Diabetes Mellitus, Type 1, Hypoglycemia
Conditions
Keywords
Glucagon-Like Peptide 1, Impaired hypoglycemic awareness
Brief summary
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.
Interventions
DRUGExenatide
6 weeks treatment with exenatide on top of insulin treatment
DRUGPlacebo
6 weeks treatment with placebo on top of insulin treatment
Sponsors
AstraZeneca
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 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptom score in response to insulin-induced hypoglycaemia | 30 minutes | Measured during hyperinsulinemic hypoglycaemic glucose clamps |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adrenaline response to insulin-induced hypoglycaemia | 30 minutes | Measured in plasma during hyperinsulinemic hypoglycaemic glucose clamps |
| Glucagon response to insulin-induced hypoglycaemia | 30 minutes | Measured in plasma during hyperinsulinemic hypoglycaemic glucose clamps |
| Time until glycaemic recovery from hypoglycaemia | 1 hour | Measured during hyperinsulinemic hypoglycaemic glucose clamps |
| Maximal glucose excursion post-hypoglycaemia | 1 hour | Measured during hyperinsulinemic hypoglycaemic glucose clamps |
| Time until glucose peak post-hypoglycaemia | 1 hour | Measured after hyperinsulinemic hypoglycaemic glucose clamps |
| Area under the glucose concentration curve post-hypoglycaemia | 1 hour | Measured after hyperinsulinemic hypoglycaemic glucose clamps |
| Hunger score post-hypoglycaemia | 1 hour | Measured after hyperinsulinemic hypoglycaemic glucose clamps |
| Time spent under hypoglycaemic conditions measured by glucose sensor monitoring | 1 week | optional (in participants agreeing to wear a continuous glucose sensor for 5 days) |
| Glucose variability as measured by glucose sensor monitoring | 1 week | optional (in participants agreeing to wear a continuous glucose sensor for 5 days) |
| Carbohydrate requirement after recovery from hypoglycaemia | 1 hour | Measured after hyperinsulinemic hypoglycaemic glucose clamps by showing pictures of various carbohydrate-containing snacks and beverages |
| 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 | 1 week | optional (in participants agreeing to wear a continuous glucose sensor for 5 days) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pulse rate | 6 weeks | Measured during hyperinsulinemic hypoglycaemic glucose clamps |
| Gastrointestinal side effects | 16 weeks | — |
Countries
Netherlands
Outcome results
None listed