Diabetes Mellitus, Type 1, Hypoglycemia, Hypoglycemia Unawareness
Conditions
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.
Interventions
DRUGDapagliflozin
8 weeks treatment with dapagliflozin on top of insulin treatment
DRUGPlacebo oral capsule
8 weeks treatment with placebo capsules on top of insulin treatment
Sponsors
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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 |
| Number of nocturnal 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 |
| Number of severe hypoglycaemic events during follow-up | 16 weeks | measured during follow-up |
Other
| Measure | Time frame | Description |
|---|---|---|
| Inflammatory/atherogenic phenotype of circulating monocytes from the participating patients | 45 minutes | measured during hyperinsulinemic hypoglycaemic glucose clamps |
Countries
Netherlands
Outcome results
None listed