{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:40:13Z","timestamp":1791312013821,"version":"4.3.1"},"reference-count":166,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aortic stenosis (AS), the most prevalent valvular heart disease, is increasingly recognized as an active disease process driven by a convergence of hemodynamic stress, inflammation, oxidative injury, and metabolic remodeling. While transcatheter and surgical valve replacement remain the standard interventions for severe AS, they fail to reverse the chronic myocardial remodeling that underlies adverse outcomes in many patients. Sodium\u2013glucose cotransporter 2 (SGLT2) inhibitors have emerged as promising cardioprotective agents, with effects extending well beyond glycemic control. Recent mechanistic studies reveal that SGLT2 is expressed in the myocardium of patients with AS and is linked to pathways of fibrosis, inflammation, and energetic dysfunction. Experimental models and translational data demonstrate that SGLT2 inhibition attenuates maladaptive remodeling through modulation of TGF-\u03b2, NF-\u03baB, NLRP3 inflammasome, and oxidative stress signaling while enhancing mitochondrial energetics and endothelial function. Importantly, clinical evidence from randomized and real-world studies suggests that SGLT2 inhibitors improve heart failure outcomes following valve replacement and may slow AS progression. This review integrates current pathophysiological insights with emerging molecular and clinical data to delineate the therapeutic rationale for SGLT2 inhibition in AS. By targeting both myocardial and valvular components of the disease, SGLT2 inhibitors may offer a novel disease-modifying strategy with potential implications across the AS continuum\u2014from asymptomatic stages to the post-interventional setting. Ongoing and future trials are warranted to define optimal patient selection, timing, and biomarkers for response to SGLT2 inhibitor therapy in this increasingly high-risk population.<\/jats:p>","DOI":"10.3390\/ijms26104494","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T09:58:09Z","timestamp":1746698289000},"page":"4494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Sodium\u2013Glucose Cotransporter 2 Inhibitors in Aortic Stenosis: Toward a Comprehensive Cardiometabolic Approach"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3561-5713","authenticated-orcid":false,"given":"Paschalis","family":"Karakasis","sequence":"first","affiliation":[{"name":"Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9260-6306","authenticated-orcid":false,"given":"Panagiotis","family":"Theofilis","sequence":"additional","affiliation":[{"name":"First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6899-684X","authenticated-orcid":false,"given":"Dimitrios","family":"Patoulias","sequence":"additional","affiliation":[{"name":"Second Propedeutic Department of Internal Medicine, Faculty of Medicine, School of Health Sciences Aristotle, University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0736-4942","authenticated-orcid":false,"given":"Panayotis K.","family":"Vlachakis","sequence":"additional","affiliation":[{"name":"First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5411-6461","authenticated-orcid":false,"given":"Konstantinos","family":"Pamporis","sequence":"additional","affiliation":[{"name":"First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3473-1368","authenticated-orcid":false,"given":"Marios","family":"Sagris","sequence":"additional","affiliation":[{"name":"First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0995-7015","authenticated-orcid":false,"given":"Nikolaos","family":"Ktenopoulos","sequence":"additional","affiliation":[{"name":"First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Kassimis","sequence":"additional","affiliation":[{"name":"Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6604-5581","authenticated-orcid":false,"given":"Antonios P.","family":"Antoniadis","sequence":"additional","affiliation":[{"name":"Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7158-4950","authenticated-orcid":false,"given":"Nikolaos","family":"Fragakis","sequence":"additional","affiliation":[{"name":"Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1136\/heartjnl-2023-322397","article-title":"Mortality Trends of Aortic Stenosis in High-Income Countries from 2000 to 2020","volume":"109","author":"Hibino","year":"2023","journal-title":"Heart"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1016\/j.jacc.2023.11.007","article-title":"Global Burden of Cardiovascular Diseases and Risks, 1990\u20132022","volume":"82","author":"Mensah","year":"2023","journal-title":"J. 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