Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia
Abstract
Introduction Inclisiran is a novel posttranscriptional gene silencing therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis by RNA interference and has a potent, dose-dependent, durable effect in lowering LDL-C, and therefore is an effective drug to treat dyslipidemia, reducing the risk for acute cardiovascular (CV) events. It is safe and well-tolerated. Areas covered This paper aims to review the mechanism of action of inclisiran while evaluating its efficacy and safety in the treatment of dyslipidemia from data of the clinical trials in the ORION program. Expert opinion Data from the clinical trials in the ORION program demonstrated efficacy and safety of inclisiran in patients with dyslipidemia. Adverse events were similar in the inclisiran and placebo groups in the clinical trials, although injection-site reactions were more frequent with inclisiran than with placebo. Although the combination of efficacy and safety makes inclisiran a good option for the treatment of dyslipidemia compared to other PCSK9 targeting therapeutic strategies, however, further studies should exclude the possibility that inclisiran, through lower-affinity interactions, may influence other mRNAs in the physiological milieu.
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Inclisiran blocks PCSK9 production in hepatocytes through mRNA interference against PCSK9 gene expression.
“The first-ever small interfering RNA (siRNA) medication known as Inclisiran blocks PCSK9 production in hepatocytes through mRNA interference against PCSK9 gene expression [14].”
The therapeutic mechanism of inclisiran differs from monoclonal antibodies because inclisiran operates inside cells instead of binding PCSK9 molecules outside cells.
“The therapeutic mechanism of Inclisiran differs from monoclonal antibodies because Inclisiran operates inside cells instead of binding PCSK9 molecules outside cells [14, 66].”
PCSK9 inhibitors such as evolocumab and inclisiran lower LDL cholesterol levels and reduce the rate of cardiovascular events among patients with established cardiovascular disease accompanied by T2DM.
“PCSK9 inhibitors like evolocumab and inclisiran have been shown to lower low-density lipoprotein cholesterol levels and to reduce the rate of cardiovascular events among patients with established cardiovascular disease accompanied with T2DM (81, 82).”
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“The first-ever small interfering RNA (siRNA) medication known as Inclisiran blocks PCSK9 production in hepatocytes through mRNA interference against PCSK9 gene expression [14].”
- Authors
- Banerjee, Y., Pantea Stoian, A., Cicero, A. F. G., Fogacci, F., Nikolic, D., Sachinidis, A., Rizvi, A. A., Janez, A., & Rizzo, M.
- Affiliations
- University of Dundee (GB)
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- University of Bologna (IT)
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Italy
- University of Palermo (IT)
- Emory University (US)
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Ljubljana, Slovenia
- University of South Carolina (US)
- Corresponding author
- Banerjee, Yajnavalka
- ORCID
- Venue
- Expert Opinion on Drug Safety
- Publisher
- Informa UK Limited
- Published
- 2021-10-14
- Volume
- 21
- Issue
- 1
- Pages
- 9-20
- ISSN
- 1474-0338 (ISSN-L)
- 1744-764X
- OpenAlex
- W3202104101
- Cited by
- 54
- References
- 9
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 14 · 2022: 14 · 2021: 3
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Opinion on Drug Safety (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- inclisiran, PCSK9, hypercholesterolemia, dyslipidemia, siRNA, RNA interference, post-transcriptional gene silencing, LDL cholesterol lowering, cardiovascular risk reduction, injection site reactions, off-target effects
- MeSH terms
- Proprotein Convertase 9, Animals, Cardiovascular Diseases, Humans, Hypercholesterolemia, Gene Silencing, RNA, Small Interfering, Dyslipidemias
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