Treating neutropenia and neutrophil dysfunction in glycogen ...

CLINICAL TRIALS AND OBSERVATIONS| AUGUST 27, 2020

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

Saskia B. Wortmann, Johan L. K. Van Hove, Terry G. J. Derks, Nathalie Chevalier, Vijaya Knight, Andreas Koller, Esmee Oussoren, Johannes A. Mayr, Francjan J. van Spronsen, Florian B. Lagler, Sommer Gaughan, Emile Van Schaftingen, Maria Veiga-da-Cunha

Blood (2020) 136 (9): 1033–1043.

https://doi.org/10.1182/blood.2019004465

Key Points

An SGLT2 inhibitor improves neutropenia/neutrophil dysfunction in GSD-Ib by lowering intracellular 1,5AG6P.

Empagliflozin, used in type 2 diabetes, is repurposed for neutrophil dysfunction in GSD-Ib without causing symptomatic hypoglycemia.

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.

Subjects:

Clinical Trials and Observations, Phagocytes, Granulocytes, and Myelopoiesis

Topics:

empagliflozin, glycogen storage disease, granulocyte colony-stimulating factor, neutropenia, neutrophils, sodium-glucose transporter 2 inhibitors, off-label use, glucose, hypoglycemia, infections

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