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Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a)
Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apoli...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487774/ https://www.ncbi.nlm.nih.gov/pubmed/37686428 http://dx.doi.org/10.3390/ijms241713622 |
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author | Kosmas, Constantine E. Bousvarou, Maria D. Papakonstantinou, Evangelia J. Tsamoulis, Donatos Koulopoulos, Andreas Echavarria Uceta, Rogers Guzman, Eliscer Rallidis, Loukianos S. |
author_facet | Kosmas, Constantine E. Bousvarou, Maria D. Papakonstantinou, Evangelia J. Tsamoulis, Donatos Koulopoulos, Andreas Echavarria Uceta, Rogers Guzman, Eliscer Rallidis, Loukianos S. |
author_sort | Kosmas, Constantine E. |
collection | PubMed |
description | Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80–90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off. |
format | Online Article Text |
id | pubmed-10487774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104877742023-09-09 Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a) Kosmas, Constantine E. Bousvarou, Maria D. Papakonstantinou, Evangelia J. Tsamoulis, Donatos Koulopoulos, Andreas Echavarria Uceta, Rogers Guzman, Eliscer Rallidis, Loukianos S. Int J Mol Sci Review Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80–90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off. MDPI 2023-09-03 /pmc/articles/PMC10487774/ /pubmed/37686428 http://dx.doi.org/10.3390/ijms241713622 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Kosmas, Constantine E. Bousvarou, Maria D. Papakonstantinou, Evangelia J. Tsamoulis, Donatos Koulopoulos, Andreas Echavarria Uceta, Rogers Guzman, Eliscer Rallidis, Loukianos S. Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a) |
title | Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a) |
title_full | Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a) |
title_fullStr | Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a) |
title_full_unstemmed | Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a) |
title_short | Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a) |
title_sort | novel pharmacological therapies for the management of hyperlipoproteinemia(a) |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487774/ https://www.ncbi.nlm.nih.gov/pubmed/37686428 http://dx.doi.org/10.3390/ijms241713622 |
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