Effect of Dapagliflozin on IAH in T1DM
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Dapagliflozin Dapagliflozin 10 mg capsule once daily for 8 weeks |
Drug: Dapagliflozin
8 weeks treatment with dapagliflozin on top of insulin treatment
Other Names:
|
| Placebo Comparator: Placebo oral capsule Placebo matched to dapagliflozin 10 mg capsule once daily for 8 weeks |
Drug: Placebo oral capsule
8 weeks treatment with placebo capsules on top of insulin treatment
|
Outcome Measures
Primary Outcome Measures
- 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
- 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 severe hypoglycaemic events during follow-up [16 weeks]
measured during follow-up
- 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
Other Outcome Measures
- Inflammatory/atherogenic phenotype of circulating monocytes from the participating patients [45 minutes]
measured during hyperinsulinemic hypoglycaemic glucose clamps
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Radboud university medical center | Nijmegen | Netherlands | 6500HB |
Sponsors and Collaborators
- Radboud University Medical Center
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- T1DM_IAH_dapa