Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor
Open Access
- 27 August 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 136 (9), 1033-1043
- https://doi.org/10.1182/blood.2019004465
Abstract
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.This publication has 42 references indexed in Scilit:
- G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunctionGlycobiology, 2011
- SGLT2 inhibition — a novel strategy for diabetes treatmentNature Reviews Drug Discovery, 2010
- A Syndrome with Congenital Neutropenia and Mutations inG6PC3The New England Journal of Medicine, 2009
- Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type IbBlood, 2008
- Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase–βJCI Insight, 2007
- Functional characterization of mitochondria in neutrophils: a role restricted to apoptosisCell Death & Differentiation, 2003
- Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b)Blood, 2003
- A Gene on Chromosome 11q23 Coding for a Putative Glucose- 6-Phosphate Translocase Is Mutated in Glycogen-Storage Disease Types Ib and IcAmerican Journal of Human Genetics, 1998
- In Vitro Bactericidal Capacity of Human Polymorphonuclear Leukocytes: Diminished Activity in Chronic Granulomatous Disease of Childhood *JCI Insight, 1967
- THE CHEMOTACTIC EFFECT OF MIXTURES OF ANTIBODY AND ANTIGEN ON POLYMORPHONUCLEAR LEUCOCYTESThe Journal of Experimental Medicine, 1962