Inhibiting PCSK9 — biology beyond LDL control
Open accessAbstract
Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.
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PCSK9 production remains suppressed over time because inclisiran causes long-term reduction of the protein source, leading to increased LDLR expression and low blood LDL cholesterol.
“PCSK9 production remains suppressed throughout time because the source of the protein receives long-term reduction which leads to increased LDLR expression that keeps LDL cholesterol levels in the blood low [18, 19].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [18]
The available passages consist of the title and bibliographic metadata (including passages labeled Abstract, with no page number). Searches for inclisiran, sustained PCSK9 suppression, LDL receptors, and LDL cholesterol found no passage describing the claimed mechanism or duration of effect. The title alone cannot establish the claim. (LLM, conf=0.75)
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“PCSK9 production remains suppressed throughout time because the source of the protein receives long-term reduction which leads to increased LDLR expression that keeps LDL cholesterol levels in the blood low [18, 19].”
- Authors
- Stoekenbroek, R. M., Lambert, G., Cariou, B., & Hovingh, G. K.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Hovingh, G. Kees
- Venue
- Nature Reviews Endocrinology
- Published
- 2018-10-26
- Volume
- 15
- Issue
- 1
- Pages
- 52-62
- ISSN
- 1759-5029 (ISSN-L)
- 1759-5037
- OpenAlex
- W2898502019
- Cited by
- 141
- References
- 17
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 18 · 2023: 25 · 2022: 19 · 2021: 26 · 2020: 21 · 2019: 7 · 2018: 1
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Nature Reviews Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Funders
- European Commission (603091)
- Agence Nationale de la Recherche (ANR-16-RHUS-0007)
- Fondation Leducq (016.156.445, 13CVD03)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.156.445)
- Centre Hospitalier Universitaire de Nantes
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PCSK9, PCSK9 inhibitors, LDL cholesterol, LDL receptor, cholesterol metabolism, cardiovascular disease prevention, pancreas, central nervous system, liver
- MeSH terms
- Proprotein Convertase 9, Cardiovascular Diseases, Female, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Receptors, LDL, Sensitivity and Specificity, Biomarkers, Lipid Metabolism
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