Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes
Primary Purpose
Diabetes Mellitus, Type 1
Status
Completed
Phase
Phase 3
Locations
Switzerland
Study Type
Interventional
Intervention
Forxiga 10mg
Placebo
Sponsored by
About this trial
This is an interventional other trial for Diabetes Mellitus, Type 1
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
Sites / Locations
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Forxiga first, placebo second
Placebo first, Forxiga second
Arm Description
Forxiga followed by placebo
Placebo followed by forxiga
Outcomes
Primary Outcome Measures
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.
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.
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.
Secondary Outcome Measures
Area under the curve for glucagon-like peptide I in euglycemic, hyperinsulinemic clamp
Glucagon-like peptide I will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Area under the curve for ketone body concentrations in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Ketone bodies will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Area under the curve for ketone body concentrations in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Ketone bodies 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.
Area under the curve for free fatty acids in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Free fatty acids will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Area under the curve for free fatty acids in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Free fatty acids 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.
Area under the curve for glucagon in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Glucagon will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Area under the curve for glucagon in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Glucagon 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.
Area under the curve for somatostatin in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Somatostatin will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Area under the curve for somatostatin in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Somatostatin 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.
Full Information
NCT ID
NCT04035031
First Posted
July 24, 2019
Last Updated
March 13, 2023
Sponsor
Insel Gruppe AG, University Hospital Bern
1. Study Identification
Unique Protocol Identification Number
NCT04035031
Brief Title
Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes
Official Title
Effects of SGLT-2 Inhibitor Dapagliflozin on Hormonal Glucose Regulation and Ketogenesis in Patients With Type 1 Diabetes - a Randomised, Placebo-controlled, Open-label, Cross-over Intervention Study
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
January 9, 2020 (Actual)
Primary Completion Date
November 12, 2020 (Actual)
Study Completion Date
November 12, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Insel Gruppe AG, University Hospital Bern
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1
7. Study Design
Primary Purpose
Other
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Model Description
Randomised, placebo-controlled, open-label, cross over intervention study
Masking
None (Open Label)
Allocation
Randomized
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Forxiga first, placebo second
Arm Type
Experimental
Arm Description
Forxiga followed by placebo
Arm Title
Placebo first, Forxiga second
Arm Type
Experimental
Arm Description
Placebo followed by forxiga
Intervention Type
Drug
Intervention Name(s)
Forxiga 10mg
Other Intervention Name(s)
Dapagliflozin
Intervention Description
Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)
Primary Outcome Measure Information:
Title
Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
Description
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.
Time Frame
From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Title
Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
Description
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.
Time Frame
During visit 3 (day 7): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Title
Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
Description
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.
Time Frame
During visit 5 (day 31): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Secondary Outcome Measure Information:
Title
Area under the curve for glucagon-like peptide I in euglycemic, hyperinsulinemic clamp
Description
Glucagon-like peptide I will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time Frame
From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Title
Area under the curve for ketone body concentrations in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Description
Ketone bodies will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time Frame
From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Title
Area under the curve for ketone body concentrations in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Description
Ketone bodies 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.
Time Frame
From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Title
Area under the curve for free fatty acids in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Description
Free fatty acids will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time Frame
From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Title
Area under the curve for free fatty acids in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Description
Free fatty acids 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.
Time Frame
From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Title
Area under the curve for glucagon in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Description
Glucagon will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time Frame
From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Title
Area under the curve for glucagon in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Description
Glucagon 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.
Time Frame
From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Title
Area under the curve for somatostatin in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Description
Somatostatin will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time Frame
From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Title
Area under the curve for somatostatin in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Description
Somatostatin 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.
Time Frame
From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Markus Laimer, Prof. MD
Organizational Affiliation
Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism, University Clinics Bern, Inselspital, Bern, Switzerland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
According to Swiss National Fund (SNF) policy on Open Research Data, Data will be uploaded to an open data registry.
Learn more about this trial
Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes
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