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Objective: To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics., Research Design and Methods: Aptamer-based proteomics was used to quantify 3,713 proteins 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. The 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, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/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, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration., Conclusions: 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., (© 2020 by the American Diabetes Association.)