In this issue of Blood, Wortmann et al describe successful treatment of neutropenia and neutrophil dysfunction in a cohort of patients with glycogen storage disease type Ib (GSD-Ib) using empagliflozin, an inhibitor of the sodium glucose transport protein 2 (SGLT2).1 

Off-label use of a diabetes medication for treatment of a disorder associated with hypoglycemia and aberrant endogenous glucose production initially would seem risky and foolhardy. In this study, however, the authors convincingly demonstrate amelioration of neutropenia, improved neutrophil function, and normalization of neutrophil chemotaxis in this population with congenital neutropenia without causing significant untoward effects.

The association between GSD-Ib and congenital neutropenia was recognized in 1980, and life-threatening infections frequently occurred in this population before the introduction of therapy using granulocyte colony-stimulating factor (G-CSF).2,3  Treatment with G-CSF has markedly improved the prognosis for people with GSD-Ib, but recent concerns about complications associated with use of the hematopoietic growth factor have arisen. Not only is G-CSF therapy associated with severe splenic complications, including splenic rupture and infarction, but there is increasing evidence that chronic use in this population can predispose patients to myelodysplasia and acute myeloid leukemia.4,5  Notably, Li et al6  recently demonstrated shortening of telomere length in patients with GSD-Ib who are treated with continuing G-CSF therapy. Telomere shortening has been associated with chromosomal instability and possible proliferation of abnormal hematopoietic cells leading to the development of the hematologic malignancies.

Although G-CSF–induced stimulation of white blood cell production has been the primary treatment for neutropenia for the last 30 years, the therapy is not directed at the cause of the pathology. Several studies convincingly demonstrated that white blood cell maturation is normal in GSD-Ib, but survival of the neutrophil progenitors is impacted because of premature apoptosis.7,8  Accumulation of a toxic metabolite was hypothesized, and 1,5-anhydroglucitol-6-phosphate (1,5AG6P) was identified by Veiga-da-Cunha et al9  in 2019 as the potential cause of neutrophil apoptosis in the GSD-Ib population and also in those with congenital neutropenia resulting from glucose-6-phosphatase 3 (G6PC3) deficiency. Subsequent studies demonstrated that 1,5AG6P shares excretion patterns similar to those of its structural analog glucose, and use of an SGLT2 inhibitor in the murine models of the diseases resulted in amelioration of the neutropenia.

In this first-in-human trial of an SGLT2 inhibitor, Wortmann et al have shown that increased urinary excretion of 1,5AG6P results in improved neutrophil survival and function in a small cohort of people with GSD-Ib. Better neutrophil function also resulted in fewer infections, and the patients experienced marked improvement in their associated inflammatory bowel disease. Although the significance of the improvement should not be minimized, it is critical to note that neutropenia was not cured with the intervention. The studies were also performed in only 4 individuals who phenotypically were more severe than most GSD-Ib patients. SGLT2 inhibitors have not been approved for use in the pediatric population, and their use has been associated with hypoglycemia and genitourinary infections.10  Therefore, more studies are strongly recommended before this therapy is widely adopted, as was noted by the authors. This is particularly important in very young children who may be at higher risk for infections because of the chronic exposure to glycosuria in the setting of diaper use. Continuous glucose monitoring is also recommended to better assess the risk of hypoglycemia, and data should be captured as part of a larger clinical trial or international registry.

Inhibition of SGLT2 offers the potential of minimizing or discontinuing G-CSF therapy in the GSD-Ib population. This study also demonstrates the importance of understanding the pathophysiology of diseases instead of simply treating the phenotype. In light of the toxicity associated with using G-CSF treatment in the GSD-Ib population, this study is the most significant advancement in this field in decades, and the importance should not be underestimated because of the small study population.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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