Favorable outcome of empagliflozin treatment in two pediatric glycogen storage disease type 1b patients

Abstract

BackgroundGlycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in SLC37A4 gene. Affected patients present with episodes of fasting hypoglycemia and lactic acidosis, hepatomegaly, growth retardation, hyperlipidemia and renal impairment. In addition, patients present neutropenia, neutrophil dysfunction and oral, and skin infections as well as a significant predisposition to develop inflammatory bowel disease (IBD). Low neutrophil counts and function is related to the toxic accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Recently, several reports have shown that off-label treatment with empagliflozin (EMPA), an inhibitor of the renal glucose transporter SGLT2, decreased blood 1,5-anhydroglucitol (1,5-AG), and neutrophil 1,5-AG6P, thus resulting in a new therapeutic option for neutropenia and neutrophil dysfunction in patients.MethodsOff-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment.ResultsA 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18–24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter.ConclusionsRepurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.

Patient‐reported outcomes on empagliflozin treatment in glycogen storage disease type Ib: An international questionnaire study

“…SGLT2 inhibitors have emerged as a new and very promising treatment option for the neutropenia‐/neutrophil dysfunction‐associated signs and symptoms in patients with GSD Ib. In contrast to G‐CSF, SGLT2 inhibitors do not only increase the neutrophil number but also improve neutrophil function 3,5,6 . Experiences on more than 120 GSD Ib patients have been published within the last 2 years 3–14 .…”

“…In contrast to G-CSF, SGLT2 inhibitors do not only increase the neutrophil number but also improve neutrophil function. 3,5,6 Experiences on more than 120 GSD Ib patients have been published within the last 2 years. [3][4][5][6][7][8][9][10][11][12][13][14] This study corroborates the clear improvement of neutropenia, mucosal lesions, skin infections, inflammatory bowel disease and anemia as it was reported by more than 80% of patients.…”

“…3,5,6 Experiences on more than 120 GSD Ib patients have been published within the last 2 years. [3][4][5][6][7][8][9][10][11][12][13][14] This study corroborates the clear improvement of neutropenia, mucosal lesions, skin infections, inflammatory bowel disease and anemia as it was reported by more than 80% of patients. Of note, many of the patients will have been included in our previous publication.…”

Glycogen storage disease type I: Genetic etiology, clinical manifestations, and conventional and gene therapies

“…A report of the clinical data from 112 pediatric and adult individuals with GSDIb clearly showed that empagliflozin markedly improves neutrophil counts and has a positive effect for neutrophil dysfunction‐related symptoms 65,66 . Empagliflozin has also been used to treat GSDIb patients, resulting in decreased serum 1,5‐AG and neutrophil 1,5‐AG6P levels 43,44,67,68 …”

“…65,66 Empagliflozin has also been used to treat GSDIb patients, resulting in decreased serum 1,5-AG and neutrophil 1,5-AG6P levels. 43,44,67,68 In addition, there are several novel pharmacological agents developed for the treatment of GSDIa patients. VK2809, a thyroid hormone receptor agonist selective for liver tissues, was used to treat GSDIa mice.…”