Prediction of inclisiran efficacy in patients with established atherosclerotic cardiovascular disease: the SIRIUS in-silico modelling of cardiovascular outcomes
Open accessAbstract
Aims Inclisiran, an siRNA-targeting hepatic PCSK9 mRNA, reduces low-density lipoprotein cholesterol (LDL-C), but its effect on major adverse cardiovascular event (MACE) remains unconfirmed. The SIRIUS in-silico modelling programme aimed to predict the efficacy of inclisiran on MACE in virtual patients with atherosclerotic cardiovascular disease (ASCVD). Methods and results The SIRIUS simulation (NCT05974345) used a validated mechanistic model of ASCVD and lipid-lowering therapy (LLT) effects in a virtual population with established ASCVD and LDL-C ≥ 70 mg/dL. Each virtual patient served as their own control to compare inclisiran vs. placebo as an adjunct to high-intensity statin therapy, alone or with ezetimibe over 5 years. The model did not account for non-adherence, recurrent events, or adverse effects. Among 204 691 virtual patients, inclisiran was predicted to reduce LDL-C by 49.7% vs. placebo (from 91.1 to 48.3 mg/dL). Relative to placebo, inclisiran was predicted to lower 5 years risk of 3-point MACE by 25.2% (11.3% vs. 14.9%), myocardial infarction by 34.8% [5.7% vs. 8.6%; hazard ratio (HR) 0.65], ischaemic stroke by 26% (2.6% vs. 3.4%; HR 0.74), and major adverse limb event by 34.1% (0.5% vs. 0.8%; HR 0.66). A 7.1% relative reduction of cardiovascular death was predicted (4.2% vs. 4.5%; HR 0.93). Conclusion SIRIUS is the first in-silico simulation using a knowledge-based mechanistic model to predict the efficacy of LLT on cardiovascular outcomes in ASCVD. These findi…
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The SIRIUS in silico trial estimated that inclisiran could reduce the risk of 3-point MACE by 25% over 5 years compared to placebo, when added to high-intensity statins with or without ezetimibe.
“This innovative approach, calibrated and validated against major outcome trials such as FOURIER19 and ORION-10, estimated that inclisiran could reduce the risk of 3-point MACE by 25% over 5 years compared to placebo, when added to high-intensity statins with or without ezetimibe.”
From Small Interfering RNA for LDL-Cholesterol Reduction (2026) · cites this paper as [20]
The SIRIUS findings provide early, model-based evidence supporting the potential cardioprotective effects of inclisiran.
“These findings provide early, model-based evidence supporting the potential cardioprotective effects of inclisiran, several years before results from ongoing outcome trials such as ORION-4 and VICTORION-2P are available.20”
From Small Interfering RNA for LDL-Cholesterol Reduction (2026) · cites this paper as [20]
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Small Interfering RNA for LDL-Cholesterol Reduction
Batista, F., Mamede, I., & Dacoregio, M. (2026) · JACC: Advances · doi:10.1016/j.jacadv.2026.102932
- Authors
- Angoulvant, D., Peyronnet, E., Cariou, B., Amarenco, P., Boccara, F., Boissel, J.-P., Bastien, A., Courcelles, E., Diatchenko, A., Filipovics, A., Granjeon-Noriot, S., Kahoul, R., Mahé, G., Portal, L., Porte, S., Wang, Y., Bechet, E., & Steg, P. G.
- Affiliations
- Université de Tours (FR)
- Nova In Silico, Lyon, F-69000, France
- Centre National de la Recherche Scientifique (FR)
- Université Paris Cité (FR)
- Inserm (FR)
- Novartis (France) (FR)
- CIC Rennes (FR)
- Université Paris-Cité, AP-HP, Hôpital Bichat, and FACT, INSERM U-1148/LVTS , Paris, F-75000 ,
- Corresponding author
- Angoulvant, Denis
- ORCID
- Venue
- European Journal of Preventive Cardiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-12-26
- Volume
- 33
- Issue
- 11
- Pages
- 2057-2066
- ISSN
- 2047-4873 (ISSN-L)
- 2047-4881
- OpenAlex
- W7117368553
- Cited by
- 4
- References
- 0
- Citations by year
- 2026: 4
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Journal of Preventive Cardiology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- Funders
- SIRIUS (NCT05974345)
- Novartis Pharma SAS
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Coronary Interventions and Diagnostics
- Keywords
- inclisiran, PCSK9 inhibition, siRNA, atherosclerotic cardiovascular disease, major adverse cardiovascular events, LDL cholesterol lowering, mechanistic simulation model, virtual patient population, high-intensity statin therapy, ezetimibe, cardiovascular risk prediction, cardiovascular mortality, myocardial infarction, ischemic stroke, major adverse limb events
- MeSH terms
- RNAi Therapeutics, Proprotein Convertase 9, Computer Simulation, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Risk Factors, Time Factors, Biomarkers, Treatment Outcome, Risk Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Small Interfering, Dyslipidemias, Atherosclerosis
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