GLP-1 and Microvascular Function in Type 2 Diabetes (GLP-1ADDS)

Does Glucagon-like Polypeptide 1 Improve Vascular Function and Inflammation?

Some gut hormones, called incretins, stimulate insulin production in order to control sugar levels but also activate brain centres and signal to stop eating. Current administration of incretin-based therapies mimicking these gut hormones is by subcutaneous (just under the skin) injection and has been routinely available for diabetic patients for more than 4 years. It is an effective treatment for the lowering of blood glucose with an average weight loss of about 3-4kg.Recent evidence, from animal studies and limited human studies, suggests that incretins based treatments may also have beneficial effects on blood vessel function. However, it is not known whether this effect is by direct action on the blood vessel independent of an improvement of latent inflammation which is typically associated with weight loss or an anti-inflammatory effect of the incretin treatment itself. The aim of this study is to determine whether the incretin-based diabetes treatment with the GLP-1 (Glucagon-like peptide 1) analogue Liraglutide (also known as Victoza), which mimics the actions of incretins, improves blood vessel function in individuals with type 2 diabetes. It will determine whether the improvement in blood vessel function is independent of the effect of weight loss and changes in inflammation. This by the study of vascular function before and after 4 months of Victoza treatment in subjects with Type 2 diabetes in comparison with 1) participants randomized to hypo-caloric diet to achieve a similar weight loss than with Victoza and 2) participants randomized to treatment with once daily aspirin. Comprehensive assessment of blood vessel function, body fat distribution and metabolic profile at baseline and at the end of the treatment phase will be combined with assessments of inflammation markers in blood and in fat tissue biopsies.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Liraglutide; Other: diet; Drug: Aspirin

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Exeter, United Kingdom, EX2 5DW
    • Peninsula Clinical Research Facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 diabetes and an HbA1C between 7-8.5% on a stable dose of sulphonylurea and/or metformin

Exclusion Criteria:

• use of insulin
• corticosteroids
• contraceptives, tamoxifen
• methotrexate
• DPP-IV inhibitors
• pregnancy
• lactation
• endocrine disorders
• acute MI or cerebrovascular disease
• Raynaud's disease or connective tissue disease
• current or previous history of malignancy
• subjects treated with ergotamine derivatives
• unstable blood pressure for the last 3 months
• current treatment with warfarin
• subjects on any anti-inflammatory or anti-platelet agents
• history of any bleeding disorders and GI bleeds.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Liraglutide; Liraglutide (Victoza) daily injections	Drug: Liraglutide; Administered once daily; Other Names: Victoza; GLP-1 analogue
Placebo Comparator: diet; reduction in calorie intake	Other: diet; reduction of caloric intake to promote weight loss; Other Names: caloric restriction
Placebo Comparator: Aspirin; Aspirin 300mg once daily	Drug: Aspirin; 300mg of Aspirin per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change of baseline skin maximum hyperaemia at 4 months	laser doppler fluximetry	baseline and 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change of baseline peripheral arterial tone at 4 months	ITAMAR	baseline and 4 months
change of baseline endothelial-dependent vasodilation at 4 months	iontophoresis	baseline and 4 months
change of baseline capillary density at 4 months	capillaroscopy	baseline and 4 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
change of baseline clot structure at 4 months	rigidity and elasticity of clot structure	baseline and 4 months
change of baseline adipose tissue inflammation at 4 months	adipose tissue biopsies will be analysed for gene expression and protein content of inflammatory cytokines	baseline and 4 months

Collaborators and Investigators

• Sponsor: Royal Devon and Exeter NHS Foundation Trust
• Collaborators: University of Exeter
• Investigators: Principal Investigator: Katarina Kos, MD,PhD, University of Exeter

Publications and helpful links

General Publications

• Pastel E, McCulloch LJ, Ward R, Joshi S, Gooding KM, Shore AC, Kos K. GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction. Clin Sci (Lond). 2017 Mar 1;131(5):343-353. doi: 10.1042/CS20160803. Epub 2017 Jan 3.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: November 22, 2012
• First Submitted That Met QC Criteria: December 3, 2012
• First Posted (Estimate): December 4, 2012

Study Record Updates

• Last Update Posted (Actual): February 17, 2017
• Last Update Submitted That Met QC Criteria: February 16, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: inflammation; microvascular; fat tissue; GLP-1 analogues; clot structure
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Aspirin; Liraglutide
• Other Study ID Numbers: 066; 10/H0106/29 (Other Identifier: Research Ethics Committee)