Exenatide and Impaired Hypoglycaemic Awareness in Type 1 Diabetes

Study Overview
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Brief Summary
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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.

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

Conditions
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Diabetes Mellitus, Type 1, Hypoglycemia

Intervention / Treatment
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* Drug: Exenatide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EXENATIDE<br>Exenatide week 1-2: 5 µg twice daily week 3-6: 10 µg twice daily (if tolerated) | Drug: Exenatide<br>* 6 weeks treatment with exenatide on top of insulin treatment<br>* Other names: Byetta;|
| Placebo Comparator: PLACEBO<br>Placebo matched to exenatide week 1-2: 5 µg twice daily week 3-6: 10 µg twice daily (if tolerated) | Drug: Placebo<br>* 6 weeks treatment with placebo on top of insulin treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom score in response to insulin-induced hypoglycaemia | Measured during hyperinsulinemic hypoglycaemic glucose clamps | 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adrenaline response to insulin-induced hypoglycaemia | Measured in plasma during hyperinsulinemic hypoglycaemic glucose clamps | 30 minutes | 
| Glucagon response to insulin-induced hypoglycaemia | Measured in plasma during hyperinsulinemic hypoglycaemic glucose clamps | 30 minutes | 
| Time until glycaemic recovery from hypoglycaemia | Measured during hyperinsulinemic hypoglycaemic glucose clamps | 1 hour | 
| Maximal glucose excursion post-hypoglycaemia | Measured during hyperinsulinemic hypoglycaemic glucose clamps | 1 hour | 
| Time until glucose peak post-hypoglycaemia | Measured after hyperinsulinemic hypoglycaemic glucose clamps | 1 hour | 
| Area under the glucose concentration curve post-hypoglycaemia | Measured after hyperinsulinemic hypoglycaemic glucose clamps | 1 hour | 
| Hunger score post-hypoglycaemia | Measured after hyperinsulinemic hypoglycaemic glucose clamps | 1 hour | 
| Carbohydrate requirement after recovery from hypoglycaemia | Measured after hyperinsulinemic hypoglycaemic glucose clamps by showing pictures of various carbohydrate-containing snacks and beverages | 1 hour | 
| Number of severe hypoglycaemic events during follow-up |  | 16 weeks | 
| Number of nocturnal hypoglycaemic events during follow-up |  | 16 weeks | 
| Number of any hypoglycaemic events during follow-up |  | 16 weeks | 
| Number of hypoglycaemic events measured by glucose sensor monitoring | optional (in participants agreeing to wear a continuous glucose sensor for 5 days) | 1 week | 
| Time spent under hypoglycaemic conditions measured by glucose sensor monitoring | optional (in participants agreeing to wear a continuous glucose sensor for 5 days) | 1 week | 
| Glucose variability as measured by glucose sensor monitoring | optional (in participants agreeing to wear a continuous glucose sensor for 5 days) | 1 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucagon-Like Peptide 1, Impaired hypoglycemic awareness