Adding Liraglutide to High Dose Insulin: Breaking the Cycle

Ildiko Lingvay71 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Type 2 Diabetes Mellitus Obesity

Interventions

LiraglutideDRUG

Liraglutdie 1.8mg injected subcutaneously from pen device once daily for 6-months

SalineDRUG

Placebo injection of 1.8mg saline once daily for 6-months

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (1)

UT Southwestern

Dallas, Texas, United States

Outcomes

Primary Outcomes

Glycemic Control Measured by HbA1c

HbA1c (%)

Time frame: 6-months

Secondary Outcomes

Pancreatic and Hepatic Triglyceride Content

Liver Triglyceride and Pancreatic Triglyceride

Time frame: 6-months

Weight

Time frame: 6-months

Beta-Cell Function

Fasting Glucose as a Measure of Beta-Cell Function

Time frame: 6-months

Glucagon

Measured during mixed meal challenge test.

Time frame: 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.

Time frame: 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.

Time frame: 6-months

Blood Pressure

Time frame: 6-months

Lipid Profile

Time frame: 6-months

Liver Function Blood Test

Time frame: 6-months

Data from ClinicalTrials.gov

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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

Time frame: 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.

Time frame: 6-months

Beta-Cell Function

Fasting C-peptide as a Measure of Beta-Cell Function

Time frame: 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.

Time frame: 6 months

Beta-cell Function

AUC c-peptide

Time frame: 6 Months

Ratio (AUC C-peptide/AUC Glucose)

Time frame: 6 months

AUC Glucose

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 6 months