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A metabolomics‐based molecular pathway analysis of how the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin may slow kidney function decline in patients with diabetes

Diabetes, Obesity and Metabolism Apr 02, 2020

Mulder S, Hammarstedt A, Nagaraj SB, et al. - Researchers intended to define the molecular processes implicated in the renal protective effects of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, and therefore, they determined the metabolic pathways targeted by dapagliflozin. Baseline as well as follow‐up (week 12) samples from the EFFECT II trial were analyzed. These samples were obtained from patients with type 2 diabetes with non‐alcoholic fatty liver disease who were given dapagliflozin 10 mg/day (n = 19) or placebo (n = 6). The European Renal cDNA Biobank was also used to identify transcriptomic signatures from tubular compartments from kidney biopsies taken from patients suffering from diabetic kidney disease (DKD) (n = 17) and healthy controls (n = 30). Four enriched pathways influenced by dapagliflozin and related to estimated glomerular filtration rate were discovered by the combination of metabolites and transcripts: glycine degradation (mitochondrial function), TCA cycle II (energy metabolism), L‐carnitine biosynthesis (energy metabolism) and superpathway of citrulline metabolism (nitric oxide synthase and endothelial function). These molecular pathways targeted by dapagliflozin and related to DKD are indicative of the likely contribution of modifying molecular processes associated with energy metabolism, mitochondrial function and endothelial function, to its renal protective effect.

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