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Adding Liraglutide to High Dose Insulin: Breaking the Cycle

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ClinicalTrials.gov Identifier: NCT01505673
Recruitment Status : Completed
First Posted : January 6, 2012
Results First Posted : December 15, 2017
Last Update Posted : January 16, 2018
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
Ildiko Lingvay, University of Texas Southwestern Medical Center

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Obesity Drug: Liraglutide Drug: Saline Phase 4

Detailed Description:

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Adding Liraglutide to High Dose Insulin: Breaking the Cycle
Study Start Date : January 2012
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Liraglutide Drug: Liraglutide
Liraglutdie 1.8mg injected subcutaneously from pen device once daily for 6-months
Other Name: Victoza
Placebo Comparator: Saline injection Drug: Saline
Placebo injection of 1.8mg saline once daily for 6-months


Outcome Measures
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Primary Outcome Measures :
  1. Glycemic Control Measured by HbA1c [ Time Frame: 6-months ]
    HbA1c (%)


Secondary Outcome Measures :
  1. Pancreatic and Hepatic Triglyceride Content [ Time Frame: 6-months ]
    Liver Triglyceride and Pancreatic Triglyceride

  2. Weight [ Time Frame: 6-months ]
  3. Beta-Cell Function [ Time Frame: 6-months ]
    Fasting Glucose as a Measure of Beta-Cell Function

  4. Glucagon [ Time Frame: 6-months ]
    Measured during mixed meal challenge test.

  5. Total Daily Insulin Dose [ Time Frame: 6-months ]
    The 3 days average of the total daily dose of insulin used within 3 consecutive days prior office visit 6 month.

  6. Number of Daily Injections [ Time Frame: 6-months ]
    The 3 days average of the number of daily injections performed within 3 consecutive days prior office visit 6 month.

  7. Blood Pressure [ Time Frame: 6-months ]
  8. Lipid Profile [ Time Frame: 6-months ]
  9. Liver Function Blood Test [ Time Frame: 6-months ]
  10. Hypoglycemic Events [ Time Frame: 6-months ]
    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

  11. Quality of Life Survey (QoL) - General Health Perception [ Time Frame: 6-months ]
    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.

  12. Beta-Cell Function [ Time Frame: 6 months ]
    Fasting C-peptide as a Measure of Beta-Cell Function

  13. Matsuda Index as a Measure of Beta Cell Function [ Time Frame: 6 months ]
    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.

  14. Beta-cell Function [ Time Frame: 6 Months ]
    AUC c-peptide

  15. Ratio (AUC C-peptide/AUC Glucose) [ Time Frame: 6 months ]
  16. AUC Glucose [ Time Frame: 6 months ]
  17. Quality of Life Survey (QoL) - Current Health Perception [ Time Frame: 6 months ]
    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.

  18. Quality of Life Survey (QoL) - Treatment Satisfaction [ Time Frame: 6 months ]
    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.

  19. Quality of Life Survey (QoL) - Treatment Impact [ Time Frame: 6 months ]
    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.

  20. Quality of Life Survey (QoL) - Social or Vocational Worry [ Time Frame: 6 months ]
    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.

  21. Quality of Life Survey (QoL) - Hypoglycemia Fear [ Time Frame: 6 months ]
    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.

  22. Quality of Life Survey (QoL) - Glycemia Control Perception [ Time Frame: 6 months ]
    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.

  23. Quality of Life Survey (QoL) - Lifestyle Flexibility [ Time Frame: 6 months ]
    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.

  24. Quality of Life Survey (QoL) - Social Stigma [ Time Frame: 6 months ]
    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.

  25. Quality of Life Survey (QoL) - Satisfaction With Insulin Treatment [ Time Frame: 6 months ]
    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.

  26. Quality of Life Survey (QoL) - Willingness to Continue Insulin Treatment [ Time Frame: 6 months ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01505673


Locations
United States, Texas
UT Southwestern
Dallas, Texas, United States, 75390
Sponsors and Collaborators
Ildiko Lingvay
Novo Nordisk A/S
Investigators
Principal Investigator: Ildiko Lingvay, MD UT Southwestern
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Ildiko Lingvay, Assistant Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01505673     History of Changes
Other Study ID Numbers: IIS-000235
First Posted: January 6, 2012    Key Record Dates
Results First Posted: December 15, 2017
Last Update Posted: January 16, 2018
Last Verified: December 2017

Keywords provided by Ildiko Lingvay, University of Texas Southwestern Medical Center:
Insulin
Glucagon-like peptide
Liraglutide
 Beta-Cell
pancreatic steatosis
hepatic steatosis

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin
 Liraglutide
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists