Dapagliflozin in Physical Exercise in Type 1 Diabetes

Study Overview
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Brief Summary
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Inhibitors of sodium-dependent glucose-transporter 2 (SGLT-2 inhibitors, including dapagliflozin) inhibit glucose reabsorption in renal tubular cells, hereby increasing glycosuria in the hyperglycemic state. Its mechanisms of action are independent of insulin, which makes SGLT-2 inhibitors a potential adjunct to insulin in type 1 diabetes mellitus (T1DM). However, a higher risk for diabetic ketoacidosis (DKA) was reported in patients with T1DM taking SGLT-2 inhibitors. DKA depends on an accumulation of ketone bodies in the blood stream, which equals an accumulation of acids that lead to acidosis. The underlying mechanisms of this observation are unknown. Ketone body production depends on the molar ratio of glucagon to insulin, with insulin suppressing but glucagon stimulating ketone body production. This translates into higher production during relative insulin deficiency, carbohydrate deficiency, and prolonged fasting, which occurs during sickness but also physical exercise. Physical exercise is a recommended cornerstone in the treatment of T1DM and current treatment guidelines recommend both, reductions of insulin doses and ingestion of additional carbohydrates to avoid hypoglycemic events. These adaptions might increase relative insulin deficiency, hyperglycemia and glycaemic variability, which might in turn promote ketone body production. The addition of SGLT-2 inhibitors further may promote ketogenesis even though there are reports of SGLT-2 inhibitors increase Glucagon-like-peptide-1 (GLP-1) in patients with T1DM. GLP-1 is a suppressor of glucagon secretion. In summary, knowledge about the effects of SGLT-2 inhibition on ketone body production is scarce, especially during exercise in patients with T1DM. The study seeks to illustrate the effect of SGLT-2 inhibition on glycemic variability and ketone body production during and after recreational exercise in patients with T1DM. The results of study 2 will provide the basis for future studies investigating the underlying mechanisms of potentially modified ketone body production during and after exercise under SGLT-2 inhibition.

Official Title
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SGLT-2 Inhibition Using Dapagliflozin During and After Physical Exercise - Effects on Glycemic Variability, Hormonal Regulators of Glucose Homeostasis and Ketone Body in Type 1 Diabetes - a Randomized, 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: Written informed consent Diagnosis of T1DM Duration of T1DM > 5 years Male or female sex Insulin therapy via multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) Body mass index (BMI) between 20 and 29 kg/m2 Adherence to sufficient contraceptive measures (double barrier method combining hormonal with mechanical barriers). Ability to perform a 60 minutes exercise session at 50% VO2max. Exclusion Criteria: Diagnosis of renal and/or hepatic dysfunction History of malignancy of any kind Intake of drugs influencing glucose homeostasis during the last three months Alcohol or drug abuse Inadequate vein status on both forearms Active smoker Known pregnancy, positive plasma beta human choriogonadotropine test prior to study inclusion or intention to become pregnant during the study period.

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, placebo-controlled, open-label, crossover
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin first, placebo second<br>Dapagliflozin followed by placebo | Drug: Forxiga 10mg<br>* Dapagliflozin 10mg per 24 hours, oral, for 7 consecutive days<br>* Other names: Dapagliflozin;Drug: Placebo<br>* Placebo 1 tablet per 24 hours, oral, for 7 consecutive days<br>|
| Experimental: Placebo first, Dapagliflozin second<br>Placebo followed by dapagliflozin | Drug: Forxiga 10mg<br>* Dapagliflozin 10mg per 24 hours, oral, for 7 consecutive days<br>* Other names: Dapagliflozin;Drug: Placebo<br>* Placebo 1 tablet per 24 hours, oral, for 7 consecutive days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Amplitude of Glucose Excursions (MAGE) after physical exercise | MAGE will be calculated via sensor glucose measurements obtained over 72 hours after physical exercise | From completion of physical exercise at day 7 of each intervention period to 72 hours after | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve for glucagon-like peptide I before, during and after physical exercise | Glucagon-like peptide I will be measured at the beginning, during and after physical exercise following each intervention period | From time-point 0 to 120 minutes before, during and after physical exercise session | 
| Area under the curve for glucagon before, during and after physical exercise | Glucagon will be measured at the beginning, during and after physical exercise following each intervention period | From time-point 0 to 120 minutes before, during and after physical exercise session |