Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes

NCT04035031 | Completed Phase 3

• 1 other identifier: CUI_002_01
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (3)

• Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp

  Glucagon-like peptide I will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.

  From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

• Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp

  Glucagon-like peptide I will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.

  During visit 3 (day 7): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

• Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp

  Glucagon-like peptide I will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.

  During visit 5 (day 31): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

Secondary Outcomes (9)

• Area under the curve for glucagon-like peptide I in euglycemic, hyperinsulinemic clamp

  From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

• Area under the curve for ketone body concentrations in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo

  From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

• Area under the curve for ketone body concentrations in oral glucose tolerance test clamp following dapagliflozin compared with placebo

  From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

• Area under the curve for free fatty acids in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo

  From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

• Area under the curve for free fatty acids in oral glucose tolerance test clamp following dapagliflozin compared with placebo

  From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

Study Arms (2)

Forxiga first, placebo second

EXPERIMENTAL

Forxiga followed by placebo

Drug: Forxiga 10mg; Drug: Placebo

Placebo first, Forxiga second

EXPERIMENTAL

Placebo followed by forxiga

Drug: Forxiga 10mg; Drug: Placebo

Interventions

Forxiga 10mg DRUG

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

Also known as: Dapagliflozin

Forxiga first, placebo second; Placebo first, Forxiga second

Placebo DRUG

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

Forxiga first, placebo second; Placebo first, Forxiga second

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \[like: condom, diaphragm\]).

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Study Sites (1)

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

Bern, 3010, Switzerland

Location

Related Publications (1)

• 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.

  PMID: 40629004 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Markus Laimer, Prof. MD

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised, placebo-controlled, open-label, cross over intervention study

Study Record Dates

• First Submitted: July 24, 2019
• First Posted: July 29, 2019
• Study Start: January 9, 2020
• Primary Completion: November 12, 2020
• Study Completion: November 12, 2020
• Last Updated: March 14, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR

Locations

CH (1)