An update on inclisiran for the treatment of elevated LDL cholesterol
Abstract
Introduction The burden of atherosclerotic cardiovascular disease (ASCVD) persists globally, demanding innovative therapeutic strategies. This manuscript provides an expert opinion on the significance of managing low-density lipoprotein cholesterol in ASCVD prevention and introduces inclisiran, a novel small interfering RNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). Areas covered This work delves into the intricate mechanism of inclisiran, highlighting its unique approach of hepatic intracellular PCSK9 inhibition, its precision and low off-target effects risk. Pharmacodynamic and pharmacokinetic distinctions from PCSK9 monoclonal antibodies are explored, underlining inclisiran's efficiency, extended duration, and clearance. Clinical trials, including pivotal phase-III placebo-controlled studies (ORION-9, -10, -11), the open-label ORION-3 and pooled safety analysis of these trails including the open-label phase of ORION-8, as well as real-word data are discussed to provide a comprehensive evaluation of inclisiran's efficacy and safety. Expert opinion Inclisiran stands as a first-in-class breakthrough in lipid-lowering therapies, showing potential in alleviating the global burden of ASCVD and is supported by multiple global regulatory approvals. To optimize inclisiran's utilization and comprehend its long-term effects, future directions include pediatric studies, cardiovascular outcome trials, and extended-duration investigations. Overall, inclisiran emerg…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Long-term studies have established inclisiran as a fundamental drug for lipid management due to its ability to ensure high patient adherence and long-term LDL-C control.
“Long-term studies have established inclisiran as a fundamental drug for lipid management due to its ability to ensure high patient adherence and long-term LDL-C control [47, 48].”
The research evidence indicates that inclisiran extends its therapeutic benefits beyond basic LDL-C reduction because it demonstrates a wider range of lipid-modulating activities that benefit cardiovascular risk reduction.
“The research evidence indicates that Inclisiran extends its therapeutic benefits beyond basic LDL-C reduction because it demonstrates a wider range of lipid-modulating activities that benefit cardiovascular risk reduction [47, 60].”
Monoclonal antibodies achieve slightly higher LDL-C reductions (~60%) than inclisiran, while inclisiran's twice-yearly dosing may enhance adherence and long-term persistence in real-world settings.
“While mAbs achieve slightly higher LDL-C reductions (~ 60%), inclisiran’s twice-yearly dosing may enhance adherence and long-term persistence in real-world settings.”
The dual aspects of PCSK9 suppression and twice-yearly treatment schedule make inclisiran effective while creating better conditions for patients to adhere to their treatments.
“The dual aspects of PCSK9 suppression and twice-yearly treatment schedule make Inclisiran effective while creating better conditions for patients to adhere to their treatments [47, 72].”
The LDL-C lowering capability of inclisiran reaches approximately 45%, ranking it as one of the strongest lipid-lowering medications but falling short of the 60% reduction seen with PCSK9 monoclonal antibodies evolocumab and alirocumab.
“The LDL-C lowering capability of Inclisiran reaches approximately 45% which ranks it as one of the strongest lipid-lowering medications but falls short of the 60% reduction seen with PCSK9 monoclonal antibodies evolocumab and alirocumab [47, 73].”
Cites
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615664 · Cited by 6,138 · see citing works
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes
Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., Darius, H., Lewis, B. S., Ophuis, T. O., Jukema, J. W., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1410489 · Cited by 4,487 · see citing works
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801174 · Cited by 3,634 · see citing works
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1912387 · Cited by 1,665 · see citing works
Self-citationInclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia
Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L. J., Curcio, D., Jaros, M. J., Leiter, L. A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913805 · Cited by 818 · see citing works
Self-citationA highly durable RNAi therapeutic inhibitor of PCSK9
Fitzgerald, K., White, S., Borodovsky, A., Bettencourt, B. R., Strahs, A., Clausen, V., Wijngaard, P., Horton, J. D., Taubel, J., Brooks, A., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1609243 · Cited by 768 · see citing works
Ray, K. K., Troquay, R. P. T., Visseren, F. L. J., Leiter, L. A., Scott Wright, R., Vikarunnessa, S., Talloczy, Z., Zang, X., Maheux, P., Lesogor, A., et al. (2023) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(22)00353-9 · Cited by 328 · see citing works
Self-citationTargeting proprotein convertase subtilisin/kexin type 9 (PCSK9): From bench to bedside
Bao, X., Liang, Y., Chang, H., Cai, T., Feng, B., Gordon, K., Zhu, Y., Shi, H., He, Y., & Xie, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01690-3 · Cited by 187 · see citing works
The dawn of a new era of targeted lipid-lowering therapies
Tokgözoğlu, L., & Libby, P. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehab841 · Cited by 171 · see citing works
Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
Kasichayanula, S., Grover, A., Emery, M. G., Gibbs, M. A., Somaratne, R., Wasserman, S. M., & Gibbs, J. P. (2018) · Clinical Pharmacokinetics · doi:10.1007/s40262-017-0620-7 · Cited by 135 · see citing works
Kallend, D., Stoekenbroek, R., He, Y., Smith, P. F., & Wijngaard, P. (2022) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2022.01.001 · Cited by 73 · see citing works
Ebenezer, O., Comoglio, P., Wong, G. K.-S., & Tuszynski, J. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044019 · Cited by 39 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 research evidence indicates that Inclisiran extends its therapeutic benefits beyond basic LDL-C reduction because it demonstrates a wider range of lipid-modulating activities that benefit cardiovascular risk reduction [47, 60].”
Influential
- Authors
- Barkas, F., & Ray, K.
- Affiliations
- University of Ioannina (GR)
- Imperial College London (GB)
- Corresponding author
- Barkas, Fotios
- Venue
- Expert Opinion on Pharmacotherapy
- Publisher
- Informa UK Limited
- Published
- 2024-03-03
- Volume
- 25
- Issue
- 4
- Pages
- 349-358
- ISSN
- 1465-6566 (ISSN-L)
- 1744-7666
- OpenAlex
- W4393314184
- Cited by
- 9
- References
- 12
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1
- FWCI
- 0.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Opinion on Pharmacotherapy (publishedVersion)
- PubMed (publishedVersion)
- 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, PCSK9 inhibition, siRNA, LDL cholesterol lowering, atherosclerotic cardiovascular disease, lipid-lowering therapy, pharmacokinetics, pharmacodynamics, PCSK9 monoclonal antibodies, treatment efficacy and safety, pediatric use
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Animals, Anticholesteremic Agents, Cardiovascular Diseases, Humans, Hypercholesterolemia, Cholesterol, LDL, RNA, Small Interfering, Atherosclerosis
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
