Empagliflozin lowers 1,5AG plasma levels and restores neutrophil function in GSD-Ib patients by lowering neutrophil 1,5AG6P. 1,5AG is a nondegradable glucose analog present in blood (∼150 µM). It is slowly phosphorylated to 1,5AG6P by the side activities of hexokinases and adenosine 5′-diphosphate–dependent glucokinase present in neutrophils. To prevent its accumulation, 1,5AG6P is transported into the endoplasmic reticulum by G6PT and dephosphorylated by the phosphatase G6PC3. (A) In GSD-Ib patients who are deficient in G6PT, 1,5AG6P accumulates in neutrophils. It is the rise in the concentration of 1,5AG6P that intoxicates neutrophils by strongly inhibiting hexokinases and depleting the intracellular pool of G6P (Gluc-6P) that is vital for neutrophils to survive and function.¹⁴  (B) Inhibiting the renal SGLT2 with empagliflozin leads to glucosuria by preventing the renal reabsorption of glucose, but also of 1,5AG, which results in its urinary excretion. Consequently, this leads to an approximate fourfold reduction in the concentration of 1,5AG in blood and of 1,5AG6P in neutrophils. This relieves the inhibition of hexokinases and increases the pool of G6P and of the metabolites in downstream pathways, improving glycolysis, respiratory burst, and protein glycosylation. Neutrophils function better, and neutropenia is partly corrected.