{"id":"doi:10.1093/eurjpc/zwaf783","kind":"article","title":"Prediction of inclisiran efficacy in patients with established atherosclerotic cardiovascular disease: the SIRIUS in-silico modelling of cardiovascular outcomes","authors":["Angoulvant D","Peyronnet E","Cariou B","Amarenco P","Boccara F","Boissel JP","Bastien A","Courcelles E","Diatchenko A","Filipovics A","Granjeon-Noriot S","Kahoul R","Mahé G","Portal L","Porte S","Wang Y","Bechet E","Steg PG"],"author_count":18,"year":2026,"published":"2026-09-01","venue":"European journal of preventive cardiology","cited_by":6,"doi":"10.1093/eurjpc/zwaf783","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1093/eurjpc/zwaf783","archive_url":"https://space-kitty.com/papers/doi:10.1093/eurjpc/zwaf783","updated":null,"pmid":"41453135","pmcid":null,"openalex_id":null,"pdf_url":null,"abstract":"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 findings offer an early model-based prediction of inclisiran's potential cardiovascular benefit ahead of Phase 3 outcome trials. Lay summary The SIRIUS in-silico simulation used a validated knowledge-based mechanistic computational model to computationally simulate inclisiran efficacy on 5-year MACE in 204 691 virtual patients with atherosclerotic cardiovascular disease (ASCVD).Mean predicted percentage reduction in LDL-C with inclisiran vs. placebo was 49.7% at 5 years, with a 25.2% reduction in 3-point MACE.This simulation provides early insights into the potential effect of inclisiran on cardiovascular event reduction in advance of results from ongoing Phase 3 trial.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Prediction of inclisiran efficacy in patients with established atherosclerotic cardiovascular disease: the SIRIUS in-silico modelling of cardiovascular outcomes\" by Angoulvant D, Peyronnet E, Cariou B et al., https://doi.org/10.1093/eurjpc/zwaf783, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"cardiovascular-innovation","name":"Cardiovascular Therapeutics","domain_slug":"medicine"}],"cited_in_dossiers":[]}