@article{10.37349/ec.2026.1012113,
abstract = {Sodium–glucose cotransporter 2 inhibitors (SGLT2i) were originally developed as glucose-lowering therapies for type 2 diabetes mellitus. However, robust clinical evidence has demonstrated substantial cardiovascular and renal protective effects that extend beyond glycemic control. Emerging data highlight their systemic influence across the cardiovascular–renal–metabolic (CRM) continuum, a conceptual framework describing the shared pathophysiological links between metabolic dysfunction, heart failure (HF), and chronic kidney disease (CKD). Despite the rapid expansion of clinical and mechanistic evidence, the integration of these insights into coordinated therapeutic implementation across cardiology, nephrology, and endocrinology remains incompletely synthesized. This structured narrative review synthesized evidence from PubMed/MEDLINE, Embase, and Google Scholar to identify relevant studies published between January 2016 and December 2025. Emphasis was placed on randomized controlled trials, meta-analyses, large observational cohorts, guideline documents, and translational mechanistic investigations evaluating pharmacologic mechanisms, clinical efficacy, and multidisciplinary applications of SGLT2i across CRM conditions. Cardiovascular and renal outcome trials consistently show that SGLT2i reduce hospitalization for heart failure, delay CKD progression, and improve major cardiovascular outcomes in both diabetic and non-diabetic populations. Mechanistically, these agents restore tubuloglomerular feedback, enhance cardiac energy efficiency through increased ketone utilization, attenuate inflammatory and profibrotic signaling pathways, and improve mitochondrial bioenergetics. These multisystem effects contribute to therapeutic benefits across HF phenotypes and CKD stages while also improving metabolic parameters such as adiposity, blood pressure, and hepatic steatosis. Collectively, current evidence supports SGLT2i as foundational disease-modifying therapies across the CRM spectrum. Future investigations should prioritize precision-based treatment approaches, biomarker-guided patient selection, and rational combination pharmacotherapy to further optimize outcomes across interconnected cardiovascular, renal, and metabolic diseases.},
author = {Tariq, Nabil and Islam, Afra Wasama and Dhadke, Preshita and Patel, Tabish and Muhammad, Mehreen Rasheed and Aawesh, Mohammed and Muhammad, Subia Rasheed and Tahir, Burhan},
doi = {10.37349/ec.2026.1012113},
journal = {Exploration of Cardiology},
elocation-id = {1012113},
title = {Reframing SGLT2 inhibition as systematic metabolic stress modulation across the cardiovascular-renal-metabolic axis},
url = {https://www.explorationpub.com/Journals/ec/Article/1012113},
volume = {4},
year = {2026}
}