Harnessing RNA Interference for Cholesterol Lowering: The Bench‐to‐Bedside Story of Inclisiran
Open accessAbstract
Lowering low‐density lipoprotein cholesterol (LDL‐C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL‐C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline‐recommended LDL‐C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease‐related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL‐C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice‐yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL‐C levels by ≈50% versus placebo when added to maximally tolerated statins. Long‐term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL‐C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.
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The most common adverse event was injection-site reactions affecting 5-17% of patients across studies, but these were mild to moderate and short-lived with minimal treatment discontinuation.
“The most common adverse event was injection-site reactions affecting 5–17% of patients in different studies but these reactions were mild to moderate and short-lived with minimal need to stop treatment [15, 81].”
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 [15]
The Clinical Development section reports injection-site adverse events in 5% of inclisiran recipients and says they were mostly mild, with none severe or persistent. The Factors to Consider section reports rates of 8.2% in pooled phase 3 trials and 5.9% in ORION-8, and describes the reactions as mostly mild and short-lived. Our copy does not substantiate the 17% upper end of the claimed range or say that reactions rarely required treatment discontinuation; page numbers were not provided. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInclisiran's chemical structure includes a GalNAc-triantennary N-acetylgalactosamine linked to a double-stranded siRNA, enabling hepatocyte-specific uptake through ASGPR.
“The chemical structure of Inclisiran includes a GalNAc-triantennary N-acetylgalactosamine linked to a double-stranded siRNA which enables hepatocyte-specific uptake through asialoglycoprotein receptors (ASGPR) [15, 16].”
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ONE YEAR EXPERIENCE WITH INCLISIRAN IN AN ACADEMIC LIPID CLINIC:
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- [87]Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia. Technology appraisal guidance [TA733].National Institute for Health and Care Excellence. October 6, 2021. Accessed September 1, 2022. https://www.nice.org.uk/guidance/ta733/chapter/1‐Recommendations 40802800
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Parvin, N., Mandal, T. K., & Joo, S. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16111366 · Cited by 32 · see citing works
Inclisiran, Reasons for a Novel Agent in a Crowded Therapeutic Field
Barbagallo, F. D. G., Andreychuk, N., Scicali, R., González-Lleó, A. M., Piro, S., Masana, L., & Ibarretxe, D. (2025) · Current Atherosclerosis Reports · doi:10.1007/s11883-024-01271-x · Cited by 32 · see citing works
Life Course Approach for Managing Familial Hypercholesterolemia
Gidding, S. S., Blom, D. J., McCrindle, B. W., Ramaswami, U., Santos, R. D., Watts, G. F., & Wiegman, A. (2025) · Journal of the American Heart Association · doi:10.1161/jaha.124.038458 · Cited by 24 · see citing works
Alsaidan, A. A. (2025) · International Journal of Clinical Practice · doi:10.1155/ijcp/7233591 · Cited by 22 · see citing works
Current usage of inclisiran for cardiovascular diseases: overview of current clinical trials
Harbi, M. H. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1449712 · Cited by 20 · see citing works
Obesity and Heart Failure: Mechanistic Insights and the Regulatory Role of MicroRNAs
Sahu, P., Bestepe, F., Vehbi, S., Ghanem, G. F., Blanton, R. M., & Icli, B. (2025) · Genes · doi:10.3390/genes16060647 · Cited by 12 · see citing works
Jianu, N., Nițu, E.-T., Merlan, C., Nour, A., Buda, S., Suciu, M., Luca, S. A., Sbârcea, L., Andor, M., & Buda, V. O. (2025) · Pharmaceuticals · doi:10.3390/ph18081150 · Cited by 14 · see citing works
Real-world experience of inclisiran prescription at the University of Pennsylvania Health Systems
Wei, N. M., Tobin, R., Jacoby, D. S., & Bajaj, A. (2024) · Journal of clinical lipidology · doi:10.1016/j.jacl.2024.07.008 · Cited by 6 · see citing works
Self-citationAddressing Knowledge Gaps in the Primary Prevention of Atherosclerotic Heart Disease
Gidding, S. S. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.033991 · Cited by 6 · see citing works
Satyam, S. M., El-Tanani, M., Patni, M. A., Rehman, A., Irshad, S. M., Raheem, R., Junais, E., John, A. A., Rassal, R. Y., Kumari, R., et al. (2026) · BMC Cardiovascular Disorders · doi:10.1186/s12872-026-05515-3 · Cited by 5 · see citing works
“The chemical structure of Inclisiran includes a GalNAc-triantennary N-acetylgalactosamine linked to a double-stranded siRNA which enables hepatocyte-specific uptake through asialoglycoprotein receptors (ASGPR) [15, 16].”
Insights from a real-world experience with inclisiran at a large United States lipid clinic
Mazdeyasnan, D., Birs, A. S., Chiou, T. T., Diano, L., & Wilkinson, M. J. (2025) · Journal of clinical lipidology · doi:10.1016/j.jacl.2025.06.015 · Cited by 5 · see citing works
Self-citationNowacka, A., Śniegocki, M., & Ziółkowska, E. (2025) · Cells · doi:10.3390/cells14181479 · Cited by 5 · see citing works
Maidman, S. D., & Rosenson, R. S. (2025) · BioDrugs · doi:10.1007/s40259-025-00731-3 · Cited by 6 · see citing works
Cheeley, M. K., Kirkpatrick, C. F., Brown, E. E., Dixon, D. L., Gunter, H., Osborn, D., & Wilkinson, M. J. (2025) · Journal of clinical lipidology · doi:10.1016/j.jacl.2025.05.002 · Cited by 4 · see citing works
Self-citationClinical Considerations for Healthcare Provider-Administered Lipid-Lowering Medications
Bertolet, B. D., Cabral, K. P., Sullenberger, L. E., McAlister, J., Sandroni, T., & Patel, D. S. (2024) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-024-00665-1 · Cited by 4 · see citing works
Doggrell, S. A. (2024) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2024.2425343 · Cited by 4 · see citing works
RNA ‐Based Therapies for Inherited Metabolic Disorders
Reddy, S. V., Gurung, S., Ghosh, R., Mills, P. B., Baruteau, J., & Zhou, H. (2026) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.70150 · Cited by 3 · see citing works
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Kamanu, C., & Karalis, D. G. (2025) · Current Atherosclerosis Reports · doi:10.1007/s11883-025-01283-1 · Cited by 4 · see citing works
A Facile and Promising Delivery Platform for siRNA to Solid Tumors
Leng, Q., Anand, A., & Mixson, A. J. (2024) · Molecules · doi:10.3390/molecules29235541 · Cited by 3 · see citing works
Basak, A. (2025) · Biomolecules · doi:10.3390/biom15040468 · Cited by 3 · see citing works
Dovaizem, N. L., Rebolledo, L. P., Ha, A. T., Chammas, R. J., Andrade, L. N. D. S., & Afonin, K. A. (2026) · ACS Nano Medicine · doi:10.1021/acsnanomed.6c00004 · Cited by 1 · see citing works
RNA interference for lipid disorders: is this the future?
Nassif, M., Fazoli, R. T., & Generoso, G. (2026) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000001033 · Cited by 1 · see citing works
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Ali, I., Qiu, J., Cheang, W. S., Wang, G., & Xu, S. (2026) · Research · doi:10.34133/research.1288 · Cited by 1 · see citing works
Myśliwiec, A., Leksa, D., Bartusik‐Aebisher, D., & Aebisher, D. (2026) · Journal of Applied Biomedicine · doi:10.32725/jab.2026.007 · Cited by 1 · see citing works
Nadim, M. K., & Akgun, Y. (2026) · Transfusion and Apheresis Science · doi:10.1016/j.transci.2026.104483 · Cited by 1 · see citing works
Masana, L., & Ibarretxe, D. (2024) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2024.07.004 · Cited by 1 · see citing works
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Masana, L., & Ibarretxe, D. (2024) · Clínica e Investigación en Arteriosclerosis (English Edition) · doi:10.1016/j.artere.2025.100739
Balarezo-García, M. G., Suárez-Páez, D. A., Ávila-Díaz, C. A., & Paguay-Pingos, H. N. (2025) · Sanitas. Revista arbitrada de ciencias de la salud. · doi:10.62574/shpqzd15
Liu, D., Liu, J., Mao, W., Li, X., Hu, B., Zhang, L., & Hu, J. Y. (2025) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001778
RNA-Based Therapies for Hypercholesterolemia and Coronary Artery Disease
Mendoza, M. J. L., Figueroa, N. C., Mena, M. J. V., Ulloa, A., Vindas, J. J., & Estrada, M. A. S. (2026) · Cureus · doi:10.7759/cureus.103877
Familial hypercholesterolemia: diagnosis, genetic aspects, and current treatment approaches
Bazhin, M. A., Свеклина, Т. С., Krutikova, A. A., Strelkov, D. A., & Bessonov, E. Y. (2026) · Bulletin of the Russian Military Medical Academy · doi:10.17816/brmma682901
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A narrative review of PCSK9 inhibitors: from evolocumab to novel discoveries
Liu, H., Li, S. N., & Li, J. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1800502
Hargovan, S., Hunt, N., Kostakis, H., & Chow, C. K. (2026) · International Journal of Cardiology Cardiovascular Risk and Prevention · doi:10.1016/j.ijcrp.2026.200687
Engineering the Future of Precision Medicine: A Comprehensive Guide to RNA Therapeutics
Athanasopoulou, K., Daneva, G. N., Michalopoulou, V.-I., Stamelou, M.-L., Tsiakanikas, P., & Adamopoulos, P. G. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48080809
A Look At Non-Statin Lipid-Lowering Pharmacological Therapy
Vedernikov, A., Михайлович, М. Е., Vedernikova, S. A., & Vyalkina, Y. A. (2026) · The Russian Archives of Internal Medicine · doi:10.33396/2226-6704-2026-16-5-325-335
Stamatopoulou, V., Kouvela, A., Ahtypi, K., Douka, E., Kominatou, C., Meimaroglou, A., Spyropoulou, K., Taxari, S., Theodoridou, S., & Plotas, P. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1935318
- Authors
- Wilkinson, M. J., Bajaj, A., Brousseau, M. E., & Taub, P. R.
- Affiliations
- University of California San Diego (US)
- University of Pennsylvania (US)
- Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research Cambridge MA USA
- Corresponding author
- Taub, Pam R.
- Venue
- Journal of the American Heart Association
- Published
- 2024-03-19
- Volume
- 13
- Issue
- 6
- Pages
- e032031-e032031
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC11010004
- OpenAlex
- W4392594886
- Cited by
- 37
- References
- 72
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 8
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Novartis Pharmaceuticals Corporation (GPP 2022)
- 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
- inclisiran, RNA interference, PCSK9, LDL cholesterol lowering, atherosclerotic cardiovascular disease, familial hypercholesterolemia, primary hyperlipidemia, statin therapy, drug development, clinical trials, drug safety and tolerability, cardiovascular outcomes
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Anticholesteremic Agents, Cardiovascular Diseases, Cholesterol, Humans, Cholesterol, LDL, RNA Interference, RNA, Small Interfering
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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