ESPE Yearbook of Paediatric Endocrinology

Nat Med. 2025. Jun 6. Online ahead of print. PMID: 40481206 doi: 10.1038/s41591-025-03723-6.

Brief summary: In this 22-week, double-blind, randomized, placebo-controlled study, dapagliflozin (5mg) used as an adjunct therapy to insulin was compared to placebo in 98 youth (age 12-21 years) with type 1 diabetes (T1D). Dapagliflozin reduced measured GFR (mGFR) and HbA1c, and improved time in range (TIR) and BMI.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), such as dapagliflozin and empagliflozin, are drugs which increase urinary glucose excretion by blocking glucose reabsorption in the renal proximal tubule and improve glucose levels in an insulin-independent manner (1). Extensive evidence suggests cardio-renal benefits in adults with type 2 diabetes (2). In adults with T1D, the use of SGLT2i as an adjunct therapy to insulin was associated with significant reductions in HbA1c and body weight and improved renal function (3).

The ATTEMPT (Adolescent Type 1 Diabetes Treatment with SGLT2i for Hyperglycemia and Hyperfiltration Trial) trial tested the efficacy and safety of dapagliflozin in youth with T1D from North America. Compared to placebo, treatment with dapagliflozin decreased mGFR by 8.8 ml min^-1 1.73 m^-2, HbA1c by 0.47%, and increased TIR (glucose levels 4-10 mmol/l) by 9.0%. Dapagliflozin also resulted in a 1.2 kg/m² BMI reduction. Notably, when combined with ketone monitoring and a DKA risk mitigation strategy, there were no differences in the rates of ketosis, DKA, genitourinary tract infections, or hypoglycemia between the dapagliflozin and placebo groups.

Improvement in renal function, along with reductions in BMI and improved glycemia, may lead to positive outcomes, particularly in overweight and obese youth, during the challenging adolescent and young adult period characterized by persistently high HbA1c and suboptimal TIR (4).

Limitations of this study include the short treatment period (16-weeks), a relatively low mean HbA1c compared to that reported in North America registries, and the inclusion of participants primarily with normoalbuminuria and a high GFR. Further studies in larger, more diverse cohorts with longer follow up are needed to confirm the reported favorable renal and metabolic effects and the acceptable safety profile of dapagliflozin.

References: 1. van Bommel EJM, Muskiet MHA, Tonneijck L, et al. SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome. Clin J Am Soc Nephrol. 2017 Apr 3;12(4):700-710.2. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019 Jan 5;393(10166):31-39.3. Palanca A, van Nes F, Pardo F, et al. Real-world Evidence of Efficacy and Safety of SGLT2 Inhibitors as Adjunctive Therapy in Adults With Type 1 Diabetes: A European Two-Center Experience. Diabetes Care. 2022 Mar 1;45(3):650-658.4. Ebekozien O, Mungmode A, Sanchez J, et al. Longitudinal Trends in Glycemic Outcomes and Technology Use for Over 48,000 People with Type 1 Diabetes (2016-2022) from the T1D Exchange Quality Improvement Collaborative. Diabetes Technol Ther. 2023;25(11):765-773.