Beyond glycemic control: SGLT2 inhibitors as time-sensitive organ-protective agents in acute injury-mechanistic insights and translational implications.

BACKGROUND

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were initially developed as glucose-lowering therapies for type 2 diabetes mellitus. However, large cardiovascular and renal outcome trials have demonstrated rapid reductions in heart failure events and slowing of kidney disease progression, including in patients without diabetes, suggesting benefits beyond glycemic control.

OBJECTIVE

To summarize the mechanistic, preclinical, and clinical evidence supporting SGLT2is as acute organ-protective agents and to evaluate their translational potential in time-sensitive clinical settings.

METHODS

A structured narrative review was conducted using PubMed, Web of Science, and Embase, focusing on mechanistic studies, experimental acute injury models, randomized controlled trials, post hoc analyses, meta-analyses, and real-world studies published predominantly within the last 5-7 years.

RESULTS

SGLT2is may exert acute organ-protective effects through integrated mechanisms involving improved cellular stress adaptation, modulation of ionic and metabolic homeostasis, and hemodynamic as well as immuno-endothelial regulation. Current clinical evidence is most consistent in acute heart failure and early post-myocardial infarction (post-MI) remodeling, whereas evidence in acute kidney injury arrhythmias, stroke, acute lung injury, and liver injury remains limited or exploratory.

CONCLUSION

SGLT2is should no longer be viewed solely as glucose-lowering agents. Accumulating evidence supports their broader role as potential time-sensitive organ-protective therapies in acute illness, particularly within the cardiorenal spectrum. However, substantial heterogeneity in evidence quality persists, and dedicated acute-care trials are needed to clarify therapeutic timing, patient selection, and safety considerations.