Changes in plasma and urine metabolites associated with empagliflozin in patients with type 1 diabetes

Aim: To examine the impact of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on plasma and urine metabolites in participants with type 1 diabetes. Material and Methods: Participants (n = 40, 50% male, mean age 24.3 years) with type 1 diabetes and without overt evidence of diabetic kidney disease had baseline assessments performed under clamped euglycaemia and hyperglycaemia, on two consecutive days. Participants then proceeded to an 8-week, open-label treatment period with empagliflozin 25 mg/day, followed by repeat assessments under clamped euglycaemia and hyperglycaemia. Plasma and urine metabolites were first grouped into metabolic pathways using MetaboAnalyst software. Principal component analysis was performed to create a representative value for each sufficiently represented metabolic group (false discovery rate ≤ 0.1) for further analysis. Results: Of the plasma metabolite groups, tricarboxylic acid (TCA) cycle (P <.0001), biosynthesis of unsaturated fatty acids (P =.0045), butanoate (P <.0001), propanoate (P =.0053), and alanine, aspartate and glutamate (P <.0050) metabolites were increased after empagliflozin treatment under clamped euglycaemia. Of the urine metabolite groups, only butanoate metabolites (P =.0005) were significantly increased. Empagliflozin treatment also attenuated the increase in a number of urine metabolites observed with acute hyperglycaemia. Conclusions: Empagliflozin was associated with increased lipid and TCA cycle metabolites in participants with type 1 diabetes, suggesting a shift in metabolic substrate use and improved mitochondrial function. These effects result in more efficient energy production and may contribute to end-organ protection by alleviating local hypoxia and oxidative stress.