Exenatide and Impaired Hypoglycaemic Awareness in Type 1 Diabetes

Radboud University Medical Center10 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Diabetes Mellitus, Type 1 Hypoglycemia

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Symptom score in response to insulin-induced hypoglycaemia

Measured during hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 30 minutes

Secondary Outcomes

Adrenaline response to insulin-induced hypoglycaemia

Measured in plasma during hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 30 minutes

Glucagon response to insulin-induced hypoglycaemia

Measured in plasma during hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 30 minutes

Time until glycaemic recovery from hypoglycaemia

Measured during hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 1 hour

Maximal glucose excursion post-hypoglycaemia

Measured during hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 1 hour

Time until glucose peak post-hypoglycaemia

Measured after hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 1 hour

Area under the glucose concentration curve post-hypoglycaemia

Measured after hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 1 hour

Hunger score post-hypoglycaemia

Measured after hyperinsulinemic hypoglycaemic glucose clamps

Time frame: 1 hour

Carbohydrate requirement after recovery from hypoglycaemia

Measured after hyperinsulinemic hypoglycaemic glucose clamps by showing pictures of various carbohydrate-containing snacks and beverages

Time frame: 1 hour

Number of severe hypoglycaemic events during follow-up

Time frame: 16 weeks

Number of nocturnal hypoglycaemic events during follow-up

Time frame: 16 weeks

Number of any hypoglycaemic events during follow-up

Time frame: 16 weeks

Number of hypoglycaemic events measured by glucose sensor monitoring

optional (in participants agreeing to wear a continuous glucose sensor for 5 days)

Time frame: 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)

Time frame: 1 week

Glucose variability as measured by glucose sensor monitoring

optional (in participants agreeing to wear a continuous glucose sensor for 5 days)

Time frame: 1 week

Exenatide and Impaired Hypoglycaemic Awareness in Type 1 Diabetes

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes