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Dapagliflozin and Empagliflozin in Paediatric Indications: A Systematic Review

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Abstract

Introduction

In adults, sodium-glucose cotransporter type 2 inhibitors have revolutionised the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease.

Objective

We aimed to review information on compassionate use, clinical pharmacology, efficacy, and safety of dapagliflozin and empagliflozin in children.

Methods

We conducted a systematic review of published clinical trials, case reports, and observational studies in Medline, Excerpta Medica, and Web of Science databases from inception to September 2023. For the two randomised controlled trials on type 2 diabetes mellitus (T2DM), we implemented a meta-analysis on the primary outcome (mean difference in glycosylated haemoglobin [HbA1c] between intervention and placebo groups). Review Manager (RevMan), version 5.4.1, was used for this purpose.

Results

Thirty-five articles (nine case reports, ten case series, one prospective non-controlled trial, four controlled randomised trials, two surveys, six pharmacokinetic studies, and three pharmacovigilance studies) were selected, in which 415 children were exposed to either dapagliflozin or empagliflozin: 189 diabetic patients (mean age 14.7 ± 2.9 years), 32 children with glycogen storage disease type Ib (GSD Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, or severe congenital neutropenia type 4 (8.5 ± 5.1 years), 47 children with kidney disease or heart failure (11.2 ± 6.1 years), 84 patients in pharmacokinetic studies (15.1 ± 2.3 years), and 63 patients in toxicological series. The effect of dapagliflozin and empagliflozin in T2DM was demonstrated by HbA1c reduction in two randomised trials among a total of 177 adolescents, with a mean HbA1c difference of -0.82% (95% confidence interval -1.34 to -0.29) as compared to placebo (no heterogeneity, I2 = 0%). Dosage ranged between 5 and 20 mg (mean 11.4 ± 3.7) once daily for dapagliflozin and between 5 and 25 mg (mean 15.4 ± 7.4) once daily for empagliflozin. Among the paediatric cases of GSD Ib, empagliflozin 0.1–1.3 mg/kg/day improved neutropenia, infections, and gastrointestinal health. Dapagliflozin (mean dosage 6.9 ± 5.2 mg once daily) was well-tolerated in children with chronic kidney disease and heart failure. Side effects were generally mild, the most frequent being hypoglycaemia in children with GSD Ib (33% of patients) or T2DM (14% of patients) on concomitant hypoglycaemic drugs. Diabetic ketoacidosis is rare in children.

Conclusion

Early evidence suggests that dapagliflozin and empagliflozin are well tolerated in children. A clinical pharmacology rationale currently exists only for adolescents with diabetes mellitus.

Prospero Registration Number

CRD42023438162.

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Acknowledgements

Dr. Lava is the current recipient of research grants from Fonds de perfectionnement, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland; Fondation SICPA, Prilly, Switzerland; Fondazione Dr. Ettore Balli, Bellinzona, Switzerland; Fondazione per il bambino malato della Svizzera italiana, Bellinzona, Switzerland; and Frieda Locher-Hofmann Stiftung, Zurich, Switzerland.

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Authors and Affiliations

  1. Pediatric Cardiology Unit, Department of Pediatrics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland

    Sebastiano A. G. Lava & Nicole Sekarski

  2. Heart Failure and Transplantation, Department of Paediatric Cardiology, Great Ormond Street Hospital, London, UK

    Sebastiano A. G. Lava, Craig Laurence & Michael Burch

  3. Clinical Pharmacology and Therapeutics Group, University College London, London, UK

    Sebastiano A. G. Lava, Alessandro Di Deo & Oscar Della Pasqua

  4. Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland

    Sebastiano A. G. Lava

Authors
  1. Sebastiano A. G. Lava
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  2. Craig Laurence
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  3. Alessandro Di Deo
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  4. Nicole Sekarski
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  5. Michael Burch
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  6. Oscar Della Pasqua
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Corresponding author

Correspondence to Sebastiano A. G. Lava.

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Conflict of interest

The authors have no competing interests to declare that are relevant to the content of this article.

Funding

The authors did not receive support from any organisation for the submitted work.

Data availability

The data presented in this study are available from the corresponding author upon reasonable request.

Ethics approval, standard of reporting, registration

This being a systematic review, ethical approval was not required. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed. This systematic review was pre-registered on PROSPERO, with number CRD42023438162.

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Not applicable.

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Not applicable.

Code availability

Not applicable.

Author contributions

SL conceived and designed the study. SL and CL conducted the literature search and performed article selection, data extraction, and reporting quality assessment. SL performed data analysis, including statistical analysis and meta-analysis, and wrote the first draft of the manuscript. ADD contributed to table and figure preparation, and supervised statistical analysis. NS, MB, and ODP critically revised the draft of the manuscript. All authors approved the final version of the manuscript.

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Lava, S.A.G., Laurence, C., Di Deo, A. et al. Dapagliflozin and Empagliflozin in Paediatric Indications: A Systematic Review. Pediatr Drugs 26, 229–243 (2024). https://doi.org/10.1007/s40272-024-00623-z

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