Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Forxiga 10mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomised, placebo-controlled, open-label, cross over intervention study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Forxiga first, placebo second<br>Forxiga followed by placebo | Drug: Forxiga 10mg<br>* Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)<br>* Other names: Dapagliflozin;Drug: Placebo<br>* Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)<br>|
| Experimental: Placebo first, Forxiga second<br>Placebo followed by forxiga | Drug: Forxiga 10mg<br>* Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)<br>* Other names: Dapagliflozin;Drug: Placebo<br>* Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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. | 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 | 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. | 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 | 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. | 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 | 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. | From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes | 
| 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. | From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes | 
| 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. | From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes | 
| 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. | From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes | 
| 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. | From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes |