137.","journal-title":"Am J Cardiol"},{"issue":"6","key":"1269_CR9","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1111\/imj.12444","volume":"44","author":"MM Page","year":"2014","unstructured":"Page MM, Ekinci EI, Jones RM, Angus PW, Gow PJ, O\u2019Brien RC. Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid-lowering therapies. Intern Med J. 2014;44(6):601\u20134. https:\/\/doi.org\/10.1111\/imj.12444.","journal-title":"Intern Med J"},{"key":"1269_CR10","first-page":"295","volume":"255","author":"DW Bilheimer","year":"1988","unstructured":"Bilheimer DW. Portacaval shunt surgery and liver transplantation in the treatment of homozygous familial hypercholesterolemia. Prog Clin Biol Res. 1988;255:295\u2013304.","journal-title":"Prog Clin Biol Res"},{"issue":"1 Suppl","key":"1269_CR11","first-page":"I152","volume":"9","author":"GR Thompson","year":"1989","unstructured":"Thompson GR, Barbir M, Okabayashi K, Trayner I, Larkin S. Plasmapheresis in familial hypercholesterolemia. Arteriosclerosis. 1989;9(1 Suppl):I152\u20137.","journal-title":"Arteriosclerosis"},{"issue":"1","key":"1269_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0021-9150(02)00251-4","volume":"167","author":"GR Thompson","year":"2003","unstructured":"Thompson GR. LDL apheresis. Atherosclerosis. 2003;167(1):1\u201313.","journal-title":"Atherosclerosis"},{"issue":"6","key":"1269_CR13","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1097\/MOL.0b013e32833e13fd","volume":"21","author":"GR Thompson","year":"2010","unstructured":"Thompson GR. Lipoprotein apheresis. Curr Opin Lipidol. 2010;21(6):487\u201391. https:\/\/doi.org\/10.1097\/MOL.0b013e32833e13fd.","journal-title":"Curr Opin Lipidol"},{"issue":"10","key":"1269_CR14","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.1016\/S0022-2275(20)37137-6","volume":"38","author":"AD Marais","year":"1997","unstructured":"Marais AD, Naoumova RP, Firth JC, Penny C, Neuwirth CK, Thompson GR. Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia. J Lipid Res. 1997;38(10):2071\u20138.","journal-title":"J Lipid Res"},{"issue":"21","key":"1269_CR15","doi-asserted-by":"publisher","first-page":"2469","DOI":"10.1161\/01.CIR.0000018744.58460.62","volume":"105","author":"C Gagne","year":"2002","unstructured":"Gagne C, Gaudet D, Bruckert E, Ezetimibe Study G. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105(21):2469\u201375.","journal-title":"Circulation"},{"issue":"2","key":"1269_CR16","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1056\/NEJMoa061189","volume":"356","author":"M Cuchel","year":"2007","unstructured":"Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356(2):148\u201356. https:\/\/doi.org\/10.1056\/NEJMoa061189.","journal-title":"N Engl J Med"},{"issue":"9860","key":"1269_CR17","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/S0140-6736(12)61731-0","volume":"381","author":"M Cuchel","year":"2013","unstructured":"Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40\u20136. https:\/\/doi.org\/10.1016\/S0140-6736(12)61731-0. This is the pivotal study that led to the registration of lomitapide.","journal-title":"Lancet"},{"issue":"3","key":"1269_CR18","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1161\/CIRCULATIONAHA.117.028208","volume":"136","author":"DJ Blom","year":"2017","unstructured":"Blom DJ, Averna MR, Meagher EA, du Toit Theron H, Sirtori CR, Hegele RA, et al. Long-term efficacy and safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in patients with homozygous familial hypercholesterolemia. Circulation. 2017;136(3):332\u20135. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.117.028208.","journal-title":"Circulation"},{"issue":"5","key":"1269_CR19","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1093\/eurjpc\/zwab229","volume":"29","author":"L D\u2019Erasmo","year":"2022","unstructured":"D\u2019Erasmo L, Steward K, Cefal\u00f9 AB, Di Costanzo A, Boersma E, Bini S, et al. Efficacy and safety of lomitapide in homozygous familial hypercholesterolaemia: the pan-european retrospective observational study. Eur J Prev Cardiol. 2022;29(5):832\u201341. https:\/\/doi.org\/10.1093\/eurjpc\/zwab229. The largest cohort study of lomitapide published thus far.","journal-title":"Eur J Prev Cardiol"},{"issue":"1","key":"1269_CR20","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1186\/s13023-021-01999-8","volume":"16","author":"L D\u2019Erasmo","year":"2021","unstructured":"D\u2019Erasmo L, Gallo A, Cefalu AB, Di Costanzo A, Saheb S, Giammanco A, et al. Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey. Orphanet J Rare Dis. 2021;16(1):381. https:\/\/doi.org\/10.1186\/s13023-021-01999-8.","journal-title":"Orphanet J Rare Dis"},{"issue":"7","key":"1269_CR21","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1007\/s12325-019-00985-8","volume":"36","author":"T Ben-Omran","year":"2019","unstructured":"Ben-Omran T, Masana L, Kolovou G, Ariceta G, Novoa FJ, Lund AM, et al. Real-world outcomes with Lomitapide Use in Paediatric patients with homozygous familial hypercholesterolaemia. Adv Ther. 2019;36(7):1786\u2013811. https:\/\/doi.org\/10.1007\/s12325-019-00985-8.","journal-title":"Adv Ther"},{"key":"1269_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2019.03.001","author":"APM Chacra","year":"2019","unstructured":"Chacra APM, Ferrari MC, Rocha VZ, Santos RD. Case report: the efficiency and safety of lomitapide in a homozygous familial hypercholesterolemic child. J Clin Lipidol. 2019. https:\/\/doi.org\/10.1016\/j.jacl.2019.03.001.","journal-title":"J Clin Lipidol"},{"key":"1269_CR23","doi-asserted-by":"publisher","first-page":"S23","DOI":"10.1016\/j.atherosclerosis.2023.06.945","volume":"379","author":"L Masana","year":"2023","unstructured":"Masana L, Zambon A, Schmitt C, Taylan C, Driemeyer J, Cohen H, et al. Lomitapide for the treatment of paediatric homozygous familial hypercholesterolaemia patients - results from the efficacy phase of the APH-19 study. Atherosclerosis. 2023;379:S23\u20134. https:\/\/doi.org\/10.1016\/j.atherosclerosis.2023.06.945.","journal-title":"Atherosclerosis"},{"issue":"2","key":"1269_CR24","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.jacl.2015.11.011","volume":"10","author":"DJ Blom","year":"2016","unstructured":"Blom DJ, Fayad ZA, Kastelein JJ, Larrey D, Makris L, Schwamlein C, et al. LOWER, a registry of lomitapide-treated patients with homozygous familial hypercholesterolemia: Rationale and design. J Clin Lipidol. 2016;10(2):273\u201382. https:\/\/doi.org\/10.1016\/j.jacl.2015.11.011.","journal-title":"J Clin Lipidol"},{"issue":"6","key":"1269_CR25","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.jacl.2020.08.006","volume":"14","author":"JA Underberg","year":"2020","unstructured":"Underberg JA, Cannon CP, Larrey D, Makris L, Blom D, Phillips H. Long-term safety and efficacy of lomitapide in patients with homozygous familial hypercholesterolemia: five-year data from the Lomitapide Observational Worldwide evaluation Registry (LOWER). J Clin Lipidol. 2020;14(6):807\u201317. https:\/\/doi.org\/10.1016\/j.jacl.2020.08.006.","journal-title":"J Clin Lipidol"},{"issue":"2","key":"1269_CR26","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1111\/liv.15497","volume":"43","author":"D Larrey","year":"2023","unstructured":"Larrey D, D\u2019Erasmo L, O\u2019Brien S, Arca M, Italian Working Group on L. Long-term hepatic safety of lomitapide in homozygous familial hypercholesterolaemia. Liver Int. 2023;43(2):413\u201323. https:\/\/doi.org\/10.1111\/liv.15497. This study summarizes hepatic safety data for lomitapide from multiple cohorts.","journal-title":"Liver Int"},{"issue":"9719","key":"1269_CR27","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/S0140-6736(10)60284-X","volume":"375","author":"FJ Raal","year":"2010","unstructured":"Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998\u20131006. https:\/\/doi.org\/10.1016\/S0140-6736(10)60284-X. The pivotal study of mipomersen in HoFH.","journal-title":"Lancet"},{"key":"1269_CR28","doi-asserted-by":"publisher","unstructured":"Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arteriosclerosis, thrombosis, and vascular biology. 2015;35(3):689\u201399. https:\/\/doi.org\/10.1161\/ATVBAHA.114.304549","DOI":"10.1161\/ATVBAHA.114.304549"},{"issue":"6","key":"1269_CR29","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.jacl.2014.08.002","volume":"8","author":"N Hashemi","year":"2014","unstructured":"Hashemi N, Odze RD, McGowan MP, Santos RD, Stroes ESG, Cohen DE. Liver histology during Mipomersen therapy for severe hypercholesterolemia. J Clin Lipidol. 2014;8(6):606\u201311. https:\/\/doi.org\/10.1016\/j.jacl.2014.08.002.","journal-title":"J Clin Lipidol"},{"issue":"8","key":"1269_CR30","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1373\/clinchem.2016.255794","volume":"62","author":"FJ Raal","year":"2016","unstructured":"Raal FJ, Stein EA. The effects of Mipomersen on inhibiting hepatic VLDL apolipoprotein B100 synthesis and propensity for Hepatic Steatosis. Clin Chem. 2016;62(8):1052\u20133. https:\/\/doi.org\/10.1373\/clinchem.2016.255794.","journal-title":"Clin Chem"},{"issue":"6","key":"1269_CR31","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1097\/MOL.0b013e3283587563","volume":"23","author":"DA Marais","year":"2012","unstructured":"Marais DA, Blom DJ, Petrides F, Goueffic Y, Lambert G. Proprotein convertase subtilisin\/kexin type 9 inhibition. Curr Opin Lipidol. 2012;23(6):511\u20137. https:\/\/doi.org\/10.1097\/MOL.0b013e3283587563.","journal-title":"Curr Opin Lipidol"},{"issue":"2","key":"1269_CR32","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/ng1161","volume":"34","author":"M Abifadel","year":"2003","unstructured":"Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154\u20136. https:\/\/doi.org\/10.1038\/ng1161.","journal-title":"Nat Genet"},{"issue":"3","key":"1269_CR33","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1097\/MOL.0000000000000072","volume":"25","author":"FK Welty","year":"2014","unstructured":"Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol. 2014;25(3):161\u20138. https:\/\/doi.org\/10.1097\/MOL.0000000000000072.","journal-title":"Curr Opin Lipidol"},{"issue":"40","key":"1269_CR34","doi-asserted-by":"publisher","first-page":"4272","DOI":"10.1093\/eurheartj\/ehad596","volume":"44","author":"F Raal","year":"2023","unstructured":"Raal F, Fourie N, Scott R, Blom D, De Vries Basson M, Kayikcioglu M, et al. Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial. Eur Heart J. 2023;44(40):4272\u201380. https:\/\/doi.org\/10.1093\/eurheartj\/ehad596.","journal-title":"Eur Heart J"},{"issue":"20","key":"1269_CR35","doi-asserted-by":"publisher","first-page":"2408","DOI":"10.1161\/CIRCULATIONAHA.112.144055","volume":"126","author":"F Raal","year":"2012","unstructured":"Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin\/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation. 2012;126(20):2408\u201317. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.112.144055.","journal-title":"Circulation"},{"issue":"9965","key":"1269_CR36","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/S0140-6736(14)61399-4","volume":"385","author":"FJ Raal","year":"2015","unstructured":"Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331\u201340. https:\/\/doi.org\/10.1016\/S0140-6736(14)61399-4.","journal-title":"Lancet"},{"issue":"19","key":"1269_CR37","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1161\/CIRCULATIONAHA.113.004678","volume":"128","author":"EA Stein","year":"2013","unstructured":"Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin\/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128(19):2113\u201320. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.113.004678. The first trial to evaluate the use of PCSK9 inhibitors in patients with HoFH.","journal-title":"Circulation"},{"issue":"9965","key":"1269_CR38","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/S0140-6736(14)61374-X","volume":"385","author":"FJ Raal","year":"2015","unstructured":"Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341\u201350. https:\/\/doi.org\/10.1016\/S0140-6736(14)61374-X. The first large study of a PCSK9 inhibitor in HoFH.","journal-title":"Lancet"},{"issue":"3","key":"1269_CR39","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1161\/ATVBAHA.117.310217","volume":"38","author":"A Thedrez","year":"2018","unstructured":"Thedrez A, Blom DJ, Ramin-Mangata S, Blanchard V, Croyal M, Chemello K, et al. Homozygous familial hypercholesterolemia patients with identical mutations variably Express the LDLR (low-Density lipoprotein receptor): implications for the efficacy of Evolocumab. Arterioscler Thromb Vasc Biol. 2018;38(3):592\u20138. https:\/\/doi.org\/10.1161\/ATVBAHA.117.310217.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"6","key":"1269_CR40","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.jacc.2019.12.020","volume":"75","author":"RD Santos","year":"2020","unstructured":"Santos RD, Stein EA, Hovingh GK, Blom DJ, Soran H, Watts GF, et al. Long-term evolocumab in patients with familial hypercholesterolemia. J Am Coll Cardiol. 2020;75(6):565\u201374. https:\/\/doi.org\/10.1016\/j.jacc.2019.12.020.","journal-title":"J Am Coll Cardiol"},{"issue":"2","key":"1269_CR41","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.jacc.2020.05.027","volume":"76","author":"DJ Blom","year":"2020","unstructured":"Blom DJ, Harada-Shiba M, Rubba P, Gaudet D, Kastelein JJP, Charng MJ, et al. Efficacy and safety of Alirocumab in adults with homozygous familial hypercholesterolemia: the ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020;76(2):131\u201342. https:\/\/doi.org\/10.1016\/j.jacc.2020.05.027.","journal-title":"J Am Coll Cardiol"},{"issue":"6","key":"1269_CR42","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1016\/j.jacl.2021.10.003","volume":"15","author":"S Bansal","year":"2021","unstructured":"Bansal S, Ruzza A, Sawhney J, Kulkarni G, Iyengar S, Mehta V, et al. Evolocumab in patients with homozygous familial hypercholesterolemia in India. J Clin Lipidol. 2021;15(6):814\u201321. https:\/\/doi.org\/10.1016\/j.jacl.2021.10.003.","journal-title":"J Clin Lipidol"},{"key":"1269_CR43","doi-asserted-by":"publisher","unstructured":"Bruckert E, Caprio S, Wiegman A, Charng MJ, Zarate-Morales CA, Baccara-Dinet MT et al. Efficacy and safety of Alirocumab in Children and adolescents with homozygous familial hypercholesterolemia: phase 3, multinational open-label study. Arteriosclerosis, thrombosis, and vascular biology. 2022;42(12):1447\u201357. https:\/\/doi.org\/10.1161\/ATVBAHA.122.317793","DOI":"10.1161\/ATVBAHA.122.317793"},{"key":"1269_CR44","doi-asserted-by":"publisher","unstructured":"Raal FJ, Hegele RA, Ruzza A, Lopez JAG, Bhatia AK, Wu J et al. Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies. Arteriosclerosis, thrombosis, and vascular biology. 2024;44(5):1156\u201364. https:\/\/doi.org\/10.1161\/ATVBAHA.123.320268","DOI":"10.1161\/ATVBAHA.123.320268"},{"key":"1269_CR45","doi-asserted-by":"publisher","first-page":"S24","DOI":"10.1016\/j.atherosclerosis.2023.06.948","volume":"379","author":"F Raal","year":"2023","unstructured":"Raal F, Mehta V, Kayikcioglu M, Blom D, Gupta P, Daniels C, et al. Randomized, open-label, cross-over, phase-3 study to evaluate efficacy and safety of LIB003 compared with evolocumab in homozygous familial hypercholesterolaemia patients on stable lipid-lowering therapy (liberate-HOFH). Atherosclerosis. 2023;379:S24\u20135. https:\/\/doi.org\/10.1016\/j.atherosclerosis.2023.06.948.","journal-title":"Atherosclerosis"},{"issue":"6","key":"1269_CR46","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/j.jacc.2023.11.029","volume":"83","author":"DJ McClintick","year":"2024","unstructured":"McClintick DJ, O\u2019Donoghue ML, De Ferrari GM, Ferreira J, Ran X, Im K, et al. Long-term efficacy of Evolocumab in patients with or without Multivessel Coronary Disease. J Am Coll Cardiol. 2024;83(6):652\u201364. https:\/\/doi.org\/10.1016\/j.jacc.2023.11.029.","journal-title":"J Am Coll Cardiol"},{"issue":"16","key":"1269_CR47","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1056\/NEJMoa1913805","volume":"382","author":"FJ Raal","year":"2020","unstructured":"Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520\u201330. https:\/\/doi.org\/10.1056\/NEJMoa1913805.","journal-title":"N Engl J Med"},{"issue":"22","key":"1269_CR48","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1161\/circulationaha.119.044431","volume":"141","author":"GK Hovingh","year":"2020","unstructured":"Hovingh GK, Lepor NE, Kallend D, Stoekenbroek RM, Wijngaard PLJ, Raal FJ. Inclisiran Durably Lowers Low-Density Lipoprotein Cholesterol and Proprotein Convertase Subtilisin\/Kexin Type 9 expression in homozygous familial hypercholesterolemia: the ORION-2 pilot study. Circulation. 2020;141(22):1829\u201331. https:\/\/doi.org\/10.1161\/circulationaha.119.044431.","journal-title":"Circulation"},{"issue":"5","key":"1269_CR49","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1161\/CIRCULATIONAHA.122.063460","volume":"149","author":"F Raal","year":"2024","unstructured":"Raal F, Durst R, Bi R, Talloczy Z, Maheux P, Lesogor A, et al. Efficacy, Safety, and tolerability of Inclisiran in patients with homozygous familial hypercholesterolemia: results from the ORION-5 Randomized Clinical Trial. Circulation. 2024;149(5):354\u201362 The pivotal study of inclisiran in HoFH.","journal-title":"Circulation"},{"issue":"12","key":"1269_CR50","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1016\/j.cjca.2023.06.002","volume":"39","author":"E Thorin","year":"2023","unstructured":"Thorin E, Labb\u00e9 P, Lambert M, Mury P, Dagher O, Miquel G, et al. Angiopoietin-Like proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular diseases. Can J Cardiol. 2023;39(12):1736\u201356. https:\/\/doi.org\/10.1016\/j.cjca.2023.06.002.","journal-title":"Can J Cardiol"},{"issue":"2","key":"1269_CR51","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1097\/mol.0000000000000910","volume":"35","author":"Y Wen","year":"2024","unstructured":"Wen Y, Chen YQ, Konrad RJ. Angiopoietin-like protein 8: a multifaceted protein instrumental in regulating triglyceride metabolism. Curr Opin Lipidol. 2024;35(2):58\u201365. https:\/\/doi.org\/10.1097\/mol.0000000000000910.","journal-title":"Curr Opin Lipidol"},{"key":"1269_CR52","doi-asserted-by":"publisher","first-page":"101140","DOI":"10.1016\/j.plipres.2021.101140","volume":"85","author":"R Zhang","year":"2022","unstructured":"Zhang R, Zhang K. An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues. Prog Lipid Res. 2022;85:101140. https:\/\/doi.org\/10.1016\/j.plipres.2021.101140.","journal-title":"Prog Lipid Res"},{"issue":"23","key":"1269_CR53","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1056\/NEJMoa1002926","volume":"363","author":"K Musunuru","year":"2010","unstructured":"Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363(23):2220\u20137. https:\/\/doi.org\/10.1056\/NEJMoa1002926.","journal-title":"N Engl J Med"},{"issue":"2","key":"1269_CR54","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1097\/mol.0000000000000668","volume":"31","author":"M Arca","year":"2020","unstructured":"Arca M, D\u2019Erasmo L, Minicocci I. Familial combined hypolipidemia: angiopoietin-like protein-3 deficiency. Curr Opin Lipidol. 2020;31(2):41\u20138. https:\/\/doi.org\/10.1097\/mol.0000000000000668.","journal-title":"Curr Opin Lipidol"},{"issue":"3","key":"1269_CR55","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1056\/NEJMoa1612790","volume":"377","author":"FE Dewey","year":"2017","unstructured":"Dewey FE, Gusarova V, Dunbar RL, O\u2019Dushlaine C, Schurmann C, Gottesman O, et al. Genetic and pharmacologic inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017;377(3):211\u201321. https:\/\/doi.org\/10.1056\/NEJMoa1612790.","journal-title":"N Engl J Med"},{"issue":"9","key":"1269_CR56","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1194\/jlr.RA120000888","volume":"61","author":"RC Adam","year":"2020","unstructured":"Adam RC, Mintah IJ, Alexa-Braun CA, Shihanian LM, Lee JS, Banerjee P, et al. Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance. J Lipid Res. 2020;61(9):1271\u201386. https:\/\/doi.org\/10.1194\/jlr.RA120000888.","journal-title":"J Lipid Res"},{"issue":"8","key":"1269_CR57","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1056\/NEJMoa2004215","volume":"383","author":"FJ \u25cf\u25cf Raal","year":"2020","unstructured":"Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383(8):711\u201320. https:\/\/doi.org\/10.1056\/NEJMoa2004215. The pivotal trial of evinacumab in HoFH.","journal-title":"N Engl J Med"},{"key":"1269_CR58","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae325","author":"D Gaudet","year":"2024","unstructured":"Gaudet D, Greber-Platzer S, Reeskamp LF, Iannuzzo G, Rosenson RS, Saheb S, et al. Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy. Eur Heart J. 2024. https:\/\/doi.org\/10.1093\/eurheartj\/ehae325.","journal-title":"Eur Heart J"},{"issue":"5","key":"1269_CR59","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1161\/circulationaha.123.065529","volume":"149","author":"A Wiegman","year":"2024","unstructured":"Wiegman A, Greber-Platzer S, Ali S, Reijman MD, Brinton EA, Charng MJ, et al. Evinacumab for Pediatric patients with homozygous familial hypercholesterolemia. Circulation. 2024;149(5):343\u201353. https:\/\/doi.org\/10.1161\/circulationaha.123.065529.","journal-title":"Circulation"},{"key":"1269_CR60","unstructured":"Evaluate the efficacy and safety of SHR-1918 in patients with homozygous familial hypercholesterolemia. Clinical Trials.gov. https:\/\/clinicaltrials.gov\/study\/NCT06009393. Accessed 09 July 2024."},{"issue":"18","key":"1269_CR61","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1161\/circulationaha.122.059266","volume":"145","author":"BA Bergmark","year":"2022","unstructured":"Bergmark BA, Marston NA, Bramson CR, Curto M, Ramos V, Jevne A, et al. Effect of Vupanorsen on Non-high-density Lipoprotein Cholesterol Levels in statin-treated patients with elevated cholesterol: TRANSLATE-TIMI 70. Circulation. 2022;145(18):1377\u201386. https:\/\/doi.org\/10.1161\/circulationaha.122.059266.","journal-title":"Circulation"},{"key":"1269_CR62","doi-asserted-by":"publisher","first-page":"S43","DOI":"10.1016\/j.atherosclerosis.2023.06.805","volume":"379","author":"F Raal","year":"2023","unstructured":"Raal F, Bergeron J, Watts G, Gaudet D, Sullivan D, Turner T, et al. ARO-ANG3, an investigational RNAI therapeutic, decreases serum LDL-cholesterol, apolipoprotein B, and angiopoietin-like protein 3 in patients with homozygous familial hypercholesterolaemia. Atherosclerosis. 2023;379:S43\u20134. https:\/\/doi.org\/10.1016\/j.atherosclerosis.2023.06.805.","journal-title":"Atherosclerosis"},{"issue":"9","key":"1269_CR63","doi-asserted-by":"publisher","first-page":"2216","DOI":"10.1038\/s41591-023-02494-2","volume":"29","author":"GF Watts","year":"2023","unstructured":"Watts GF, Schwabe C, Scott R, Gladding PA, Sullivan D, Baker J, et al. RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts. Nat Med. 2023;29(9):2216\u201323. https:\/\/doi.org\/10.1038\/s41591-023-02494-2.","journal-title":"Nat Med"},{"issue":"3","key":"1269_CR64","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/s41591-023-02222-w","volume":"29","author":"RS Rosenson","year":"2023","unstructured":"Rosenson RS, Gaudet D, Ballantyne CM, Baum SJ, Bergeron J, Kershaw EE, et al. Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial. Nat Med. 2023;29(3):729\u201337. https:\/\/doi.org\/10.1038\/s41591-023-02222-w.","journal-title":"Nat Med"},{"key":"1269_CR65","doi-asserted-by":"publisher","unstructured":"Oostveen RF, Hovingh GK, Stroes ESG. Angiopoietin-like 3 inhibition and the liver: less is more? Current opinion in lipidology. 2023;34(6):267\u201371. https:\/\/doi.org\/10.1097\/mol.0000000000000898","DOI":"10.1097\/mol.0000000000000898"},{"key":"1269_CR66","unstructured":"Arrowhead pharmaceuticals to advance RNAi-based plozasiran into phase 3 CAPITAN cardiovascular outcomes trial. Arrowhead Pharma. https:\/\/arrowheadpharma.com\/news-press\/arrowhead-pharmaceuticals-to-advance-rnai-based-plozasiran-into-phase-3-capitan-cardiovascular-outcomes-trial. Accessed 15 July 2024."},{"issue":"11","key":"1269_CR67","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1038\/nm1195-1148","volume":"1","author":"M Grossman","year":"1995","unstructured":"Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark BJ 3, et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med. 1995;1(11):1148\u201354.","journal-title":"Nat Med"},{"issue":"4","key":"1269_CR68","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/ng0494-335","volume":"6","author":"M Grossman","year":"1994","unstructured":"Grossman M, Raper SE, Kozarsky K, Stein EA, Engelhardt JF, Muller D, et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet. 1994;6(4):335\u201341. https:\/\/doi.org\/10.1038\/ng0494-335.","journal-title":"Nat Genet"},{"key":"1269_CR69","unstructured":"A gene therapy study for homozygous familial hypercholesterolemia (HoFH). Clinical Trials.gov. https:\/\/clinicaltrials.gov\/study\/NCT02651675?tab=results. Accessed 09 July 2024."},{"key":"1269_CR70","unstructured":"Exosome-based nanoplatform for Ldlr mRNA delivery in FH (ENDFH). Clinical Trials.gov. https:\/\/clinicaltrials.gov\/study\/NCT05043181. Accessed 09 July 2024."},{"key":"1269_CR71","unstructured":"Our PCSK9 programs. Verve Therapeutics. https:\/\/www.vervetx.com\/our-programs\/verve-101-102.\u00a0Accessed 09 July 2024."},{"issue":"17","key":"1269_CR72","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1093\/eurjpc\/zwad203","volume":"30","author":"J Gu","year":"2023","unstructured":"Gu J, Kuznik A, Quon P, Chauhan A, Sravya TS, Raal FJ. Modelling the potential long-term survival benefit of evinacumab treatment vs. standard of care in patients with homozygous familial hypercholesterolaemia. Eur J Prev Cardiol. 2023;30(17):1874\u201380. https:\/\/doi.org\/10.1093\/eurjpc\/zwad203.","journal-title":"Eur J Prev Cardiol"}],"container-title":["Current Atherosclerosis Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11883-024-01269-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11883-024-01269-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11883-024-01269-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T10:59:59Z","timestamp":1758797999000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11883-024-01269-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,3]]},"references-count":72,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["1269"],"URL":"https:\/\/doi.org\/10.1007\/s11883-024-01269-5","relation":{},"ISSN":["1523-3804","1534-6242"],"issn-type":[{"value":"1523-3804","type":"print"},{"value":"1534-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,3]]},"assertion":[{"value":"19 December 2024","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 January 2025","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"DJ Blom DB reports personal fees from Amgen, Amryt, MSD, Novartis, Sanofi and Servier and outside the submitted work.A David Marais ADM reports no personal fees from the companies producing the agents discussed but had support for the performance of the study of atorvastatin and lomitapide by Warner Lambert Parke Davis and Aegerion, respectively.FJ Raal FJR reports personal fees from LIB Therapeutics, Amgen, Sanofi, Regeneron Pharmaceuticals, Inc., and Novartis outside the submitted work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}},{"value":"All reported studies\/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional\/national research committee standards, and international\/national\/institutional guidelines).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}],"article-number":"22"}}