Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor

Blood. 2020 Aug 27;136(9):1033-1043. doi: 10.1182/blood.2019004465.


Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P.

Publication types

  • Case Reports
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / therapeutic use*
  • Blood Glucose / analysis
  • Chemotaxis, Leukocyte / drug effects
  • Child, Preschool
  • Drug Repositioning
  • Drug Resistance
  • Female
  • Glucosides / adverse effects
  • Glucosides / therapeutic use*
  • Glycogen Storage Disease Type I / blood
  • Glycogen Storage Disease Type I / complications*
  • Glycogen Storage Disease Type I / immunology
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Granulocytes / chemistry
  • Hexosephosphates / blood*
  • Humans
  • Infant, Newborn
  • Lysosomal-Associated Membrane Protein 2 / blood
  • Male
  • Neutropenia / blood
  • Neutropenia / drug therapy*
  • Neutrophils / pathology*
  • Off-Label Use
  • Respiratory Burst / drug effects
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • Young Adult


  • Benzhydryl Compounds
  • Blood Glucose
  • Glucosides
  • Hexosephosphates
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Granulocyte Colony-Stimulating Factor
  • 1,5-anhydroglucitol-6-phosphate
  • empagliflozin

Supplementary concepts

  • Glycogen Storage Disease IB