Clinical trial NCT03556033: Effect of Dapagliflozin on IAH in T1DM
Official title: Effect of the SGLT-2 Inhibitor Dapagliflozin on Impaired Awareness of Hypoglycemia in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Hypoglycemia
Hypoglycemia Unawareness
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2018-06-14
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Symptom score in response to insulin-induced hypoglycaemia
timeFrame: 45 minutes
Secondary outcomes:
measure: Counterregulatory hormone responses to insulin-induced hypoglycaemia
timeFrame: 45 minutes
measure: Time until glycaemic recovery from hypoglycaemia
timeFrame: 45 minutes
measure: Maximal glucose excursion post-hypoglycaemia
timeFrame: 45 minutes
measure: Time until glucose peak post-hypoglycaemia
timeFrame: 45 minutes
measure: Area under the glucose concentration curve post-hypoglycaemia
timeFrame: 45 minutes
measure: Number of severe hypoglycaemic events during follow-up
timeFrame: 16 weeks
measure: Number of nocturnal hypoglycaemic events during follow-up
timeFrame: 16 weeks
measure: Number of any hypoglycaemic events during follow-up
timeFrame: 16 weeks
measure: Time spent under hypoglycaemic conditions measured by glucose sensor monitoring
timeFrame: 2 weeks
measure: Glucose variability as measured by glucose sensor monitoring
timeFrame: 2 weeks
Other outcomes:
measure: Inflammatory/atherogenic phenotype of circulating monocytes from the participating patients
timeFrame: 45 minutes
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud university medical center
Study officials:
References: