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NCT Number: NCT04035031

Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes

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.

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Key information

Conditions

Diabetes Mellitus, Type 1 Autoimmune Diseases Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Immune System Diseases Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

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

Bern, 3010, Switzerland

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Forxiga 10mg

Drug

Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)

Other names: Dapagliflozin

Placebo

Drug

Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)

Primary outcomes

  1. Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp

    Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

    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.

  2. Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp

    Time frame: During visit 3 (day 7): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

    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.

  3. Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp

    Time frame: During visit 5 (day 31): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

    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.

Secondary outcomes

  1. Area under the curve for glucagon-like peptide I in euglycemic, hyperinsulinemic clamp

    Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

    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.

  2. Area under the curve for ketone body concentrations in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

    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.

  3. Area under the curve for ketone body concentrations in oral glucose tolerance test clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

    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.

  4. Area under the curve for free fatty acids in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

    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.

  5. Area under the curve for free fatty acids in oral glucose tolerance test clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

    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.

  6. Area under the curve for glucagon in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

    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.

  7. Area under the curve for glucagon in oral glucose tolerance test clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

    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.

  8. Area under the curve for somatostatin in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes

    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.

  9. Area under the curve for somatostatin in oral glucose tolerance test clamp following dapagliflozin compared with placebo

    Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes

    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.

Sponsors and collaborators

Lead sponsor

Insel Gruppe AG, University Hospital Bern

Other

Registry information

Official study title

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

Important dates

Study start
2020
Primary completion
2020
Study completion
2020
First posted
Jul 29, 2019
Registry last updated
Mar 14, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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