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Adding Liraglutide to High Dose Insulin: Breaking the Cycle

Primary Purpose

Type 2 Diabetes Mellitus, Obesity

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Liraglutide

Saline

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring Insulin, Glucagon-like peptide, Liraglutide, Beta-Cell, pancreatic steatosis, hepatic steatosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

UT Southwestern

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Liraglutide

Saline injection

Arm Description

Outcomes

Primary Outcome Measures

Glycemic Control Measured by HbA1c

HbA1c (%)

Secondary Outcome Measures

Pancreatic and Hepatic Triglyceride Content

Liver Triglyceride and Pancreatic Triglyceride

Weight

Beta-Cell Function

Fasting Glucose as a Measure of Beta-Cell Function

Glucagon

Measured during mixed meal challenge test.

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.

Number of Daily Injections

The 3 days average of the number of daily injections performed within 3 consecutive days prior office visit 6 month.

Blood Pressure

Lipid Profile

Liver Function Blood Test

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

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.

Beta-Cell Function

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

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.

Beta-cell Function

AUC c-peptide

Ratio (AUC C-peptide/AUC Glucose)

AUC Glucose

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01505673

First Posted

January 4, 2012

Last Updated

December 15, 2017

Sponsor

Ildiko Lingvay

Collaborators

Novo Nordisk A/S

1. Study Identification

Unique Protocol Identification Number

NCT01505673

Brief Title

Adding Liraglutide to High Dose Insulin: Breaking the Cycle

Official Title

Adding Liraglutide to High Dose Insulin: Breaking the Cycle

Study Type

Interventional

2. Study Status

Record Verification Date

December 2017

Overall Recruitment Status

Completed

Study Start Date

January 2012 (undefined)

Primary Completion Date

June 2016 (Actual)

Study Completion Date

June 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Ildiko Lingvay

Collaborators

Novo Nordisk A/S

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes Mellitus, Obesity

Keywords

Insulin, Glucagon-like peptide, Liraglutide, Beta-Cell, pancreatic steatosis, hepatic steatosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

71 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Liraglutide

Arm Type

Active Comparator

Arm Title

Saline injection

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Liraglutide

Other Intervention Name(s)

Victoza

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Saline

Intervention Description

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

Primary Outcome Measure Information:

Title

Glycemic Control Measured by HbA1c

Description

HbA1c (%)

Time Frame

6-months

Secondary Outcome Measure Information:

Title

Pancreatic and Hepatic Triglyceride Content

Description

Liver Triglyceride and Pancreatic Triglyceride

Time Frame

6-months

Title

Weight

Time Frame

6-months

Title

Beta-Cell Function

Description

Fasting Glucose as a Measure of Beta-Cell Function

Time Frame

6-months

Title

Glucagon

Description

Measured during mixed meal challenge test.

Time Frame

6-months

Title

Total Daily Insulin Dose

Description

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

Title

Number of Daily Injections

Description

The 3 days average of the number of daily injections performed within 3 consecutive days prior office visit 6 month.

Time Frame

6-months

Title

Blood Pressure

Time Frame

6-months

Title

Lipid Profile

Time Frame

6-months

Title

Liver Function Blood Test

Time Frame

6-months

Title

Hypoglycemic Events

Description

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

Title

Quality of Life Survey (QoL) - General Health Perception

Description

Time Frame

6-months

Title

Beta-Cell Function

Description

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

Time Frame

6 months

Title

Matsuda Index as a Measure of Beta Cell Function

Description

Time Frame

6 months

Title

Beta-cell Function

Description

AUC c-peptide

Time Frame

6 Months

Title

Ratio (AUC C-peptide/AUC Glucose)

Time Frame

6 months

Title

AUC Glucose

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Current Health Perception

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Treatment Satisfaction

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Treatment Impact

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Social or Vocational Worry

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Hypoglycemia Fear

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Glycemia Control Perception

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Lifestyle Flexibility

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Social Stigma

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Satisfaction With Insulin Treatment

Description

Time Frame

6 months

Title

Quality of Life Survey (QoL) - Willingness to Continue Insulin Treatment

Description

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ildiko Lingvay, MD

Organizational Affiliation

UT Southwestern

Official's Role

Principal Investigator

Facility Information:

Facility Name

UT Southwestern

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

27273731

Citation

Vanderheiden A, Harrison L, Warshauer J, Li X, Adams-Huet B, Lingvay I. Effect of Adding Liraglutide vs Placebo to a High-Dose lnsulin Regimen in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA Intern Med. 2016 Jul 1;176(7):939-47. doi: 10.1001/jamainternmed.2016.1540.

Results Reference

derived

PubMed Identifier

26909799

Citation

Vanderheiden A, Harrison LB, Warshauer JT, Adams-Huet B, Li X, Yuan Q, Hulsey K, Dimitrov I, Yokoo T, Jaster AW, Pinho DF, Pedrosa I, Lenkinski RE, Pop LM, Lingvay I. Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin. J Clin Endocrinol Metab. 2016 Apr;101(4):1798-806. doi: 10.1210/jc.2015-3906. Epub 2016 Feb 24.

Results Reference

derived

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Adding Liraglutide to High Dose Insulin: Breaking the Cycle

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