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.

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