Empagliflozin in GSD-Ib: Long-term safety and sustained recovery of neutrophil function including NET formation

Abstract

Glycogen storage disease type Ib (GSD-Ib) engenders neutropenia and severe neutrophil dysfunction, leading to recurrent infections and inflammatory complications. Recent studies have identified intracellular accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) as a key mechanism underlying neutrophil impairment and have suggested therapeutic benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower plasma levels of its precursor 1,5-AG. In this study, we performed a four-year longitudinal evaluation of empagliflozin therapy in a genetically confirmed GSD-Ib infant, contributing to the growing body of long-term data on empagliflozin treatment in GSD-Ib. Routine laboratory parameters and key neutrophil effector functions were assessed before and during treatment, as well as in two additional GSD-Ib patients with and without therapy. Empagliflozin therapy resulted in complete restoration of neutrophil function, including reactive oxygen species (ROS) production and bactericidal activity. Notably, neutrophil extracellular trap (NET) formation and neutrophil survival recovered to levels comparable to healthy donors. These functional improvements occurred in conjunction with reduced plasma 1,5-AG levels, supporting the concept that GSD-Ib neutrophils are sensitive to physiological 1,5-AG concentrations. Functional recovery and normalization of neutrophil survival observed in vitro , was paralleled by improvement of absolute neutrophil counts to low-normal levels in vivo . Clinically, treatment was associated with a substantial reduction of severe infections. Collectively, these findings further support that empagliflozin corrects neutrophil dysfunction in GSD-Ib and demonstrate its potential to improve long-term clinical outcome across the lifespan, from infancy through adulthood.