Dapagliflozin in Physical Exercise in Type 1 Diabetes

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Forxiga 10mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Markus Laimer, Prof. MD; Phone Number: +41 31 63 2 30 62; Email: Markus.Laimer@insel.ch
• Study Contact Backup: Name: Christoph Stettler, Prof. MD; Phone Number: +41316323062 +41 31 632 42 21; Email: Christoph.Stettler@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve for ketone bodies before, during and after physical exercise	Ketone bodies will be measured at the beginning, 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	Free fatty acids will be measured at the beginning, 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	Somatostatin will be measured at the beginning, during and after physical exercise	From time-point 0 to 120 minutes before, during and after physical exercise session

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Principal Investigator: Christoph Stettler, Prof. MD, Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism, University Clinics Bern, Inselspital, Bern, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2020
• Primary Completion (Actual): April 26, 2023
• Study Completion (Actual): May 10, 2023

Study Registration Dates

• First Submitted: August 5, 2019
• First Submitted That Met QC Criteria: August 5, 2019
• First Posted (Actual): August 7, 2019

Study Record Updates

• Last Update Posted (Estimated): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: CUI_002_02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: From July, 30th 2021 ongoing
• IPD Sharing Access Criteria: Contact with the Study Sponsor
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No