Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes

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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

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
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Investigators: Principal Investigator: Markus Laimer, 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): January 9, 2020
• Primary Completion (Actual): November 12, 2020
• Study Completion (Actual): November 12, 2020

Study Registration Dates

• First Submitted: July 24, 2019
• First Submitted That Met QC Criteria: July 24, 2019
• First Posted (Actual): July 29, 2019

Study Record Updates

• Last Update Posted (Actual): March 14, 2023
• Last Update Submitted That Met QC Criteria: March 13, 2023
• Last Verified: March 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_01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to Swiss National Fund (SNF) policy on Open Research Data, Data will be uploaded to an open data registry.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; 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