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PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, ca...

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Autores principales: Katzmann, Julius L., Gouni-Berthold, Ioanna, Laufs, Ulrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701092/
https://www.ncbi.nlm.nih.gov/pubmed/33304274
http://dx.doi.org/10.3389/fphys.2020.595819
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author Katzmann, Julius L.
Gouni-Berthold, Ioanna
Laufs, Ulrich
author_facet Katzmann, Julius L.
Gouni-Berthold, Ioanna
Laufs, Ulrich
author_sort Katzmann, Julius L.
collection PubMed
description In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2–4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of ∼46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available.
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spelling pubmed-77010922020-12-09 PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects Katzmann, Julius L. Gouni-Berthold, Ioanna Laufs, Ulrich Front Physiol Physiology In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2–4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of ∼46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available. Frontiers Media S.A. 2020-11-16 /pmc/articles/PMC7701092/ /pubmed/33304274 http://dx.doi.org/10.3389/fphys.2020.595819 Text en Copyright © 2020 Katzmann, Gouni-Berthold and Laufs. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Katzmann, Julius L.
Gouni-Berthold, Ioanna
Laufs, Ulrich
PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects
title PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects
title_full PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects
title_fullStr PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects
title_full_unstemmed PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects
title_short PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects
title_sort pcsk9 inhibition: insights from clinical trials and future prospects
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701092/
https://www.ncbi.nlm.nih.gov/pubmed/33304274
http://dx.doi.org/10.3389/fphys.2020.595819
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