{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T05:10:55Z","timestamp":1793250655625,"version":"4.5.0"},"reference-count":73,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CEU Santander via Proyectos de Investigaci\u00f3n+Docencia","award":["IDOC 24-03"],"award-info":[{"award-number":["IDOC 24-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Sodium\u2013glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-\u03b1, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1\u03b1\/PPAR\u03b1). Modest weight loss (~2\u20134 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential.<\/jats:p>","DOI":"10.3390\/metabo15080536","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"536","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["SGLT2 Inhibitors: Multifaceted Therapeutic Agents in Cardiometabolic and Renal Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8958-6711","authenticated-orcid":false,"given":"Ana","family":"Checa-Ros","sequence":"first","affiliation":[{"name":"Grupo de Investigaci\u00f3n en Enfermedades Cardiorrenales y Metab\u00f3licas, Departamento de Medicina y Cirug\u00eda, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, C\/Santiago Ram\u00f3n y Cajal s\/n, 46115 Valencia, Spain"},{"name":"Aston Institute of Health & Neurodevelopment (AIHN), School of Life & Health Sciences, The Aston Triangle, Aston University, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6805-7738","authenticated-orcid":false,"given":"Owahabanun-Joshua","family":"Okojie","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n en Enfermedades Cardiorrenales y Metab\u00f3licas, Departamento de Medicina y Cirug\u00eda, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, C\/Santiago Ram\u00f3n y Cajal s\/n, 46115 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0148-891X","authenticated-orcid":false,"given":"Luis","family":"D\u2019Marco","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n en Enfermedades Cardiorrenales y Metab\u00f3licas, Departamento de Medicina y Cirug\u00eda, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, C\/Santiago Ram\u00f3n y Cajal s\/n, 46115 Valencia, Spain"},{"name":"Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, AB T6G 0M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"306","DOI":"10.2337\/db07-0381","article-title":"Metformin Inhibits Hepatic Gluconeogenesis Through AMP-Activated Protein Kinase\u2013Dependent Regulation of the Orphan Nuclear Receptor SHP","volume":"57","author":"Kim","year":"2008","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N. 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