Abstract
Despite substantial advances in the secondary prevention of cardiovascular disease, atherosclerosis of the coronary arteries and its consequences remain the leading cause of death worldwide. Residual cardiovascular risk refers to the ongoing risk of recurrent cardiovascular events that persists in patients with coronary artery disease despite receiving optimal secondary prevention treatment and effective control of conventional risk factors. Lifestyle modification and therapies modulating thrombosis, blood pressure and LDL-cholesterol levels represent the standard approach for the prevention of recurrent cardiovascular events in patients with coronary artery disease. However, current evidence-based therapies and lifestyle modification strategies only partially modulate the pathophysiological pathways involved in the progression and destabilization of atherosclerotic disease, and other mechanisms might have an important role, accounting, at least in part, for the residual cardiovascular risk in these patients. In this Review, we appraise the available evidence and latest insights into the mechanisms and associated biomarkers of recurrent adverse cardiovascular events and provide perspectives on strategies to reduce residual cardiovascular risk in patients with coronary artery disease.
Key points
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Despite adherence to secondary prevention measures, many patients with coronary artery disease continue to have residual cardiovascular risk and recurrent ischaemic events.
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Contributors to residual cardiovascular risk, including thrombotic, lipid, metabolic and inflammatory pathways, as well as emerging factors, have a pivotal role beyond traditional determinants of cardiovascular risk.
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New biomarkers and mechanistic insights can improve patient stratification and guide targeted therapies aimed at reducing recurrent events.
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New therapeutic approaches, such as low-dose colchicine, PCSK9 inhibitors, antithrombotic therapies, GLP1 receptor agonists and SGLT2 inhibitors, offer new therapeutic avenues for reducing residual risk.
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An in-depth understanding of the mechanisms and synergy of existing and novel therapies is key to tailoring treatment strategies and achieving a favourable risk–benefit profile.
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Artificial intelligence will have a pivotal role in analysing complex datasets to enable precise stratification of patients and to identify optimal therapeutic targets.
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Acknowledgements
M. Galli declares that he is the principal investigator of the active grant Sapienza University of Rome (Grant protocol no. RG1241910F5A1A50). M. Gaudino is principal investigator in the active grants NIH/NHLBI Grant R01NS123639-01, NIH/NHLBI Grant R01HL152021, NIH/NHLBI Grant R01HL170570-01, NIH/NHLBI Grant1R01HL170566-0, and Research Award PCORI PLACER Award 30048.
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M. Galli has received consulting fees from Genomadix and Werfen. M.P.B. is the Executive Director of CPC, a non-profit academic research organization affiliated with the University of Colorado that receives or has received research grant/consulting funding between August 2021 and present from Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma, Alnylam Pharmaceuticals, Amgen, Angionetics, Anthos Therapeutics, Array BioPharma, AstraZeneca and affiliates, Atentiv, Audentes Therapeutics, Bayer and Affiliates, Bristol-Meyers Squibb, Cambrian Biopharma, Cardiol Therapeutics, CellResearch, Cleerly, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading, Epizon Pharma, Esperion Therapeutics, Everly Well, Exicon Consulting, Faraday Pharmaceuticals, Foresee Pharmaceuticals, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, Janssen and affiliates, Kowa Research Institute, Lexicon Pharmaceuticals, Medimmune, Merck and affiliates, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Prairie Education and Research Cooperative, Prothena Biosciences, Regeneron Pharmaceuticals, Regio Biosciences, Sanofi-Aventis Groupe, Silence Therapeutics, Smith & Nephew, Stealth BioTherapeutics, VarmX and Virta Health Corporation. D.A.G. declares institutional research grants from AstraZeneca and speaker’s honoraria and advisory board fees from BMS, Chiesi and Janssen. M.L.O. reports research grants via Brigham and Women’s Hospital from Amgen, AstraZeneca, Marea Therapeutics and Novartis, and consulting and/or Data and Safety Monitoring Board fees from Amgen, Janssen, New Amsterdam, Novartis, Novo Nordisk and Verve Therapeutics. P.G.S. received research grants from Amarin and Sanofi; has received honoraria from Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Idorsia, Janssen, Lilly, Merck, Novartis, Novo Nordisk, Pfizer and Sanofi; and is Chief Medical Officer for Bioquantis and Senior Associate Editor at Circulation. D.J.A. has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer and Sanofi, and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis and the Scott R. MacKenzie Foundation. The other authors declare no competing interests.
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Galli, M., Abbate, A., Bonaca, M.P. et al. Residual cardiovascular risk in coronary artery disease: from pathophysiology to established and novel therapies. Nat Rev Cardiol (2026). https://doi.org/10.1038/s41569-026-01249-z
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DOI: https://doi.org/10.1038/s41569-026-01249-z
