Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors

Veiga‐da‐Cunha, Maria; Wortmann, Saskia B.; Grünert, Sarah C.; Schaftingen, Emile Van

doi:10.3390/diagnostics13101803

Cited by 17 publications

(6 citation statements)

References 120 publications

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“…Regarding the number of white blood cells, two clinical trials show the therapeutic role of empagliflozin in neutropenia. 111 , 112 This issue has also been confirmed by Veiga-da-Cunha et al 113 In relation to canagliflozin, another clinical trial showed the opposite effect and that treatment with canagliflozin causes a decrease in white blood cells. 114 In order to determine the role of this drug in relation to the number of white blood cells, large clinical trials are needed.…”

Section: Blood Components and Electrolytesmentioning

confidence: 62%

Drug Safety Evaluation of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Comorbid Patients by Review of Systemic Extraglycemic Effects

Omari,

Naseri,

Hassan

2024

DMSO

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Purpose The aim of this study is to evaluate the safety of this drug in diabetic patients with comorbidities of all systems. Method In this review, the beneficial effects of this drug and its mechanism on the disorders of every system of humans in relation to diabetes have been studied, and finally, its adverse effects have also been discussed. The search for relevant information is carried out in the PubMed and Google Scholar databases by using the following terms: diabetes mellitus type 2, SGLT, SGLT2 inhibitors, (SGLT2 inhibitors) AND (Pleiotropic effects). All English-published articles from 2016 to 2023 have been used in this study. It should be noted that a small number of articles published before 2016 have been used in the introduction and general informations. Results Its beneficial effects on improving cardiovascular disease risk factors and reducing adverse events caused by cardiovascular and renal diseases have proven in most large clinical studies that these effects are almost certain. It also has beneficial effects on other human systems such as the respiratory system, the gastrointestinal system, the circulatory system, and the nervous system; more of them are at the level of clinical and pre-clinical trials but have not been proven in large clinical trials or meta-analyses. Conclusion With the exception of a few adverse effects, this drug is considered a good choice and safe for all diabetic patients with comorbidities of all systems.

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Section: Blood Components and Electrolytesmentioning

confidence: 62%

Drug Safety Evaluation of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Comorbid Patients by Review of Systemic Extraglycemic Effects

Omari,

Naseri,

Hassan

2024

DMSO

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“… 19 Recent studies have indicated that empagliflozin, a sodium glucose co-transporter 2 inhibitor, represents a safe and promising alternative for treating neutropenia in individuals with GSD1b, IBD, and neutropenia. 20 In this study, empagliflozin was prescribed to Patient 2 at the age of 6 years, leading to a gradual discontinuation of G-CSF. Subsequently, the patient experienced an improvement in gastrointestinal symptoms, with a normal ANC observed during the last follow-up and no reported adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review

Wang,

Zhao,

Jia

et al. 2023

J Int Med Res

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Glycogen storage disease type 1b (GSD1b) is a rare genetic disorder, resulting from mutations in the SLC37A4 gene located on chromosome 11q23.3. Although the SLC37A4 gene has been identified as the pathogenic gene for GSD1b, the complete variant spectrum of this gene remains to be fully elucidated. In this study, we present three patients diagnosed with GSD1b through genetic testing. We detected five variants of the SLC37A4 gene in these three patients, with three of these mutations (p. L382Pfs*15, p. G117fs*28, and p. T312Sfs*13) being novel variants not previously reported in the literature. We also present a literature review and general overview of the currently reported SLC37A4 gene variants. Our study expands the mutation spectrum of SLC37A4, which may help enable genetic testing to facilitate prompt diagnosis, appropriate intervention, and genetic counseling for affected families.

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“…Importantly, empagliflozin, an SGLT2 inhibitor frequently used to treat type 2 diabetes, has successfully resolved neutrophil defects in patients with G6PC3 deficiency by lowering the 1,5-AG blood concentrations 30,33,34 . Along with the use of this highly effective, safe, and easy-to-take oral alternative to granulocyte-colonystimulating factor (G-CSF) injections, early disease diagnosis may improve outcomes of G6PC3 deficient patients 35,36 .…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

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Background: G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Objective: The G6PC3 c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it. Methods: Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date. Results: Based on the length of haplotypes shared amongst ten carriers of the G6PC3 c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency. Conclusion: The G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

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Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors

Cited by 17 publications

References 120 publications

Drug Safety Evaluation of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Comorbid Patients by Review of Systemic Extraglycemic Effects

Drug Safety Evaluation of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Comorbid Patients by Review of Systemic Extraglycemic Effects

Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

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