Dapagliflozin Alters Plasma Metabolome in Patients With Type 1 Diabetes During Ketosis

ABSTRACT Aims Use of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 1 diabetes (T1D) is limited by increased risk of ketoacidosis. We aimed to determine metabolic pathways affected by SGLT2i treatment in adults with T1D during ketosis induced by insulin withdrawal. Materials and Methods Plasma metabolomic and lipidomic analysis by ultra‐high‐performance liquid chromatography/mass spectrometry was performed at baseline and after supervised insulin withdrawal in 17 adults with T1D treated with usual care (UC) and (DP) dapagliflozin (10 mg daily for 14 days). Results Plasma glucose levels were lower, and ketone levels were higher after insulin withdrawal in DP compared to UC. Pathway analysis of differentially altered metabolites revealed that DP altered amino acids and TCA cycle metabolites during ketosis. DP treatment increased citrate and aconitate at baseline, with a trend towards increased branched chain ketoacids and acylcarnitines. Citrate, aconitate, α‐ketoglutarate and malate were increased during insulin withdrawal after UC whereas insulin withdrawal after DP resulted in unchanged α‐ketoglutarate and malate and significantly decreased fumarate and succinate. Acetylcarnitine was significantly higher during insulin withdrawal after DP compared to UC. DP effected subtle changes in amino acids and amino acid derivatives. Symmetric dimethylarginine and pseudouridine were significantly elevated at baseline and after insulin withdrawal after DP. Lipidomics revealed increased very long TG species in DP and differences in phospholipids, particularly phosphatidylcholine. Conclusion In adults with T1D, dapagliflozin alters TCA cycle metabolites, amino acid metabolites and certain lipids during insulin withdrawal. Future work will validate findings and further investigate the metabolic basis of SGLT2i‐mediated ketoacidosis risk.