Mechanisms of sodium-glucose cotransporter-2 inhibition: Insights from Large-Scale Proteomics

Objective To assess the effects of empagliflozin, a selective SGLT2 inhibitor, on broad biological systems through proteomics.

Research Design and Methods 3,713 proteins were quantified using aptamer-based proteomics in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance, before and after 4 weeks of empagliflozin 25 mg/day. Biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected p<0.05) was discerned through Ingenuity Pathway Analysis.

Results Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid binding protein 3 and 4 (FABPA), neurotrophic receptor tyrosine kinase (NTRK2), renin, thrombospondin-4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1 (TFRC), neogenin, growth differentiation factor 2 (GDF-2), and ß2-microglobulin) and 1 to spingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, growth differentiation factor-15 (GDF15), and sulphydryl oxidase 2 precursor (QSOX2) were increased, while ferritin, thrombospondin-3, and REarranged during Transfection (RET) were decreased by empagliflozin administration

Conclusion SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1 and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies, using targeted proteomics and a prospective design.