Pleiotropic mechanisms and translational trajectory of SGLT2 inhibitors in sepsis-induced cardiomyopathy: Navigating the evidence hierarchy.

Sepsis-induced cardiomyopathy (SICM) is a common but heterogeneous syndrome of acute myocardial dysfunction characterized by inflammatory dysregulation, endothelial and microcirculatory injury, mitochondrial bioenergetic failure, ionic instability, and regulated cell injury. Although recognition of SICM is increasing, management remains largely supportive, and no therapy has yet been established to directly modify myocardial vulnerability. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed as glucose-lowering agents, exert pleiotropic cardiovascular effects that intersect with several dominant injury axes of SICM. This interface appears most compelling at the metabolic-mitochondrial level, with additional anti-inflammatory, redox-modulating, and endothelial-protective effects. This review examines the mechanistic rationale for SGLT2 inhibition in SICM, the strength and limits of the current evidence, and the principal barriers to translation. Available evidence most strongly supports an AMPK-centered mitochondrial protective network as the leading mechanistic interface between SGLT2 inhibition and SICM. Anti-inflammatory, redox-modulating, and cell-protective effects are biologically coherent but are supported more by cross-model consistency than by direct validation in septic myocardium. Human evidence remains even more limited, deriving mainly from observational data on antecedent outpatient exposure rather than from prospective ICU initiation, while randomized evidence in broader acute-care populations has not demonstrated automatic clinical benefit. Current data therefore support biologic plausibility, but not routine clinical use, for SGLT2 inhibition in SICM. The immediate implication is not bedside adoption, but disciplined prospective testing after initial hemodynamic stabilization in phenotype-defined SICM, rather than de novo initiation during early septic shock.