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Adjunct-to-insulin therapy using SGLT2 inhibitors in youth with type 1 diabetes: a randomized controlled trial

Nature Medicine volume 31, pages 2317–2324 (2025)Cite this article

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Abstract

Sodium glucose co-transporter 2 inhibitors (SGLT2i) reduce the risk of chronic kidney disease (CKD) progression in type 2 diabetes, but their effects in type 1 diabetes (T1D) are not completely understood. ATTEMPT (Adolescent Type 1 Diabetes Treatment with SGLT2i for Hyperglycemia and Hyperfiltration Trial) is a 22-week, double-blind, randomized, placebo-controlled trial to assess dapagliflozin, as an adjunct to insulin, in youth with T1D. Ninety-eight participants (12–21 years of age, 53% female) were randomly assigned to dapagliflozin 5 mg or placebo alongside ketone monitoring and diabetic ketoacidosis (DKA) risk mitigation education. The primary outcome was change in measured glomerular filtration rate (mGFR) using iohexol clearance. Dapagliflozin reduced mGFR by 8.8 ml min−1 1.73 m−2 when compared to placebo (95% confidence interval (CI): −12.7 to −4.8; P < 0.0001), and participants with higher baseline mGFR experienced greater attenuation with dapagliflozin (r: −0.58; P < 0.0001). HbA1c decreased by 0.47% (95% CI: −0.66 to −0.28), and time in range (glucose levels 70–180 mg dl−1, 4–10 mmol L−1) increased by 9.0% (95% CI: 3.8–14.3). Body weight decreased by 2.8 kg (95% CI: −3.7 to −2.0) with dapagliflozin. No differences were observed with respect to total daily insulin dose (U kg−1). Adverse events were similar between groups, with one mild DKA case in the dapagliflozin group. In youth with T1D, dapagliflozin as an adjunct-to-insulin treatment reduced mGFR, improved glycemic control and was safe when combined with ketone testing and risk mitigation strategies. ClinicalTrials.gov: NCT04333823.

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Fig. 1: CONSORT diagram of study participant flow, randomization, drug allocation, follow-up and analysis in ATTEMPT.
Fig. 2: Measured and estimated GFR from ATTEMPT.
Fig. 3: Glycemic outcomes from ATTEMPT.

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Data availability

Due to confidentiality reasons (that is, limitations of informed consent and ethics board approval), the datasets used in this study are not publicly available. Qualified researchers, however, can submit data requests for academic purposes only within 12 months after the publication date, and de-identified data and a data dictionary will be made accessible for up to 12 months. Proposals and statistical analysis plans should be directed to the corresponding author and principal investigator (F.H.M.). Upon proposal acceptance by the corresponding author and the Hospital for Sick Children Research Ethics Board, qualified researchers will be granted access to the data within a reasonable timeframe of approximately 3 months after signing a data-sharing agreement. Corresponding author contact: farid.mahmud@sickkids.ca. Source data are provided with this paper.

Code availability

The code used for data analysis is also available upon reasonable request to the corresponding author (F.H.M.) at farid.mahmud@sickkids.ca.

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Acknowledgements

We thank the study participants and the study coordinators and research nurses at each of the clinical trial sites for the overall coordination and conduct of the trial. Additionally, we thank Bay Area Research Logistics (BARL) for their services of receiving, packaging, storing and distributing study medication to the clinical trial sites.

This study was funded by Canadian Institutes for Health Research (CIHR, grant number 157203, to F.H.M.) and Breakthrough T1D (formerly Juvenile Diabetes Research Foundation Canada, grant number 3-SRA-2018-652-Q-R, to F.H.M.) as part of the Strategies for Patient Oriented Research (SPOR) Innovative Clinical Trials (iCT). Additional support was provided by the Children’s Hospital Colorado (CHCO) and University of Colorado Anschutz Medical Campus (to P.B.). The funders had no role in planning, conduct, analysis or decision to publish. AstraZeneca donated study drug and placebo. Dexcom partially donated CGM supplies. This was presented, in part, at the American Diabetes Association 84th Scientific Sessions Symposium (CT-SY47-1) in Orlando, Florida, on 24 June 2024.

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Authors and Affiliations

  1. Hospital for Sick Children, Hospital for Sick Children Research Institute and University of Toronto, Toronto, Ontario, Canada

    Farid H. Mahmud, Antoine Clarke, Samantha J. Anthony, Jacqueline Curtis, Yesmino T. Elia, Lynne McArthur, Luc Mertens, Maria Maione, Michelle Furman & Lennox Huang

  2. University of Washington Medicine Diabetes Institute, Seattle, WA, USA

    Petter Bjornstad & Kalie L. Tommerdahl

  3. Seattle Children’s Research Institute, Seattle Children’s Hospital, Seattle, WA, USA

    Petter Bjornstad & Kalie L. Tommerdahl

  4. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Petter Bjornstad & Kalie L. Tommerdahl

  5. Children’s Hospital, London Health Sciences Centre, London, Ontario, Canada

    Cheril Clarson & Funmbi Babalola

  6. Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada

    Rahim Moineddin

  7. Markham Stouffville Hospital and University of Toronto, Toronto, Ontario, Canada

    Susan Kirsch & Nicole Coles

  8. Women’s and Children’s Hospital and University of Adelaide, Adelaide, South Australia, Australia

    Jennifer Harrington

  9. York University, Toronto, Ontario, Canada

    Michael C. Riddell

  10. Department of Radiology, Endeavor Health, Evanston, IL, USA

    Pottumarthi Prasad

  11. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Hiddo J. L. Heerspink

  12. Department of Medicine, University Health Network, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    David Z. I. Cherney

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Contributions

F.H.M. and D.Z.I.C. conceptualized and designed the study, with important contributions made by P.B. and C.C. F.H.M. wrote the paper, and all coauthors (P.B., C.C., A.C., S.J.A., J.C., Y.T.E., L.M., R.M., S.K., N.C., M.M., M.F., F.B., K.L.T., J.H., M.C.R., P.P., L.H., H.J.L.H. and D.Z.I.C.) equally contributed, reviewed and edited the paper. R.M., an external and independent biostatistician, analyzed the data for this paper. The decision to submit the paper for publication was made jointly by all authors.

Corresponding author

Correspondence to Farid H. Mahmud.

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Competing interests

F.H.M. receives research support from the Canadian Institutes of Health Research (CIHR) and Breakthrough T1D (formerly Juvenile Diabetes Research Foundation (JDRF) Canada). P.B. receives salary and research support from the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute), Breakthrough T1D (formerly JDRF) and the American Heart Association. P.B. also receives research support from the University of Washington Medicine Diabetes Institute and Seattle Children’s Research Institute and holds the Raisbeck Endowed Chair of Diabetes Research at the University of Washington. P.B. reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk and Horizon Pharma. P.B. also serves or has served on advisory boards and/or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and XORTX. P.B. reports grant funding from AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer Ingelheim and Horizon Pharma. D.Z.I.C. is the Gabor Zellerman Chair in Nephrology Research at the University of Toronto and was supported by a Department of Medicine, University of Toronto, Merit Award. He receives support from the CIHR, Diabetes Canada and the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research. D.Z.I.C. is also the recipient of a 5-year CIHR–Kidney Foundation of Canada Team Grant award with additional support from Breakthrough T1D. D.Z.I.C. has received honoraria from Boehringer Ingelheim–Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Amgen, Bayer, Prometic Life Sciences, Bristol Myers Squibb, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GlaxoSmithKline, Biobridge, Vantage, Altimmune and Novo Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Lexicon, Novo Nordisk and Bayer. H.J.L.H. reports funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen and Novo Nordisk (payments to his institution, the University of Groningen); consulting fees from AstraZeneca, Alexion, Alnylam, Bayer, Boehringer Ingelheim, BioCity Biopharma, Dimerix, Eli Lilly, Gilead, Idorsia, Janssen, Novartis, Novo Nordisk, Roche and Travere Therapeutics (payments to his institution, the University of Groningen); honoraria for lectures from AstraZeneca, Bayer and Novo Nordisk; and support for traveling to and attending the American Diabetes Association meeting and the American Society of Nephrology meeting from AstraZeneca and Eli Lilly (payment to his institution, the University of Groningen). K.L.T. receives salary and research support from the National Institutes of Health (National Heart, Lung, and Blood Institute) and the American Diabetes Association. K.L.T. also receives research support from the Seattle Children’s Research Institute. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Adolescent Type 1 diabetes Treatment with SGLT2i for hyperglycEMia & hyPerfilTration Trial (ATTEMPT) Schema.

ATTEMPT is a multi-center, double blind, randomized, placebo-controlled trial designed to evaluate the effect of treatment with Dapagliflozin when compared to placebo, in combination with adjustable insulin, on measured GFR and HbA1c in adolescents with T1D over a 22-week evaluation period (16-week treatment period) to test the hypotheses that treatment with dapagliflozin, in combination with adjustable insulin, will reduce mean measured GFR and HbA1c when compared with placebo.

Supplementary information

Supplementary Information (download PDF )

Supplementary Figs. 1–3, Tables 1–4, study protocol and statistical analysis plan.

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Mahmud, F.H., Bjornstad, P., Clarson, C. et al. Adjunct-to-insulin therapy using SGLT2 inhibitors in youth with type 1 diabetes: a randomized controlled trial. Nat Med 31, 2317–2324 (2025). https://doi.org/10.1038/s41591-025-03723-6

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