The Effects of Sodium-Glucose Co-transporter 2 Inhibition on Plasma and Urine Ketones in Type 1 Diabetes
Abstract
Background: Adjunctive-to-insulin SGLT2 inhibition (SGLT2i) in type 1 diabetes (T1D) has meaningful metabolic benefits but can increase risk of ketoacidosis. Knowledge gaps include understanding ketone metabolism with and without SGLT2i treatment in T1D, and whether ketoacidosis risk in females is physiological or behavioral.Methods: Metabolomic analysis of plasma and urine beta-hydroxybutyrate and acetoacetate from stored baseline and 8-week eu- and mild hyper-glycemic samples in the 40-person single-arm Adjunctive-To-Insulin Renal MechAnistic (ATIRMA) trial of empagliflozin. Results: A significantly greater production of ketones even during mild hyperglycemia compared to euglycemia was observed, but this was compensated by increased urinary excretion leading to similar plasma concentrations. However, SGLT2i attenuated this increased excretion, resulting in higher plasma concentrations, particularly in females. Conclusions: Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion. SGLT2i further exaggerates excess production and impaired excretion especially in females, indicating physiological rather than behavioral risk for ketoacidosis.
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