A Critical Review of the Efficacy and Safety of Inclisiran
Abstract
The association between low-density cholesterol (LDL-C) and cardiovascular disease (CVD) is well-established, with an emphasis on lowering LDL-C levels to reduce cardiovascular events. Statin therapy has been the traditional treatment for LDL-C reduction, in addition to lifestyle modifications, but studies have shown that a substantial proportion of patients does not reach target LDL-C goals despite receiving maximally tolerated statin medications. Additionally, statin therapy is associated with a few shortcomings as many patients initiated on these medications discontinue treatment within 1 year because of lack of tolerability. Furthermore, guidelines from both the American College of Cardiology and the American Heart Association highlight the importance of obtaining LDL-C goals because of the residual atherosclerotic CVD risk that remains in high-risk populations. That the residual cardiovascular risk remains despite statin therapy highlights the importance of evaluating therapeutic approaches that possess effective lipid lowering that can be used adjunctively with statins. Much focus has been directed towards the proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway, leading to the development of evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9. These agents have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk, but the need for biweekly or monthly subcutaneous injections has generated concer…
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Systemic adverse effects including liver or kidney damage occur at low rates comparable to placebo with Inclisiran.
“The occurrence of systemic adverse effects including liver or kidney damage remained low and comparable to the placebo group [31].”
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
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 · cited 3× · see citing works
“Evolocumab and alirocumab are monoclonal antibodies that target PCSK9 with high specificity, preventing degradation of the LDLRs, and studies showed that both agents reduced cardiovascular risk in high-risk patients [10, 11].”
BackgroundResultTwo 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
Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk: Insights From the FOURIER Trial
O’Donoghue, M. L., Fazio, S., Giugliano, R. P., Stroes, E. S. G., Kanevsky, E., Gouni-Berthold, I., Im, K., Lira Pineda, A., Wasserman, S. M., Češka, R., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.037184 · Cited by 984 · cited 1× · see citing works
“FOURIER revealed that evolocumab lowered Lp(a) levels by 27% from baseline and reduced the risk of coronary artery disease (CAD) death, MI, or urgent revascularization by 23% in patients with a baseline Lp(a) > 37 nmol/L (median baseline 37 nmol/L) [24, 26, 30].”
BackgroundInclisiran 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
A 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
Safety and efficacy of statin therapy
Adhyaru, B. B., & Jacobson, T. A. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0098-5 · Cited by 424 · see citing works
Ray, K. K., Stoekenbroek, R. M., Kallend, D., Nishikido, T., Leiter, L. A., Landmesser, U., Wright, R. S., Wijngaard, P. L. J., & Kastelein, J. J. P. (2019) · JAMA Cardiology · doi:10.1001/jamacardio.2019.3502 · Cited by 172 · cited 2× · see citing works
“Promising data from the ORION-1 phase II study, which demonstrated LDL-C lowering of > 50% with additional sustained pharmacodynamic effect and an ideal safety profile, led to the development of inclisiran’s phase III ORION program [16, 17].”
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Targeting 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
Insight into the Evolving Role of PCSK9
Maligłówka, M., Kosowski, M., Hachuła, M., Cyrnek, M., Bułdak, Ł., Basiak, M., Bołdys, A., Machnik, G., Bułdak, R. J., & Okopień, B. (2022) · Metabolites · doi:10.3390/metabo12030256 · Cited by 41 · 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
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 occurrence of systemic adverse effects including liver or kidney damage remained low and comparable to the placebo group [31].”
- Authors
- Hardy, J., Niman, S., Pereira, E., Lewis, T., Reid, J., Choksi, R., & Goldfaden, R. F.
- Affiliations
- University of Florida (US)
- Corresponding author
- Goldfaden, Rebecca F.
- Venue
- American Journal of Cardiovascular Drugs
- Published
- 2021-05-06
- Volume
- 21
- Issue
- 6
- Pages
- 629-642
- ISSN
- 1175-3277 (ISSN-L)
- 1179-187X
- OpenAlex
- W3158442165
- Cited by
- 44
- References
- 8
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 13 · 2022: 7 · 2021: 3
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Cardiovascular Drugs (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- inclisiran, PCSK9 inhibition, siRNA, LDL cholesterol lowering, cardiovascular risk reduction, residual cardiovascular risk, evolocumab, alirocumab, hypercholesterolemia, drug safety and efficacy, subcutaneous dosing
- MeSH terms
- Humans, RNA, Small Interfering
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