Central Responses to SGLT2 Inhibition: Distinguishing Direct CNS Pharmacology from the Brain–Kidney–Metabolism Axis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that extend beyond glycemic control. Emerging studies report changes in hypothalamic and brainstem physiology following SGLT2 inhibitor administration, but the evidentiary meaning of these observations remains uncertain. This review critically evaluates clinical, in vivo, ex vivo, and cellular evidence linking SGLT2 inhibition to central metabolic regulation. We distinguish three claims that are often conflated: central pharmacological capacity after direct neural exposure, central nervous system (CNS) adaptation after systemic treatment, and therapeutically relevant CNS target engagement with causal mediation. Candidate pathways include hypothalamic nutrient sensing, insulin responsiveness, melanocortin signaling, ketone availability, glial inflammation, redox regulation, and autonomic activity. We propose a bidirectional brain–kidney–metabolism framework in which renal glucose and sodium loss generate metabolic, hormonal, inflammatory, hemodynamic, and potentially neural signals that are integrated by hypothalamic and brainstem circuits. These circuits may then convey autonomic and neuroendocrine outputs to peripheral organs. Current evidence supports central responsiveness and CNS adaptation to systemic treatment, but not a unified direct SGLT2-dependent brain mechanism. Compound-specific unbound CNS pharmacokinetics, orthogonal cell-specific target validation, compartment-restricted models, selective renal-afferent manipulation, and longitudinal human phenotyping are required to establish causality. The proposed framework complements, rather than replaces, established renal and tissue-specific mechanisms.