Paschalis Karakasis, Panagiotis Theofilis, Panayotis K Vlachakis, Anastasios Apostolos, Nikias Milaras, Nikolaos Ktenopoulos, Konstantinos Grigoriou, Aleksandra Klisic, Efstratios Karagiannidis, Barbara Fyntanidou, Dimitrios Patoulias, Antonios P Antoniadis, Nikolaos Fragakis
{"title":"SGLT2 inhibitors and cardiac fibrosis: A comprehensive review.","authors":"Paschalis Karakasis, Panagiotis Theofilis, Panayotis K Vlachakis, Anastasios Apostolos, Nikias Milaras, Nikolaos Ktenopoulos, Konstantinos Grigoriou, Aleksandra Klisic, Efstratios Karagiannidis, Barbara Fyntanidou, Dimitrios Patoulias, Antonios P Antoniadis, Nikolaos Fragakis","doi":"10.1016/j.cpcardiol.2025.103149","DOIUrl":null,"url":null,"abstract":"<p><p>Cardiac fibrosis is a key pathological substrate that drives diastolic dysfunction, arrhythmogenesis, and heart failure progression across a spectrum of cardiometabolic disorders. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for glucose lowering, have demonstrated pleiotropic effects on myocardial structure, notably attenuating fibrotic remodeling. Experimental models of diabetes, hypertension, ischemia, and cardiotoxicity consistently show that SGLT2 inhibitors mitigate interstitial and perivascular fibrosis through modulation of oxidative stress, mitochondrial function, autophagy, and canonical profibrotic signaling cascades, including TGF-β/Smad, STAT3, and mTOR. These actions are largely preserved in non-diabetic settings and appear to extend beyond hemodynamic or glycemic benefits. Clinical data, including cardiac magnetic resonance-based assessments, support the notion of diffuse fibrosis regression, particularly in heart failure with preserved ejection fraction and diabetic cardiomyopathy. Moreover, reductions in serum collagen biomarkers and improvements in myocardial energetics further substantiate their antifibrotic capacity. Nonetheless, fibrosis-specific endpoints remain underrepresented in major cardiovascular outcome trials, and histological validation in human tissue is lacking. Integrating artificial intelligence-driven fibrosis quantification, spatial transcriptomics, and high-resolution imaging may refine phenotyping and enable precision antifibrotic therapy. Whether fibrosis regression translates into durable clinical benefit remains an open question. This review comprehensively synthesizes the mechanistic, translational, and clinical evidence supporting the role of SGLT2 inhibitors as modulators of cardiac fibrosis across diverse cardiovascular disease states.</p>","PeriodicalId":51006,"journal":{"name":"Current Problems in Cardiology","volume":" ","pages":"103149"},"PeriodicalIF":3.3000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Problems in Cardiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.cpcardiol.2025.103149","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/5 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Cardiac fibrosis is a key pathological substrate that drives diastolic dysfunction, arrhythmogenesis, and heart failure progression across a spectrum of cardiometabolic disorders. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for glucose lowering, have demonstrated pleiotropic effects on myocardial structure, notably attenuating fibrotic remodeling. Experimental models of diabetes, hypertension, ischemia, and cardiotoxicity consistently show that SGLT2 inhibitors mitigate interstitial and perivascular fibrosis through modulation of oxidative stress, mitochondrial function, autophagy, and canonical profibrotic signaling cascades, including TGF-β/Smad, STAT3, and mTOR. These actions are largely preserved in non-diabetic settings and appear to extend beyond hemodynamic or glycemic benefits. Clinical data, including cardiac magnetic resonance-based assessments, support the notion of diffuse fibrosis regression, particularly in heart failure with preserved ejection fraction and diabetic cardiomyopathy. Moreover, reductions in serum collagen biomarkers and improvements in myocardial energetics further substantiate their antifibrotic capacity. Nonetheless, fibrosis-specific endpoints remain underrepresented in major cardiovascular outcome trials, and histological validation in human tissue is lacking. Integrating artificial intelligence-driven fibrosis quantification, spatial transcriptomics, and high-resolution imaging may refine phenotyping and enable precision antifibrotic therapy. Whether fibrosis regression translates into durable clinical benefit remains an open question. This review comprehensively synthesizes the mechanistic, translational, and clinical evidence supporting the role of SGLT2 inhibitors as modulators of cardiac fibrosis across diverse cardiovascular disease states.
期刊介绍:
Under the editorial leadership of noted cardiologist Dr. Hector O. Ventura, Current Problems in Cardiology provides focused, comprehensive coverage of important clinical topics in cardiology. Each monthly issues, addresses a selected clinical problem or condition, including pathophysiology, invasive and noninvasive diagnosis, drug therapy, surgical management, and rehabilitation; or explores the clinical applications of a diagnostic modality or a particular category of drugs. Critical commentary from the distinguished editorial board accompanies each monograph, providing readers with additional insights. An extensive bibliography in each issue saves hours of library research.