Annals of Clinical Pharmacology and Physiology | Volume 1, Issue 1 | Review Article | Open Access
Macit KALÇIK*
Mehmet Mustafa YILMAZ1, Macit KALÇIK2*, Oğuzhan Çelik3, Osman KARAARSLAN1, Abdullah SARIHAN4, Ömer Burak ÇELİK1, Mucahit YETİM2, Muhammet Cihat ÇELİK1, Lütfü BEKAR2, Yusuf KARAVELİOĞLU2
1Department of Cardiology, Hitit University Erol Olçok Education and Research Hospital, Corum, Turkey
2Department of Cardiology, Faculty of Medicine, Hitit University, Corum, Turkey
3Department of Cardiology, Faculty of Medicine, Muğla University, Muğla, Turkey
4Department of Cardiology, Gediz State Hospital, Kütahya, Turkey
*Correspondence to: Macit KALÇIK
Fulltext PDFSodium–glucose cotransporter-2 (SGLT2) inhibitors were initially developed as glucose-lowering agents but have evolved into therapies with significant cardiovascular impact after outcome trials demonstrated reductions in heart failure hospitalization and cardiovascular mortality that could not be attributed solely to glycemic control. Subsequent studies confirmed consistent benefits across both reduced and preserved ejection fraction, including in patients without diabetes, highlighting mechanisms beyond metabolic regulation. This review outlines the integrated pathways underlying these effects, including restoration of tubuloglomerular feedback with reduction of intraglomerular pressure and improved cardiorenal interaction, mild natriuresis leading to favorable preload reduction without neurohormonal activation, and improvements in arterial compliance and systemic hemodynamics. At the myocardial level, SGLT2 inhibition promotes metabolic reprogramming toward more efficient substrate utilization, enhances mitochondrial function, reduces lipotoxic stress, and attenuates maladaptive neurohormonal signaling. Additional structural and vascular effects include reductions in myocardial fibrosis and hypertrophy, improved endothelial function, and suppression of inflammatory and oxidative stress pathways. Together, these coordinated systemic and myocardial actions provide a mechanistic basis for the rapid and sustained reductions in heart failure events observed in clinical trials and support the positioning of SGLT2 inhibitors as disease-modifying therapies across the cardiovascular spectrum.
SGLT2 inhibitors; Heart failure; Cardiorenal interaction; Myocardial energetics; Cardiovascular outcomes
Mehmet Mustafa YILMAZ, Macit KALÇIK, Oğuzhan Çelik, Osman KARAARSLAN, Abdullah SARIHAN, Ömer Burak ÇELİK, et al. Cardiovascular Protection with SGLT2 Inhibitors: Systemic Mechanisms Beyond Glycemic Control. Annal Clin Pharm Phys. 2026;1(1):1-19.