PCSK9 inhibition in the management of familial hypercholesterolemia
Open accessAbstract
Familial hypercholesterolemia (FH) is a frequent hereditary metabolic disease characterized by high serum low-density lipoprotein (LDL) cholesterol concentration and premature atherosclerotic cardiovascular disease (ASCVD). The discovery of the LDL receptor as one of the causative genes of FH enabled us to understand the pathophysiology of FH and paved the way for developing statins. Similar to LDL receptor, discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) also created an opportunity for developing its inhibitors. Since PCSK9 degrades LDL receptor protein, inhibiting PCSK9 will be an effective strategy. Evolocumab and alirocumab, anti-PCSK9 antibodies that inhibit binding between PCSK9 and LDL receptors, are now available in Japan. Adding an anti-PCSK9 antibody to standard therapy with statin alone or statin combined with ezetimibe further reduced serum LDL cholesterol levels by around 60% and they significantly decrease cardiovascular event incidence as compared with placebo. Additionally, the strong LDL cholesterol lowering effect of anti-PCSK9 antibody therapies has reportedly enabled the frequency of lipoprotein apheresis to be reduced or to be discontinued. As alternative strategies against PCSK9, antisense oligonucleotide agents that inhibit PCSK9 protein synthesis as well as a small interfering (or short interference) RNA (siRNA) for PCSK9 are also being developed. While relatively high cost can be given as a problem, PCSK9 inhibitors are able to reduce LDL cholesterol dramatically even in FH patients who could not achieve targets until now. To ensure that these drugs are given to the patients who really need them, it is necessary to raise the diagnosis rate and family screening has to be more actively conducted. Finally, it has been reported that PCSK9 is expressed not only in hepatocytes but also in other cells such as epithelial cells in small intestine and vascular smooth muscle cells in atherosclerotic plaque. Further research regarding extra-hepatic pathophysiology of PCSK9 is expected.
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Inclisiran significantly decreases production of PCSK9 in liver and reduces LDL-C level, enabling management of autosomal dominant hypercholesterolemia (ADH).
“Inclisiran was reported to be able to significantly decrease the production of PCSK9 in liver and thus reduce the LDL-C level, which enables it to be used for the management of autosomal dominant hypercholesterolemia (ADH).[85, 86]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [86]
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RNA delivery biomaterials for the treatment of genetic and rare diseases
Zhao, W., Hou, X., Vick, O. G., & Dong, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119291 · Cited by 82 · see citing works
- Authors
- Ogura, M.
- Affiliations
- National Cerebral and Cardiovascular Center (JP)
- Corresponding author
- Ogura, Masatsune
- ORCID
- Ogura, Masatsune
- Venue
- Journal of Cardiology
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 71
- Issue
- 1
- Pages
- 1-7
- ISSN
- 0914-5087 (ISSN-L)
- OpenAlex
- W2744116768
- Cited by
- 84
- References
- 26
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 15 · 2020: 8 · 2019: 9 · 2018: 7 · 2017: 2
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Astellas Pharma
- Japan Society for the Promotion of Science (15K09130, 18K08125)
- 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
- PCSK9 inhibition, familial hypercholesterolemia, LDL cholesterol lowering, evolocumab, alirocumab, anti-PCSK9 monoclonal antibodies, statin therapy, ezetimibe, lipoprotein apheresis, antisense oligonucleotides, siRNA, atherosclerotic cardiovascular disease, LDL receptor, family screening
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Animals, Anticholesteremic Agents, Humans, Hypercholesterolemia, Hyperlipoproteinemia Type II
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