Immunometabolic Effects of SGLT2 Inhibitors on the Th17/Treg Axis: Mechanisms, Evidence, and Implications for Therapeutic Repurposing.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors confer cardiovascular and renal benefits that exceed those attributable to glycemic control alone, prompting interest in pleiotropic mechanisms, including immunomodulation. While prior research has largely focused on innate inflammatory pathways, emerging evidence suggests that SGLT2 inhibition may also influence adaptive immunity through immunometabolic reprogramming. Recent findings demonstrate functional SGLT2 expression in activated human cluster of differentiation 4 (CD4⁺) T cells and responsiveness to pharmacological inhibition, raising the possibility that both systemic metabolic remodeling and direct cellular effects contribute to immune regulation. This review examines the immunometabolic pathways linking SGLT2 inhibition to adaptive immune regulation and critically synthesizes the mechanistic, preclinical, and clinical evidence supporting effects on the T helper 17 (Th17)/regulatory T-cell (Treg) axis, the most extensively studied adaptive immune pathway in this field. Proposed mechanisms include AMP-activated protein kinase (AMPK) activation, suppression of mechanistic target of rapamycin complex 1 (mTORC1) and serum/glucocorticoid-regulated kinase 1 (SGK1), ketone-associated signaling, and broader fasting-mimetic metabolic remodeling that may favor regulatory over pro-inflammatory T-cell responses. Experimental studies frequently report attenuation of Th17-associated responses and restoration of Th17/Treg balance, whereas human evidence remains limited. However, current data support adaptive immune modulation as a biologically plausible but incompletely validated component of SGLT2 inhibitor biology. Further translational and clinical studies are required to clarify its contribution to cardiorenal benefits and its potential relevance to therapeutic repurposing in immune-mediated diseases.