Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

Grünert, Sarah C.; Derks, Terry G J; Adrian, Katarina; Al‐Thihli, Khalid; Ballhausen, Diana; Bidiuk, Joanna; Bordugo, Andrea; Boyer, Monica; Bratkovic, Drago; Brunner‐Krainz, Michaela; Burlina, Alberto; Chakrapani, Anupam; Corpeleijn, Willemijn E.; Cozens, Alison; Dawson, Charlotte; Dhamko, Helena; Milosevic, Maja Djordjevic; Eiroa, Hernán; Finezilber, Yael; Souza, Carolina Fischinger Moura de; García-Jiménez, M.C.; Gasperini, Serena; Haas, Dorothea; Häberle, Johannes; Halligan, Rebecca; Fung, Law Hiu; Hörbe-Blindt, Alexandra; Horka, Laura; Huemer, Martina; Uçar, Sema Kalkan; Kecman, Bozica; Kılavuz, Sebile; Kriván, Gergely; Lindner, Martin; Lüsebrink, Natalia; Makrilkakis, Konstantinos; Kwok, Anne Mei-Kwun; Maier, Esther M.; Maiorana, Arianna; McCandless, Shawn E.; Mitchell, John James; Mizumoto, Hiroshi; Mundy, Helen; Ochôa, Carlos; Pierce, Kathryn; Fraile, Pilar Quijada; Regier, Debra S.; Rossi, Alessandro; Santer, René; Schuman, Hester C; Sobieraj, Piotr; Spenger, Johannes; Spiegel, Ronen; Stępień, Karolina M.; Tal, Galit; Tanšek, Mojca Žerjav; Torkar, Ana Drole; Tchan, Michel; Thyagu, Santhosh; Vergano, Samantha A. Schrier; Vucko, Erika; Weinhold, Natalie; Zsidegh, Petra; Wortmann, Saskia B.

doi:10.1016/j.gim.2022.04.001

Cited by 41 publications

(57 citation statements)

References 13 publications

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“…The mechanism of the IBD-related disease improvement with empagliflozin is not well elucidated yet. Still, as others have already seen [ 9 , 20 ], better functioning leukocytes, in general, will likely positively impact the inflammatory pathways of IBD pathophysiology.…”

Section: Discussionmentioning

confidence: 83%

“…It is worth noting that our patient did not develop hypoglycemic episodes while on empagliflozin treatment, which is one of the most feared side effects of this treatment (given that GSD-I predisposes to hypoglycemias anyway). Hypoglycemia has been reported in both pediatric and adult GSD-Ib patients treated with empagliflozin [ 12 , 20 ], although it may be numerically a bit more frequent in children [ 20 ]. This issue needs further investigation in future studies since empagliflozin is not officially approved for treating diabetes mellitus in children.…”

Section: Discussionmentioning

confidence: 99%

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Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report

Makrilakis¹,

Barmpagianni²,

Veiga‐da‐Cunha³

2022

Cureus

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Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive inborn error of carbohydrate metabolism, where severe fasting hypoglycemia is associated (among other manifestations) with neutropenia and neutrophil dysfunction (predisposing to recurrent, potentially life-threatening infections) and inflammatory bowel disease (IBD). Granulocyte colony-stimulating factors (G-CSFs) are commonly used for its treatment. Although they have improved the prognosis of the disease, these medicines have also led to concerns about complications associated with their use (namely splenomegaly and hematopoietic malignancies), not to mention their increased cost. Recently, a novel new treatment for neutropenia associated with this disease was discovered. It was found that sodium-glucose cotransporter type 2 (SGLT-2) inhibitors, usually used for the treatment of diabetes mellitus, can ameliorate both neutropenia and IBDrelated symptoms and improve the quality of life in patients suffering from these diseases. They do it by inhibiting the renal reabsorption of 1,5-anhydroglucitol, a dietary analog of glucose, whose accumulation due to the specific enzyme deficiency leads to toxic effects on granulocytes. Herein we report the treatment of an adult patient suffering from GSD-Ib with empagliflozin, an SGLT-2 inhibitor.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report

Makrilakis¹,

Barmpagianni²,

Veiga‐da‐Cunha³

2022

Cureus

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“…5 Data on more than 110 patients have shown that empagliflozin has a positive impact on all neutropenia and neutrophil dysfunction related symptoms. 11 Therefore, empagliflozin is already replacing G-CSF as the first-line therapy for neutropenic GSD Ib patients. It is expected that early empagliflozin treatment will at least partially prevent infectious and inflammatory long-term complications in individuals with GSD Ib, further ameliorating the prognosis of this rare disease.…”

Section: Discussionmentioning

confidence: 99%

Two successful pregnancies and first use of empagliflozin during pregnancy in glycogen storage disease type Ib

et al. 2022

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Glycogen storage disease type Ib (GSD Ib) is caused by biallelic variants in SLC37A4. GSD Ib is characterized by hepatomegaly, recurrent hypoglycemia, neutropenia, and neutrophil dysfunction. Only seven pregnancies in four women with GSD Ib have been reported so far. We report on two further successful pregnancies in two patients with GSD Ib. One of these pregnancies was managed with empagliflozin, an SGLT2 inhibitor, repurposed for the treatment of neutropenia in GSD Ib. Both pregnancies were unremarkable and resulted in healthy offspring. Gestational care and pre-and perinatal management in GSD Ib are challenging and require close interdisciplinary metabolic and obstetric monitoring. In our patient, the use of empagliflozin during pregnancy was successful in the prevention of neutropenic symptoms and infections and enabled good wound healing after Cesarean section, while no adverse effects were observed.

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“…1,5-AG was quantified by liquid chromatography—mass spectrometry (LCMS) in plasma and urine, urinary glucose in neutralized perchloric acid extracts was measured spectrophotometrically and urinary clearance for 1,5-AG and glucose were all determined as previously described ( 9 , 15 ). Practically, 1,5-AG in plasma and in 24 h urine collections were extracted by adding respectively 4 µl of plasma or 2 µl of urine to 91 or 93 µl of a solution containing 81% methanol, 10% H2O and 9% chloroform and 5 µl of deuterated 30 µM 2-[D]-1,5AG (m/z = 164.0674), which was used as an internal standard to allow estimation of plasma or urinary 1,5-AG (m/z = 163.0612).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

Cited by 41 publications

References 13 publications

Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report

Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report

Two successful pregnancies and first use of empagliflozin during pregnancy in glycogen storage disease type Ib

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

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