Exenatide and Impaired Hypoglycaemic Awareness in Type 1 Diabetes

Effect of the GLP-1 Receptor Agonist Exenatide on Impaired Hypoglycaemic Awareness in Type 1 Diabetes

Approximately 25% of patients with type 1 diabetes have lost the capacity to timely detect hypoglycaemia, a condition referred to as impaired hypoglycaemic awareness (IHA) that causes a six-fold higher risk of severe, potentially hazardous, hypoglycaemia. IHA is usually the end-result of a process of habituation to recurrent hypoglycemia that is potentially reversible. Treatment with glucagon-like peptide (GLP)-1 Receptor Agonists (1RAs) 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 GLP-1RA, exenatide, added to basal-bolus insulin therapy will improve awareness of hypoglycaemia in patients with type 1 diabetes and IHA. In a randomized doubleblind placebo-controlled cross-over trial, patients will be treated for 6 weeks with exenatide (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, <70 years
• Insulin treatment according to basal-bolus insulin regimen (injections or insulin pump)
• Impaired hypoglycaemic awareness 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 incretin-based therapy
• Known intolerance to GLP-1RAs (including allergy)
• Treatment with glucose-modifying or immune-modifying agents, e.g. prednisolon
• Recent history of myocardial infarction or stroke (past year) or laser coagulation for proliferative retinopathy (past 6 months)
• Proliferative retinopathy
• Symptomatic diabetic neuropathy
• Diabetic nephropathy as reflected by albumin-creatinin ratio >30 mmol/mg or estimated Glomerular Filtration Rate (eGFR) <60 ml/min/1.73 m2
• Known heart failure
• History of pancreatitis (acute or chronic) or pancreatic cancer
• Body-mass index >40 kg/m2
• 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