Publication

Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor

Wortmann, S. B., Van Hove, J. L. K., Derks, T. G. J., Chevalier, N., Knight, V., Koller, A., Oussuren, E., Mayr, J. A., van Spronsen, F. J., Lagler, F. B., Gaughan, S., Van Schaftingen, E. & Veiga-da-Cunha, M., 27-Aug-2020, In : Blood. 136, 9, p. 1033-1043 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Wortmann, S. B., Van Hove, J. L. K., Derks, T. G. J., Chevalier, N., Knight, V., Koller, A., Oussuren, E., Mayr, J. A., van Spronsen, F. J., Lagler, F. B., Gaughan, S., Van Schaftingen, E., & Veiga-da-Cunha, M. (2020). Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor. Blood, 136(9), 1033-1043. https://doi.org/10.1182/blood.2019004465

Author

Wortmann, Saskia B ; Van Hove, Johan L K ; Derks, Terry G J ; Chevalier, Nathalie ; Knight, Vijaya ; Koller, Andreas ; Oussuren, Esmee ; Mayr, Johannes Am ; van Spronsen, Francjan J ; Lagler, Florian B ; Gaughan, Sommer ; Van Schaftingen, Emile ; Veiga-da-Cunha, Maria. / Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor. In: Blood. 2020 ; Vol. 136, No. 9. pp. 1033-1043.

Harvard

Wortmann, SB, Van Hove, JLK, Derks, TGJ, Chevalier, N, Knight, V, Koller, A, Oussuren, E, Mayr, JA, van Spronsen, FJ, Lagler, FB, Gaughan, S, Van Schaftingen, E & Veiga-da-Cunha, M 2020, 'Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor', Blood, vol. 136, no. 9, pp. 1033-1043. https://doi.org/10.1182/blood.2019004465

Standard

Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor. / Wortmann, Saskia B; Van Hove, Johan L K; Derks, Terry G J; Chevalier, Nathalie; Knight, Vijaya; Koller, Andreas; Oussuren, Esmee; Mayr, Johannes Am; van Spronsen, Francjan J; Lagler, Florian B; Gaughan, Sommer; Van Schaftingen, Emile; Veiga-da-Cunha, Maria.

In: Blood, Vol. 136, No. 9, 27.08.2020, p. 1033-1043.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Wortmann SB, Van Hove JLK, Derks TGJ, Chevalier N, Knight V, Koller A et al. Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor. Blood. 2020 Aug 27;136(9):1033-1043. https://doi.org/10.1182/blood.2019004465


BibTeX

@article{0c5481de07f048a7ab5f86fa4e226fb9,
title = "Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor",
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.",
author = "Wortmann, {Saskia B} and {Van Hove}, {Johan L K} and Derks, {Terry G J} and Nathalie Chevalier and Vijaya Knight and Andreas Koller and Esmee Oussuren and Mayr, {Johannes Am} and {van Spronsen}, {Francjan J} and Lagler, {Florian B} and Sommer Gaughan and {Van Schaftingen}, Emile and Maria Veiga-da-Cunha",
note = "Copyright {\textcopyright} 2020 American Society of Hematology.",
year = "2020",
month = aug,
day = "27",
doi = "10.1182/blood.2019004465",
language = "English",
volume = "136",
pages = "1033--1043",
journal = "Blood",
issn = "0006-4971",
publisher = "AMER SOC HEMATOLOGY",
number = "9",

}

RIS

TY - JOUR

T1 - Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor

AU - Wortmann, Saskia B

AU - Van Hove, Johan L K

AU - Derks, Terry G J

AU - Chevalier, Nathalie

AU - Knight, Vijaya

AU - Koller, Andreas

AU - Oussuren, Esmee

AU - Mayr, Johannes Am

AU - van Spronsen, Francjan J

AU - Lagler, Florian B

AU - Gaughan, Sommer

AU - Van Schaftingen, Emile

AU - Veiga-da-Cunha, Maria

N1 - Copyright © 2020 American Society of Hematology.

PY - 2020/8/27

Y1 - 2020/8/27

N2 - 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.

AB - 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.

U2 - 10.1182/blood.2019004465

DO - 10.1182/blood.2019004465

M3 - Article

C2 - 32294159

VL - 136

SP - 1033

EP - 1043

JO - Blood

JF - Blood

SN - 0006-4971

IS - 9

ER -

ID: 123236501