Clinical trial NCT04035031: Effects of Dapagliflozin on Hormonal Glucose Homeostasis in Type 1 Diabetes
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 1
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2019-07-29
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomised, placebo-controlled, open-label, cross over intervention study
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
timeFrame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
measure: Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
timeFrame: During visit 3 (day 7): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
measure: Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
timeFrame: During visit 5 (day 31): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Secondary outcomes:
measure: Area under the curve for glucagon-like peptide I in euglycemic, hyperinsulinemic clamp
timeFrame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
measure: Area under the curve for ketone body concentrations in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
measure: Area under the curve for ketone body concentrations in oral glucose tolerance test clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
measure: Area under the curve for free fatty acids in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
measure: Area under the curve for free fatty acids in oral glucose tolerance test clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
measure: Area under the curve for glucagon in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
measure: Area under the curve for glucagon in oral glucose tolerance test clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
measure: Area under the curve for somatostatin in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
measure: Area under the curve for somatostatin in oral glucose tolerance test clamp following dapagliflozin compared with placebo
timeFrame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Study officials:
affiliation: Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism, University Clinics Bern, Inselspital, Bern, Switzerland
name: Markus Laimer, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References: