Introduction and Objective: SGLT2 inhibitors are efficacious in patients with T2D, renal dysfunction, and heart failure; yet their use in patients with T1D is limited due to increased risk of DKA despite demonstrating improvement in A1c and percent glucose time in range. To understand the molecular basis of SGLT2i-mediated DKA risk, we performed comprehensive plasma metabolomic analyses in patients with T1D treated with SGLT2i at baseline and during insulin withdrawal.Methods: Participants were randomized to usual care (UC) or usual care plus dapagliflozin (DAPA) 10 mg daily for 2 weeks followed by a day of supervised insulin withdrawal. Baseline blood samples were obtained and then hourly glucose and β-hydroxybutyrate (BOHB) until any stopping criteria were met (patient request, nausea/vomiting, 7 hours elapsed, BOHB ≥ 3 mmol/L, glucose ≥ 400 mg/dl) and final sample collected. Twenty persons with T1D, 11 males/9 females, age 48 ±18 years, baseline A1c 7.0 ± 0.9%, and time in range 61 ± 18% (all mean ± SD) completed the study. Baseline and insulin withdrawal samples were submitted for metabolomic analysis by UHPLC/MS.Results: DAPA increased TCA cycle metabolites citrate and aconitate at baseline, with a trend toward increased branched chain ketoacids and short chain acylcarnitines at baseline. During insulin withdrawal, glucose levels increased after UC but not DAPA. BOHB, acetoacetate, and acetylcarnitine were significantly higher during insulin withdrawal after DAPA compared to UC. TCA metabolites citrate, aconitate, alpha-ketoglutarate, and malate were increased during insulin withdrawal after UC. However, insulin withdrawal after DAPA resulted in unchanged alpha-ketoglutarate and malate and significantly decreased fumarate and succinate.Conclusion: SGLT2i adjunct therapy for T1D could improve glycemic control and mitigate complications. DAPA alters TCA cycle activation during insulin withdrawal. Future work will validate these findings and further investigate the molecular basis of SGLT2i-mediated DKA risk.
S.A. DiGruccio: None. K. Cho: None. K.E. Jones: None. M.C. Petersen: None. G.J. Patti: None. J.B. McGill: Advisory Panel; Bayer Pharmaceuticals, Inc. Consultant; Jaeb Center for Health Research. Advisory Panel; Boehringer-Ingelheim, Lilly Diabetes, Novo Nordisk, MannKind Corporation. Research Support; Diagnode, Lexicon Pharmaceuticals, Inc, Biomea Fusion.
JDRF (2-SRA-2022_1190-M-B/P22-03211); Washington University in St. Louis ICTS (CTRFP1712); NIH NIDDK (K12DK133995); NIH NIDDK (K08DK142012); NIH (UL1TR002345); NIH (KL2TR002346, NIH T32DK007120); Washington University DRC (P30DK020579)
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