Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes

NCT ID: NCT04035031

Last Updated: 2023-03-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-09
• Study Completion Date: 2020-11-12

Brief Summary

Inhibitors of sodium-dependent glucose-transporter 2 (including dapagliflozin) represent intensively investigated drugs in the field of diabetes. SGLT-2 inhibition limits glucose reabsorption in renal tubular cells, hereby increasing the amount of glucose excreted via urine in the hyperglycemic state. Its mechanisms of action are independent of insulin, the indispensable standard of care in Type 1 Diabetes (T1D). Several international diabetes experts highlighted the need for adjunct therapies in T1D.

Subcutaneous application of insulin is non-physiological. Most significant, subcutaneous insulin substitution does not address the bi-hormonal character of T1D. The loss of pancreatic beta cells and subsequent endogenous insulin production uncouples alpha cell derived glucagon secretion from its paracrine suppressor. Consequently, excess glucagon concentrations occur in the fasting and the postprandial state, which promotes hyperglycemia, requires higher doses of subcutaneous insulin, and promotes glycaemic variability.

Recent studies on SGLT-2 inhibition in T1D showed better glycemic control compared to placebo, whereas a higher risk for the development of diabetic ketoacidosis was observed. Knowledge about the underlying mechanisms is scarce. Studies showed that SGLT-inhibition increased Glucagon-like-peptide 1 (GLP-1) in T1D, an incretin hormone capable of suppressing glucagon. On the other side, total concentrations of ketone bodies were higher following SGLT-2 inhibition, irrespective of ongoing subcutaneous or intravenous insulin substitution. The present study aims to investigate the effect of SGLT-2 inhibitor dapagliflozin on hormonal regulators of glucose homeostasis and ketogenesis in T1D. The primary endpoint is the difference of GLP-1 during oral glucose tolerance test clamps (OGGTc). Secondary endpoints comprise total ketone body concentrations, free fatty acids, glucagon, and somatostatin during OGTTc and hyperinsulinemic, euglycemic clamps (HEC) following dapagliflozin and placebo. The study recruits male and female patients with T1DM in a randomized, open label, cross-over intervention study.

Conditions

Diabetes Mellitus, Type 1

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Forxiga first, placebo second

Forxiga followed by placebo

Group Type: EXPERIMENTAL

Forxiga 10mg

Intervention Type: DRUG

Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)

Placebo

Intervention Type: DRUG

Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)

Placebo first, Forxiga second

Placebo followed by forxiga

Group Type: EXPERIMENTAL

Forxiga 10mg

Intervention Type: DRUG

Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)

Placebo

Intervention Type: DRUG

Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)

Interventions

Forxiga 10mg

Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)

Intervention Type: DRUG

Placebo

Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)

Intervention Type: DRUG

Other Intervention Names

Dapagliflozin

Eligibility Criteria

Inclusion Criteria

• Informed Consent as documented by signature
• Duration of T1DM > 5 years
• Male or female sex
• Body mass index (BMI) between 20 and 29 kg/m2
• Adherence to safe contraception during the study and for 2 weeks after completion of the study protocol. Safe contraception comprises double barrier methods (hormonal contraception [like: oral contraceptive pills or intrauterine contraceptive devices] together with a mechanical barrier [like: condom, diaphragm]).

Exclusion Criteria

• Contraindications to SGLT-2 inhibitors
• Contraindications to lactose
• Diagnosis of renal and/or hepatic dysfunction
• History of malignancy of any kind
• Intake of drugs influencing glucose homeostasis during the last three months (steroids, metformin, sulfonylureas, thiazolidinedione)
• Known or suspected non-compliance, drug or alcohol abuse.
• Inadequate vein status on both forearms
• Active smoker (defined as ≥1 or more cigarettes or nicotine-containing equivalents per day)
• Known pregnancy, positive plasma beta-HCG test prior to study inclusion or intention to become pregnant during the study period.
• Women who are breast feeding
• Lack of safe contraception
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Insel Gruppe AG, University Hospital Bern

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Markus Laimer, Prof. MD

Role: PRINCIPAL_INVESTIGATOR

Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism, University Clinics Bern, Inselspital, Bern, Switzerland

Locations

Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Bern, , Switzerland

Countries

Switzerland

References

Gubeli A, Steiner N, Limacher A, Mathis D, Melmer A, Laimer M. Dapagliflozin's impact on hormonal regulation and ketogenesis in type 1 diabetes: a randomised controlled crossover trial. Diabetologia. 2025 Oct;68(10):2116-2125. doi: 10.1007/s00125-025-06481-9. Epub 2025 Jul 9.

Reference Type: DERIVED

PMID: 40629004 (View on PubMed)

Other Identifiers

CUI_002_01

Identifier Type: -

Identifier Source: org_study_id