Clinical trial NCT01505673: Adding Liraglutide to High Dose Insulin: Breaking the Cycle
Official title: Adding Liraglutide to High Dose Insulin: Breaking the Cycle
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Obesity
Keywords: Insulin
Glucagon-like peptide
Liraglutide
Beta-Cell
pancreatic steatosis
hepatic steatosis
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: Novo Nordisk A/S
First posted: 2012-01-06
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Glycemic Control Measured by HbA1c
timeFrame: 6-months
Secondary outcomes:
measure: Pancreatic and Hepatic Triglyceride Content
timeFrame: 6-months
measure: Weight
timeFrame: 6-months
measure: Beta-Cell Function
timeFrame: 6-months
measure: Glucagon
timeFrame: 6-months
measure: Total Daily Insulin Dose
timeFrame: 6-months
measure: Number of Daily Injections
timeFrame: 6-months
measure: Blood Pressure
timeFrame: 6-months
measure: Lipid Profile
timeFrame: 6-months
measure: Liver Function Blood Test
timeFrame: 6-months
measure: Hypoglycemic Events
timeFrame: 6-months
measure: Quality of Life Survey (QoL) - General Health Perception
timeFrame: 6-months
measure: Beta-Cell Function
timeFrame: 6 months
measure: Matsuda Index as a Measure of Beta Cell Function
timeFrame: 6 months
measure: Beta-cell Function
timeFrame: 6 Months
measure: Ratio (AUC C-peptide/AUC Glucose)
timeFrame: 6 months
measure: AUC Glucose
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Current Health Perception
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Treatment Satisfaction
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Treatment Impact
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Social or Vocational Worry
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Hypoglycemia Fear
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Glycemia Control Perception
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Lifestyle Flexibility
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Social Stigma
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Satisfaction With Insulin Treatment
timeFrame: 6 months
measure: Quality of Life Survey (QoL) - Willingness to Continue Insulin Treatment
timeFrame: 6 months
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
Study officials:
affiliation: UT Southwestern
name: Ildiko Lingvay, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.