Adding Liraglutide to High Dose Insulin: Breaking the Cycle

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether the addition of liraglutide 1.8 mg/day to a high-dose insulin regimen (>1.8 units/kg/day) in patients with uncontrolled (HbA1c >7.5%) type 2 diabetes mellitus will improve blood sugar control. It also evaluates the effect of liraglutide on liver and pancreatic fat content, explores the mechanism of blood sugar improvement by assessing weight and pancreatic hormone release, and assesses blood pressure, lipid profile, and liver function. Finally it will look at patient quality of life and safety.

Detailed Description
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Type 2 diabetes is a progressive disease with incessant beta-cell dysfunction that often ultimately requires insulin treatment. Patients requiring high insulin dosages represent a particular treatment challenge and often have uncontrolled glycemia despite progressive dose increases and are especially prone to insulin related lipotoxicity and weight gain. Glucagon-like peptide agonists (GLP-1) such as liraglutide have many actions that position them to break the vicious cycle in this population through the following mechanisms: (1) weight loss; (2) improved hepatic steatosis; (3) improved pancreatic steatosis; (4) decreased glucagon levels; (5) improved beta-cell function. The purpose of the study is to demonstrate that liraglutide is both effective and safe when added to a high dose insulin treatment regimen. Liraglutide will improve glycemic control, weight, metabolic parameters, as well as patient satisfaction, with minimal adverse events. The study also proposes to study the mechanisms through which such improvements might occur, especially beta-cell function, glucagon levels, and hepatic and pancreatic fat content.

Official Title
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Adding Liraglutide to High Dose Insulin: Breaking the Cycle

Conditions
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Type 2 Diabetes Mellitus, Obesity

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus Insulin dose of >1.8 units/kg/day (represents total daily insulin dose, regardless of formulation, regimen, number of daily shots) HbA1c ≥ 7.5% and ≤ 11% Age ≥ 18 Stable comorbidities on stable treatment regimens Stable dose of all oral hypoglycemics for ≥ 3 months prior to enrollment Ability to provide informed consent before any trial-related activities Exclusion Criteria: Type 1 diabetes mellitus Any contraindication to the MRI procedure (metallic implants, severe claustrophobia, pregnancy, unable to lie still on a hard table for the duration of the procedure, weight above 400 lb - limit of the MRI table, magnet's inner circumference smaller than the largest body circumference) History of any pancreatic disease as it might interfere with the pancreatic TG measurement (i.e. pancreatitis, tumors, cysts, type 1 diabetes, any pancreatic surgery) End Stage Renal Disease on dialysis due to increased risk of hypoglycemia, and possible interference with accurate measurement of HbA1c Incretin therapy (any GLP-1 agonist or DPP-IV inhibitor) Unstable or decompensated comorbidities Personal or family history of medullary thyroid carcinoma or MEN-2 syndrome Severe gastroparesis Pregnancy, breast feeding, intention to become pregnant, or not using adequate contraceptive measures Organ transplant recipient or waiting list candidate Steroid use (current or potential use during the trial) Known/suspected allergy to trial medication, excipients, or related products Contraindications to study medications, worded specifically as stated in the product's prescribing information Non-English speaking volunteers since no interpreters are available and the safety of the volunteers could be jeopardized if adequate and reliable communication is not possible.

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liraglutide<br> | Drug: Liraglutide<br>* Liraglutdie 1.8mg injected subcutaneously from pen device once daily for 6-months<br>* Other names: Victoza;|
| Placebo Comparator: Saline injection<br> | Drug: Saline<br>* Placebo injection of 1.8mg saline once daily for 6-months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycemic Control Measured by HbA1c | HbA1c (%) | 6-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pancreatic and Hepatic Triglyceride Content | Liver Triglyceride and Pancreatic Triglyceride | 6-months | 
| Weight |  | 6-months | 
| Beta-Cell Function | Fasting Glucose as a Measure of Beta-Cell Function | 6-months | 
| Glucagon | Measured during mixed meal challenge test. | 6-months | 
| Total Daily Insulin Dose | The 3 days average of the total daily dose of insulin used within 3 consecutive days prior office visit 6 month. | 6-months | 
| Number of Daily Injections | The 3 days average of the number of daily injections performed within 3 consecutive days prior office visit 6 month. | 6-months | 
| Blood Pressure |  | 6-months | 
| Lipid Profile |  | 6-months | 
| Liver Function Blood Test |  | 6-months | 
| Hypoglycemic Events | Reported as hypoglycemic events per month by patient as any blood glucose <70 mg/dl or symptoms of hypoglycemia with blood glucose >70 mg/dl | 6-months | 
| Quality of Life Survey (QoL) - General Health Perception | General health perception was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 1-5, where 1 = excellent; 2 = very good; 3 = good; 4 = fair; 5 = poor. | 6-months | 
| Beta-Cell Function | Fasting C-peptide as a Measure of Beta-Cell Function | 6 months | 
| Matsuda Index as a Measure of Beta Cell Function | The Matsuda index is a measure of insulin sensitivity and has no minimum/maximum values. Index values are calculated as 500,000/square root of ((fasting glucose x fasting c-peptide x 333) x (mean 120 min post-meal glucose x mean 120 min post-meal c-peptide x 333)). Higher/lower values = better/worse insulin sensitivity. | 6 months | 
| Beta-cell Function | AUC c-peptide | 6 Months | 
| Ratio (AUC C-peptide/AUC Glucose) |  | 6 months | 
| AUC Glucose |  | 6 months | 
| Quality of Life Survey (QoL) - Current Health Perception | Current health perception was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 1-5, where 1 = much better than 3 months ago; 2 - Somewhat better now than 3 months ago; 3 - About the same; 4 - Somewhat worse now than 3 months ago; 5 Much worse now than 3 months ago. | 6 months | 
| Quality of Life Survey (QoL) - Treatment Satisfaction | Quality of Life Survey (QoL) - treatment satisfactionTreatment satisfaction was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 1-5, where 1 - very satisfied; 2 - moderately satisfied; 3 - neither satisfied nor dissatisfied; 4 - moderately dissatisfied; 5 - very dissatisfied. | 6 months | 
| Quality of Life Survey (QoL) - Treatment Impact | Treatment impact was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 1-5, where 1 - very satisfied; 2 - moderately satisfied; 3 - neither satisfied nor dissatisfied; 4 - moderately dissatisfied; 5 - very dissatisfied. | 6 months | 
| Quality of Life Survey (QoL) - Social or Vocational Worry | Social or vocational worry was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 0-5, where 0 - does not apply; 1 - never; 2 - seldom; 3 - sometimes; 4 - often; 5 - all of the time. | 6 months | 
| Quality of Life Survey (QoL) - Hypoglycemia Fear | Hypoglycemia fear was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 1-5, where 1 - never worry; 2 - rarely water; 3 - sometimes worry; 4 - often worry; 5 - very often worry. | 6 months | 
| Quality of Life Survey (QoL) - Glycemia Control Perception | Glycemia control perception was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a scale score of 1-7, where 1 - extremely controlled and 7 - not at all controlled. | 6 months | 
| Quality of Life Survey (QoL) - Lifestyle Flexibility | Lifestyle flexibility was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 1 to 5, where 1 - a great deal of choice; 2 - a lot of choice; 3 - some choice; 4 - a little choice; 5 - no choice. | 6 months | 
| Quality of Life Survey (QoL) - Social Stigma | Social stigma was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a Likert scale score of 1 to 5, where 1 strongly agree; 2 - somewhat agree; 3 - neither agree nor disagree; 4 - somewhat disagree; 5 - strongly disagree. | 6 months | 
| Quality of Life Survey (QoL) - Satisfaction With Insulin Treatment | Satisfaction with insulin treatment was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a scale score of 1 to 7, where 1 extremely satisfied to 7 - not at all satisfied. | 6 months | 
| Quality of Life Survey (QoL) - Willingness to Continue Insulin Treatment | Willingness to continue insulin treatment was measured at randomization and 6 months later using the modified Diabetes Quality of Life Clinical Trial Questionnaire. This questionnaire addresses several areas with respect to diabetes QoL. Answers are in the form of a scale score of 1 to 7, where 1 extremely willing to 7 - not at all willing. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin, Glucagon-like peptide, Liraglutide, Beta-Cell, pancreatic steatosis, hepatic steatosis