Dapagliflozin in Physical Exercise in Type 1 Diabetes

NCT04049110 | Completed Phase 3

• 1 other identifier: CUI_002_02
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Area under the curve for glucagon-like peptide I before, during and after physical exercise

  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

  From time-point 0 to 120 minutes before, during and after physical exercise session

Other Outcomes (3)

• Area under the curve for ketone bodies before, during and after physical exercise

  From time-point 0 to 120 minutes before, during and after physical exercise session

• Area under the curve for free fatty acids bodies before, during and after physical exercise

  From time-point 0 to 120 minutes before, during and after physical exercise session

• Area under the curve for somatostatin before, during and after physical exercise

  From time-point 0 to 120 minutes before, during and after physical exercise session

Study Arms (2)

Dapagliflozin first, placebo second

EXPERIMENTAL

Dapagliflozin followed by placebo

Drug: Forxiga 10mg; Drug: Placebo

Placebo first, Dapagliflozin second

EXPERIMENTAL

Placebo followed by dapagliflozin

Drug: Forxiga 10mg; Drug: Placebo

Interventions

Forxiga 10mg DRUG

Dapagliflozin 10mg per 24 hours, oral, for 7 consecutive days

Also known as: Dapagliflozin

Dapagliflozin first, placebo second; Placebo first, Dapagliflozin second

Placebo DRUG

Placebo 1 tablet per 24 hours, oral, for 7 consecutive days

Dapagliflozin first, placebo second; Placebo first, Dapagliflozin 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:

• 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.

You may not qualify if:

• 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

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

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

• Christoph Stettler, 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: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, placebo-controlled, open-label, crossover

Study Record Dates

• First Submitted: August 5, 2019
• First Posted: August 7, 2019
• Study Start: August 25, 2020
• Primary Completion: April 26, 2023
• Study Completion: May 10, 2023
• Last Updated: August 31, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR
• Time Frame: From July, 30th 2021 ongoing
• Access Criteria: Contact with the Study Sponsor

Locations

CH (1)