Liraglutide in Type 1 Diabetes

Study Overview
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Brief Summary
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A randomised, double-blind, placebo controlled study of the effect of liraglutide as an additional treatment to insulin on HbA1c, body weight and hypoglycaemia in poorly regulated type 1 diabetes patients. Background: Treatment with glucagon-like peptid 1 (GLP-1) agonists liraglutide and exanatide leads to weight loss and decrease in haemoglobin A1c in oral anti diabetic treated type 2 diabetes patients. It is estimated that 40-50 % of type 1 diabetes patients in the US suffers from overweight or poor glycaemic control (HbA1c > 8 %). Small studies, not placebo controlled, reports effects of adding liraglutide to a group of well regulated (HbA1c < 7.5 %) normal to overweight insulin treated type 1 diabetes patients for 24 weeks. A decrease in HbA1c, weight, insulin doses and glycaemic excursions measured by continuous glucose monitoring was seen. Primary objective:To investigate the effect of liraglutide 1.8 mg once daily compared to placebo for 24 weeks on change in HbA1c in patients with type 1 diabetes as an add-on therapy to insulin. Secondary objectives:To investigate the effect of liraglutide as an add-on therapy to insulin compared to placebo on change in:Weight, insulin dose,hypoglycaemic events, CGM, BMI, body composition, quality of life, treatment satisfaction,food preferences, meal test, CIMT, PWV and 24 hour blood pressure.

Detailed Description
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A randomised, double-blind, placebo controlled study of the effect of liraglutide as an additional treatment to insulin on HbA1c, body weight and hypoglycaemia in poorly regulated type 1 diabetes patients. Background Treatment with glucagon-like peptid 1 (GLP-1) agonists liraglutide and exenatide leads to weight loss and decrease in haemoglobin A1c (HbA1c) in oral anti diabetic treated type 2 diabetes patients. Smaller studies have shown similar effects in insulin treated type 2 diabetes patients, with no increased risk of hypoglycaemia. It is estimated that 40-50 % of type 1 diabetes patients in the US suffers from overweight or poor glycaemic control (HbA1c > 8 %). At present treatment of type 1 diabetes solely consists of insulin injections. A recent study reports effects of adding liraglutide to a group of well regulated (HbA1c < 7.5 %) normal to overweight insulin treated type 1 diabetes patients for 24 weeks. A decrease in HbA1c, weight, insulin doses and glycaemic excursions measured by continuous glucose monitoring was seen. The study was not placebo controlled. The available literature suggests that GLP-1 agonists reduce insulin dose and weight in well regulated type 1 diabetes patients, who are normal- to overweight. To our knowledge, no study has addressed whether liraglutide will improve HbA1c and reduce bodyweight in overweight and poorly regulated type 1 diabetes patients. At present the most efficient way to reduce HbA1c is to use insulin pump therapy, and most studies suggest that this will decreased HbA1c by approximately 0.5 %. Insulin pump therapy is however only an option in very compliant patients. In most clinics treating type 1 diabetes 40-50 % of patients will have HbA1c > 8 % and many of these patients will, due to insufficient compliance, not be candidates for an insulin pump. At Steno Diabetes Center approximately 3000 well characterized type 1 diabetes patients is followed in the outpatient clinic, and 40-50 % of these have HbA1c > 8.0 %. If liraglutide given once daily results in a reduction of HbA1c of 0.5 % it will probably be a very cost-effective additional therapy for type 1 diabetes patients in insufficient metabolic control. Several studies have shown that liraglutide lowers systolic blood pressure. Dysregulation increases the risk of microvascular complications in type 1 diabetes of which microalbuminuria results in a need for treatment with antihypertensive medication. Overweight increases the risk of hypertension and arteriosclerosis and thereby cardiovascular diseases. Carotis intima media thickness is a validated estimate for future cardiovascular disease and pulse wave velocity is a measure of arterial stiffness. We perform 24 hour blood pressure measurements to document possible effects of liraglutide on blood pressure and CIMT and PWV to investigate the effect of liraglutide on cardiovascular disease and arteriosclerosis.

Official Title
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Liraglutide in Type 1 Diabetes. A Randomised, Double-blind, Placebo Controlled Study of the Effect of Liraglutide as an Additional Treatment to Insulin on HbA1c, Body Weight and Hypoglycaemia in Poorly Regulated Type 1 Diabetes Patients

Conditions
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Diabetes Mellitus, Type 1, Overweight

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes according to WHO criteria ≥ 1 year Age ≥ 18 years BMI > 25 kg/m2 HbA1c > 8.0 % at visit 0 Exclusion Criteria: Insulin pump treatment Hypoglycaemia unawareness (unability to register low blood glucose) Diabetic gastroparesis Compromised kidney function (eGFR < 60 ml/min/1,73m2), dialysis or kidney transplantation at visit 0 Liver disease with elevated plasma alanine aminotransferase (ALT) > three times the upper limit of normal (measured at visit 0 with the possibility of one repeat analysis within a week, and the last measured value as being conclusive) Acute or chronic pancreatitis Inflammatory bowel disease Cancer unless in complete remission for > 5 years History of thyroid adenoma or carcinoma Other concomitant disease or treatment that according to the investigator's assessment makes the patient unsuitable for study participation Alcohol/drug abuse Fertile women not using contraceptives Pregnant or nursing women Known or suspected hypersensitivity to trial product or related products Receipt of an investigational drug within 30 days prior to visit 0 Simultaneous participation in any other clinical intervention trial

Ages Eligible for Study
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Minimum Age: 18 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: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liraglutide<br> | Drug: Liraglutide<br>* 1.8 mg/day subcutaneous<br>* Other names: Victoza;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 1.8 mg/day subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | To investigate the effect of liraglutide 1.8 mg once daily compared to placebo for 24 weeks on change in HbA1c in patients with type 1 diabetes as an adjunctive therapy to insulin treatment. | 24 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body weight | To investigate the effect of liraglutide 1.8 mg once daily compared to placebo for 24 weeks on change in weight, BMI and body composition | 24 weeks | 
| Cardiovascular | To investigate the effect of liraglutide 1.8 mg once daily compared to placebo for 24 weeks on change in carotis intima media thickness, pulse wave velocity, 24 hour blood pressure | 24 weeks | 
| Standardised liquid meal test | To investigate the effect of liraglutide 1.8 mg once daily compared to placebo for 24 weeks on change in postprandial glucagon levels, glycaemic excursion, gastric emptying, VAS score for appetite and food preference | 24 weeks | 
| Glycaemic excursions | To investigate the effect of liraglutide 1.8 mg once daily compared to placebo for 24 weeks on change in insulin dose, hypoglycaemic events and glycaemic excursions (time spent in hypo- and hyperglycaemia as measured by CGM) | 24 weeks | 
| Quality of life | To investigate the effect of liraglutide 1.8 mg once daily compared to placebo for 24 weeks on change in quality of life and treatment satisfaction | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Liraglutide, Hypoglycaemia, Hyperglycaemia, CIMT, PWV, Food preference, Blood pressure