GLP-1 and Non-exercise Activity Thermogenesis in RHZ

Liraglutide With or Without NEAT in Type 2 Diabetes Mellitus; Effects on HbA1c, Weight, Blood Pressure, Quality of Life and Health Care Costs.

- Rationale: Treatment with glucagon-like peptide 1 (GLP-1) has been shown to reduce plasma glucose levels to a further extent when added to standard therapy in type 2 diabetes mellitus. Given the well-known beneficial effects of GLP-1 analogues on glucose metabolism by stimulating insulin release, suppressing elevated glucagon levels, delaying gastric emptying and reducing food intake, it is anticipated that liraglutide developed by Novo Nordisk (Victoza®) also has beneficial effects in type 2 diabetes mellitus as has been proven by several trials. Type 2 diabetes mellitus is associated with obesity and sedentary lifestyle. Obesity occurs when energy intake exceeds energy expenditure (EE) over a period of time. It has been presumed that activity energy expenditure and daily energy expenditure are lower in most people in Western societies. Increasing non-exercise activity thermogenesis (NEAT), defined as all energy expended due to everyday activity, exclusive of volitional exercise, may be an effective way to maintain daily EE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviors (e.g. watching television).

This leads us to hypothesize that adding NEAT to GLP-1 analogues in type 2 diabetes has an additive effect on glucose regulation, weight control and blood pressure. On the other hand, we hypothesize that a decrease in HbA1c, weight and blood pressure could add to an improved quality of life and less health care costs. Therefore, the primary purpose of this study is to determine the synergistic effect of liraglutide and activating lifestyle by increasing NEAT on glucose metabolism and weight. First line therapy of type 2 diabetes mellitus currently consists of lifestyle changes with metformin. When failure of this regime occurs, sulfonylurea derivates and/or thiazolidinediones can be added. One third of patients with type 2 diabetes mellitus fail with this regimen after 5 years of monotherapy, and nowadays GLP-1 analogues can be added to prevent deterioration of glycaemic control. However, comparison of this strategy with NEAT has not been performed and the synergistic effect of combination of GLP-1 with increasing NEAT has not been investigated. Treatment with GLP-1 analogues in combination with NEAT could theoretically overcome all shortcomings of current treatment strategies of type 2 diabetes mellitus.

Objective:

• Primary objectives

  • To determine the change in HbA1c from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks) after 26 weeks of treatment with liraglutide versus liraglutide with NEAT
  • To determine the change in weight from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks) after 26 weeks of treatment with liraglutide versus liraglutide with NEAT

• Secondary objectives

  • To assess the change in blood pressure from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks) after 26 weeks of treatment with liraglutide versus liraglutide with NEAT
  • To assess the change in quality of life from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks) after 26 weeks of treatment with liraglutide versus liraglutide with NEAT
  • To assess the change in NEAT from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks) after 26 weeks of treatment with liraglutide versus liraglutide with NEAT
  • To asses the health-care related costs at baseline, after 26 weeks of treatment with liraglutide versus liraglutide with NEAT, and after 52 weeks (end of follow-up)

Study design: Randomized controlled intervention study

- Study population: Men and women with type 2 diabetes mellitus, insufficiënt glycaemic control during maximum (tolerable) dose monotherapy with metformin or a sulfonylurea derivate or during combination therapy with metformin and a sulfonylurea derivate or a thiazolinedione, HbA1c above 7,0%, age between 40 - 75 years old, BMI above 25 kg/m2

Intervention: One group receives once daily subcutaneously liraglutide 1.8mg added to standard anti-diabetic care and the other group receives once daily subcutaneously liraglutide 1.8mg added to standard anti-diabetic care and an activating lifestyle by increasing NEAT

Main study parameters/endpoints: The main study parameter is the percent change in HbA1c and weight. Secondary study parameters are change in blood pressure, quality of life as measured using EQ-5D and SF-36 questionnaire, NEAT as measured using an activPAL™ accelerometer and cost-effectiveness analysis.

Study Overview

• Status: Terminated
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Liraglutide; Behavioral: NEAT

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6229HX
    • Maastricht University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent obtained before any study-related activities
• Men or women with type 2 diabetes mellitus
• Insufficiënt glycaemic control during maximum (tolerable) dose monotherapy with metformin or a sulfonylurea derivate or during combination therapy with metformin and a sulfonylurea derivate or a thiazolinedione
• HbA1c ≥ 7.0% at screening
• BMI ≥ 25.0 kg/m2 at screening
• Age between 40-75 years

Exclusion Criteria:

• Type 1 diabetes mellitus
• HbA1c ≥ 10% at screening
• Use of GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide or any DDP-4 inhibitor within 3 months prior to screening
• Use of insulin within 3 months prior to screening
• An acute coronary or cerebrovascular event in the previous 3 months at screening
• Chronic heart failure NYHA class IV at screening
• Estimated glomerular filtration rate (eGFR) as per Modification of Diet in Renal Disease (MDRD) < 30 ml/min/1.73m2 at screening
• Liver disease, defined as alanine or aspartate aminotransferase levels more than 2.5 the upper limit of normal range at screening
• Malignant neoplasm
• Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or family history of medullary thyroid cancer
• Chronic or acute pancreatitis
• Abuse or dependence of alcohol or drugs (as defined by DSM-IV)
• Any acute condition or exacerbation of chronic condition that would in the investigator's opinion interfere with the study
• Known or suspected hypersensitivity or intolerance to liraglutide
• Known to be uncooperative or noncompliant
• Simultaneous participation in any other clinical study of an investigational product
• Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Liraglutide; Subjects will inject liraglutide once daily for 26 weeks	Drug: Liraglutide; Liraglutide once daily 1.8 mg injection subcutaneously, 26 weeks
Active Comparator: Liraglutide and NEAT; Subjects will inject liraglutide once daily and combine this treatment with activating lifestyle, by increasing NEAT.	Behavioral: NEAT; Increasing NEAT by activating lifestyle interventions, combined with liraglutide once daily 1.8mg injections subcutaneously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in HbA1c from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks)	6 times, screening, week 0, week 13-26-39-52
Change in weight from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks)	6 times, screening, week 0, week 13-26-39-52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood pressure from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks)		6 times, screening, week 0, week 13-26-39-52
Change in quality of life from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks)	Quality of life questionnaires SF-36 en EQ-5D will be used.	3 times, week 0, 26, 52
Change in NEAT from baseline and end of treatment (26 weeks) and end of follow-up (52 weeks)	Neat will be measured using ActivPal accelerometer during one week.	3 times, week 0, 26, 52
Health-care related costs		At baseline, after 26 weeks and after 52 weeks

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Nicolaas C Schaper, Prof., MD, Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: July 9, 2012
• First Submitted That Met QC Criteria: July 10, 2012
• First Posted (Estimate): July 11, 2012

Study Record Updates

• Last Update Posted (Estimate): December 17, 2013
• Last Update Submitted That Met QC Criteria: December 16, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: glycemic control; liraglutide; NEAT
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: METC 12-2-033