Effect of Dapagliflozin on IAH in T1DM

Phase 2

Completed

• Conditions: Hypoglycemia; Diabetes Mellitus, Type 1; Hypoglycemia Unawareness
• Interventions: Drug: Placebo oral capsule; Drug: Dapagliflozin

• Registration Number: NCT03556033
• Lead Sponsor: Radboud University Medical Center

Brief Summary

Approximately 25% of patients with type 1 diabetes have lost the capacity to timely detect hypoglycaemia, a condition referred to as impaired awareness of hypoglycaemia (IAH) that causes a six-fold higher risk of severe, potentially hazardous, hypoglycaemia. IAH is usually the end-result of a process of habituation to recurrent hypoglycaemia that is potentially reversible. Treatment with sodium glucose cotransporter (SGLT)-2 inhibitors (SGLT-2i) in addition to insulin therapy may decrease the incidence of hypoglycaemia in patients with type 1 diabetes. This study will test the hypothesis that treatment with the SGLT-2 inhibitor, dapagliflozin, added to basal-bolus insulin therapy will improve awareness of hypoglycaemia in patients with type 1 diabetes and IAH. In a randomized doubleblind placebo-controlled cross-over trial, patients will be treated for 8 weeks with dapagliflozin (or placebo), after which hypoglycemic symptoms and counterregulatory hormone responses will be examined during a hyperinsulinemic hypoglycemic glucose clamp study.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-05-17
• Study First Submitted QC: 2018-06-01
• Study First Posted: 2018-06-14
• Study Start: 2018-11-23
• Status Verified: 2019-09
• Primary Completion: 2019-12-20
• Study Completion: 2019-12-20
• Last Update Submitted: 2020-03-20
• Last Update Posted: 2020-03-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

• Type 1 diabetes, disease duration >1 year
• Age >18 years, <75 years
• BMI 19-40 kg/m^2
• Insulin treatment according to basal-bolus insulin regimen (injections or insulin pump)
• Impaired awareness of hypoglycemia as assessed by a score of 3 or more on the modified Dutch translation of the Clarke questionnaire
• Glycated haemoglobin (HbA1c) ≥42 mmol/mol (6%) and ≤75 mmol/mol (9.0%)
• Ability to provide informed consent

Exclusion Criteria

• Treatment with SGLT-2 inhibitors
• Known intolerance to SGLT-2 inhibitors
• Treatment with loop diuretics or other anti-hypertensive agents
• Treatment with glucose-modifying (other than insulin) or immune-modifying agents (e.g. prednisolon)
• Treatment with pioglitazone
• Use of statins
• A history of cardiovascular disease (e.g. myocardial infarction, stroke, heart failure) or hypotension
• A history of galactose-intolerance, lactase deficiency, glucose-galactose malabsorption
• History of diabetic ketoacidosis requiring medical intervention within 1 month before screening
• Admission to the hospital for hyperglycemia or hypoglycemia within 1 month before screening
• Frequent episodes of severe hypoglycemia within 1 month before screening
• Laser coagulation for proliferative retinopathy (past 6 months)
• Proliferative retinopathy
• Diabetic nephropathy as reflected by an albumin-creatinin ratio ˃ 30 mmol/mg or an estimated glomerular filtration rate (by MDRD) ˂60ml/min/1.73m2
• History of pancreatitis (acute or chronic) or pancreatic cancer
• Use of premixed insulin or of long-acting insulin alone
• Total daily insulin dose requirements <20 units unless on pump treatment
• Pregnancy or unwillingness to undertake measures for birth control

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo oral capsule	Placebo oral capsule	Placebo matched to dapagliflozin 10 mg capsule once daily for 8 weeks
Dapagliflozin	Dapagliflozin	Dapagliflozin 10 mg capsule once daily for 8 weeks

Primary Outcome Measures

Name	Time	Method
Symptom score in response to insulin-induced hypoglycaemia	45 minutes	Symptom scores (autonomic, neuroglycopenic and general) measured during hyperinsulinemic hypoglycaemic glucose clamps. This questionnaire consists of 18 symptoms, which can be scored between 0 (none) to 6 (severe). Total scores range between 0 and 108, the higher the score, the more symptoms patients have during and after hypoglycemia.

Secondary Outcome Measures

Name	Time	Method
Time until glucose peak post-hypoglycaemia	45 minutes	measured during hyperinsulinemic hypoglycaemic glucose clamps
Area under the glucose concentration curve post-hypoglycaemia	45 minutes	measured during hyperinsulinemic hypoglycaemic glucose clamps
Counterregulatory hormone responses to insulin-induced hypoglycaemia	45 minutes	(nor)adrenaline, glucagon, insulin, growth hormone and cortisol responses to hypoglycaemia measured during hyperinsulinemic hypoglycaemic glucose clamps
Time until glycaemic recovery from hypoglycaemia	45 minutes	measured during hyperinsulinemic hypoglycaemic glucose clamps
Maximal glucose excursion post-hypoglycaemia	45 minutes	Maximal glucose level (mmol/l) measured during the 90 minutes after ending the hypoglycaemic phase of the clamp (during restoration of euglycaemia)
Number of nocturnal hypoglycaemic events during follow-up	16 weeks	measured during follow-up
Number of severe hypoglycaemic events during follow-up	16 weeks	measured during follow-up
Number of any hypoglycaemic events during follow-up	16 weeks	measured during follow-up
Time spent under hypoglycaemic conditions measured by glucose sensor monitoring	2 weeks	measured during follow-up
Glucose variability as measured by glucose sensor monitoring	2 weeks	measured during follow-up

Trial Locations

Locations (1)

Radboud university medical center; 🇳🇱 Nijmegen, Netherlands