Efficacy and safety of empagliflozin for treating neutropenia and neutrophil dysfunction in paediatric patients with glycogen storage disease type Ib: A systematic review and meta-analysis.

Abstract

Aims: Glycogen storage disease type Ib (GSD-Ib) is a rare genetic disorder causing neutropenia and neutrophil dysfunction in children. G-CSF has been the primary treatment, but emerging data support the potential of empagliflozin, an SGLT2 inhibitor, as a promising investigational option. This systematic review and meta-analysis assess its feasibility, efficacy and safety in paediatric GSD-Ib patients.

Methods: Following the 2020 PRISMA guidelines, a systematic search was conducted in PubMed, Embase and Web of Science (2015-2025). The last search was performed on 16 May 2025. The inclusion criteria were patients <18 years with GSD-Ib and neutropenia treated with empagliflozin. Eligible study types included randomized controlled trials (RCTs), observational studies and case series. Non-English, pre-2015 and non-primary research were excluded. Bias was assessed using ROBINS-I V2, and certainty via GRADE. Meta-analyses used fixed or random effects depending on heterogeneity. The primary efficacy outcome was defined as resolution of neutropenia, and safety outcome included overall adverse events.

Results: Six non-randomized studies (n = 177; 52% male; mean age 6.7) met the inclusion criteria. Two studies showed low risk of bias; three were critically biased. All reported improved neutrophil counts (ANC > 1.5) after empagliflozin treatment. Four studies had >80% resolution of neutropenia; all showed G-CSF reduction or discontinuation. Adverse events were minimal; lactic acidosis was the most serious.

Conclusions: Empagliflozin shows promise in treating neutropenia in paediatric GSD-Ib patients, with encouraging efficacy and safety. However, findings are limited by study design and heterogeneity. The majority of included studies were non-randomized and rated as having a serious or critical risk of bias according to the ROBINS-I tool. This substantially limits the reliability and interpretability of pooled outcomes. These results should therefore be viewed as preliminary and interpreted with caution. Further randomized trials, especially those measuring 1,5-AG, are needed to confirm empagliflozin's role as promising therapy in G-CSF.