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

Sponsors

Lead Sponsor: University Hospital Inselspital, Berne

Source University Hospital Inselspital, Berne
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.

Overall Status Not yet recruiting
Start Date August 2020
Completion Date September 2021
Primary Completion Date August 2021
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Mean Amplitude of Glucose Excursions (MAGE) after physical exercise From completion of physical exercise at day 7 of each intervention period to 72 hours after
Secondary Outcome
Measure Time Frame
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
Enrollment 24
Condition
Intervention

Intervention Type: Drug

Intervention Name: Forxiga 10mg

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

Other Name: Dapagliflozin

Intervention Type: Drug

Intervention Name: Placebo

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

Eligibility

Criteria:

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-HCG test prior to study inclusion or intention to become pregnant during the study period.

Gender: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Christoph Stettler, Prof. MD Principal Investigator Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism, University Clinics Bern, Inselspital, Bern, Switzerland
Overall Contact

Last Name: Christoph Stettler, Prof. MD

Phone: +41 31 632 42 21

Phone Ext.: +41316323062

Email: [email protected]

Location
Facility: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Location Countries

Switzerland

Verification Date

April 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Dapagliflozin first, placebo second

Type: Experimental

Description: Dapagliflozin followed by placebo

Label: Placebo first, Dapagliflozin second

Type: Experimental

Description: Placebo followed by dapagliflozin

Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Crossover Assignment

Intervention Model Description: Randomized, placebo-controlled, open-label, crossover

Primary Purpose: Basic Science

Masking: None (Open Label)

Source: ClinicalTrials.gov