Dataset Information

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience.

ABSTRACT:

Introduction

Recently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib).

Methods

We present the clinical and laboratory data of 2 adult brothers with GSD Ib treated with empagliflozin for 12 months.

Results

There was no severe infection during administration of empagliflozin. The improvement of clinical symptoms of inflammatory bowel disease and arthritis along with reduction in serum CRP levels and urinary albumin excretion was noted. Neutrophil count increased, allowing for reduction or temporary withdrawal of G-CSF treatment.

Conclusions

Empagliflozin may be a new safe treatment in GSD Ib patients with an advanced stage of the disease.

SUBMITTER: Bidiuk J

PROVIDER: S-EPMC9266796 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience.

Bidiuk Joanna J Gaciong Zbigniew A ZA Sobieraj Piotr P

Archives of medical science : AMS 20220623 4

<h4>Introduction</h4>Recently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib).<h4>Methods</h4>We present the clinical and laboratory data of 2 adult brothers with GSD Ib treated with empagliflozin for 12 months.<h4>Results</h4>There was no severe infection during administration of empagliflozin. The improvement of clinical symptoms of inflammatory bowel disease and arthritis along with reduction in serum CRP levels and urinary ...[more]

PMID: 35982912

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Project description:ImportanceGlycogen storage disease type Ib (GSDIb) is a rare metabolic disorder characterized by impaired glucose-6-phosphate transporter function with limited descriptions.ObjectiveTo describe the genetic and clinical features of Chinese patients with GSDIb.Design, setting, and participantsThis retrospective cohort study retrieved the medical records of 113 Chinese patients with GSDIb treated at a single institution in Shanghai from November 1, 2000, to June 30, 2024.Main outcomes and measuresBiochemical parameters and clinical features (infections, inflammatory bowel disease [IBD], kidney and cardiovascular issues, growth and puberty) at baseline and the last follow-up, all-cause mortality, and mental and social development were assessed.ResultsA total of 113 patients (96 children [85%]; 67 males [59%]) had GSDIb genetically diagnosed at a median age of 1.4 (range, 0.0-35.5) years. Thirty-eight novel SLC37A4 variants were identified. Hypoglycemia and metabolic derangements were the primary concerns in patients aged 2 years or younger (45%). Short stature (75%), infections (75%), and recurrent epistaxis (31%) became more prevalent in patients aged 2.1 to 5.0 years. The frequency of respiratory tract infection decreased after a median age of 7.0 (IQR, 3.5-10.5) years. Forty-four patients (46%) developed IBD at a median age of 6.0 (IQR, 3.0-12.0) years, 14% of whom developed IBD-associated arthritis at a median age of 10.5 (IQR, 5.8-19.6) years. The mean (SD) difference between the z scores of actual height and target height (Δ height z scores) at the final visit (-2.11 [1.76]) did not significantly increase even after uncooked cornstarch treatment. The mean (SD) Δ height z scores of the patients with IBD (-2.99 [1.70]) were significantly lower than those without IBD (mean [SD], -1.36 [1.44]) (P < .001). Ten patients (9%) died due to complications of GSDIb, including metabolic derangements, sepsis, and/or severe pneumonia (n = 8), IBD (n = 1), and pulmonary hypertension (n = 1).Conclusions and relevanceIn this cohort study, the genetic and clinical spectra of GSDIb were broadened, suggesting associations between GSDIb and bowel, growth, and survival outcomes. To date, no previous study reported IBD-associated arthritis.

Project description: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.

Project description:Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy.

Dataset Information

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience.

Introduction

Methods

Results

Conclusions

Publications

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience.

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