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Randomized Controlled Trial
. 2025 Oct;68(10):2116-2125.
doi: 10.1007/s00125-025-06481-9. Epub 2025 Jul 9.

Dapagliflozin's impact on hormonal regulation and ketogenesis in type 1 diabetes: a randomised controlled crossover trial

Andreas Gübeli  1 , Nicole Steiner  1 , Andreas Limacher  2   3 , Déborah Mathis  4 , Andreas Melmer  1 , Markus Laimer  5
Affiliations
Randomized Controlled Trial

Dapagliflozin's impact on hormonal regulation and ketogenesis in type 1 diabetes: a randomised controlled crossover trial

Andreas Gübeli et al. Diabetologia. 2025 Oct.

Abstract

Aims/hypothesis: This study aimed to assess the impact of adding dapagliflozin to insulin therapy on key hormonal determinants of glucose regulation and ketogenesis. We hypothesise that dapagliflozin increases glucagon-like peptide 1 (GLP-1), glucagon and ketone body concentrations, based on the results of a pilot study.

Methods: The study was designed as a randomised, placebo-controlled, open-label, crossover intervention study with two periods (dapagliflozin and placebo intake), including patients of the Department of Diabetes, Endocrinology, Clinical Nutrition & Metabolism, Inselspital, Bern University Hospital, University of Bern. Individuals with type 1 diabetes (C-peptide concentrations <0.1 nmol/l) with a duration >5 years and a BMI of 20-29 kg/m2 were included. They received 10 mg of dapagliflozin or placebo daily for 7 days throughout two independent treatment periods, separated by a 14 day washout period. Allocation was done by a computed randomisation tool (REDCap), without blinding of the participants or the investigators. On day 7 of each treatment period, hyperinsulinaemic-euglycaemic clamps (HECs) and OGTT clamps (OGTTCs) were performed to assess changes in the secretion of GLP-1, glucagon, somatostatin and total ketone bodies. The objective was to evaluate the effects of adding the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin to insulin therapy on GLP-1 during OGTTC (primary endpoint), GLP-1 secretion during HEC, and glucagon, somatostatin and ketogenesis during OGTTC and HEC (secondary endpoints). The primary endpoint was concentrations of GLP-1 during OGTTC. Secondary endpoints included GLP-1 during HEC and glucagon, somatostatin and ketone body concentrations during OGTTC and HEC.

Results: A total of 13 individuals with type 1 diabetes were included and randomised. All of them received dapagliflozin and placebo, finished the sequences per protocol and were analysed per protocol. GLP-1 concentrations did not differ significantly between treatments in the OGTTC (median [IQR] dapagliflozin 192.8 [129.8-257.2] pmol/l vs placebo 176.3 [138.4-227.4] pmol/l; p=0.7) or HEC (median [IQR] dapagliflozin 208.6 [133.6-294.0] pmol/l vs placebo 203.1 [150.2-291.8] pmol/l; p=0.7). Glucagon concentrations did not significantly differ between treatments in the OGTTC (median [IQR] dapagliflozin 1.54 [0.84-3.68] ng/l vs placebo 1.54 [0.82-4.64] ng/l; p=0.8) or HEC (median [IQR] dapagliflozin 1.59 [0.87-3.54] ng/l vs placebo 1.63 [0.91-3.96] ng/l; p=0.3). Somatostatin concentrations remained comparable between treatments during the HEC (median [IQR] dapagliflozin 41.1 [26.8-73.8] pmol/l vs placebo 47.0 [23.0-77.6] pmol/l; p=0.2) and OGTTC (median [IQR] dapagliflozin 51.1 [31.1-77.0] pmol/l vs placebo 45.3 [30.0-70.5] pmol/l; p=0.2). Plasma ketone bodies were higher with dapagliflozin during the HEC (median [IQR] dapagliflozin 0.15 [0.04-0.47] mmol/l vs placebo 0.03 [0.01-0.12] mmol/l; p<0.001) and OGTTC (median [IQR] dapagliflozin 0.10 [0.03-0.22] mmol/l vs placebo 0.03 [0.01-0.12] mmol/l; p<0.001).

Conclusions/interpretation: Short-term dapagliflozin treatment in type 1 diabetes increases plasma ketone concentrations without affecting the secretion of GLP-1, glucagon or somatostatin. Higher ketone body concentrations highlight the elevated risk of diabetic ketoacidosis associated with the adjunct intake of dapagliflozin.

Trial registration: ClinicalTrials.gov NCT04035031.

Funding: Swiss National Science Foundation, project number 32003B_185019.

Keywords: Dapagliflozin; Diabetic ketoacidosis; GLP-1; Glucagon; Ketogenesis; Somatostatin; Type 1 diabetes.

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Conflict of interest statement

Acknowledgements: We express our deepest gratitude to all participants in the study for their time and effort. Data availability: Raw data are not publicly available to preserve participants’ privacy. They can be accessed in the form of a justified request via the directory of the Department of Diabetes, Endocrinology, Clinical Nutrition & Metabolism, Inselspital, Bern University Hospital, University of Bern, Switzerland ( https://udem.insel.ch/ ). Funding: Open access funding provided by University of Bern. This research was funded in whole or in part by the Swiss National Science Foundation (SNSF) (32003B_185019). The funding body played no role in the study design, data collection, data analysis and interpretation, writing of the report or decision to submit the article for publication. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: AG and NS were entrusted with participant recruitment, performed study interventions, completed electronic case report form (eCRF), interpreted data and wrote the manuscript. AL was the study statistician and contributed to the composition of the manuscript. DM provided laboratory analysis and contributed to the composition of the manuscript. AM and ML developed the study design, were entrusted with the supervision of the project, performed experimental visits, interpreted data, completed eCRFs and wrote the manuscript. All authors were included in reviewing the content and in approving the final version to be published. ML is the guarantor of this trial, who undertook the responsibility for the conduct of the study and the data acquired and controlled the final decision to publish.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
CONSORT flow diagram of study recruitment and randomisation. Following recruitment, 13 individuals with type 1 diabetes were randomised to receive either 10 mg of dapagliflozin or placebo as an adjunct to insulin therapy for an initial 7 day period, followed by the alternative treatment for another 7 days
See this image and copyright information in PMC

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