posted on 2020-06-11, 16:41authored byEle Ferrannini, Ashwin C. Murthy, Yong-ho Lee, Elza Muscelli, Sophie Weiss, Rachel M. Ostroff, Naveed Sattar, Stephen A. Williams, Peter Ganz
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.
Funding
SomaScan assays and the Covance study were funded by SomaLogic, Inc.