Abstract
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an established class of agents in the treatment of type 2 diabetes mellitus (T2DM), with proven cardiovascular and renal benefits. However, their precise mechanisms of action remain incompletely understood. Metabolomics offers a powerful approach to uncovering drug-induced alterations in metabolic pathways. AIM: This narrative review summarizes the available human evidence on the metabolomic effects of SGLT2 inhibitors, with a focus on their potential implications for metabolic adaptation and cardiorenal protection. METHODS: We performed a comprehensive literature search of human studies that applied metabolomic analyses to evaluate the effects of SGLT2 inhibitors in T2DM. Both targeted and untargeted metabolomic approaches were considered. RESULTS: Across studies, SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates. Key metabolite changes include increases in ketone bodies, alterations in branched-chain amino acids, and modulation of intermediates of the tricarboxylic acid cycle. CONCLUSION: SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates, including ketone bodies, fatty acids, and certain amino acids. These metabolomic adaptations may underlie their observed cardiovascular and renal protective effects. While these findings support the "thrifty fuel" hypothesis, additional longitudinal studies with standardized methodologies and precision medicine approaches are needed to fully define the clinical significance of these metabolic adaptations.