Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LIRAFLAME)

Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes: A Randomized, Placebo-controlled, Double-blind, Parallel Clinical PET/CT Trial The Liraflame Trial

The objective of this study is to evaluate the mechanism behind the anti-atherogenic effects of liraglutide.

In a randomized, placebo-controlled, double-blind, parallel trial we will included 100 patients with type 2 diabetes. Patients will be randomized 1:1 to an active treatment period of 26 weeks or placebo for 26 weeks.

The primary endpoint is change from baseline to week 26 in vascular inflammation, assessed by Flour Deoxy Glucose (FDG)-Positron Emission Tomography/Computed Tomography (PET/CT)

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Liraglutide; Drug: Placebo (for liraglutide)

Detailed Description

Despite multifactorial treatment patients with type 2 diabetes are still at high risk of cardiovascular disease. The clinical LEADER trial demonstrated a reduction in cardiovascular events in patients with type 2 diabetes treated with the GLP-1 receptor agonist liraglutide and there are a number of studies indicating that liraglutide has a positive effect on the vascular phenotype. Several of the animal or ex vivo studies suggest an anti-inflammatory mechanism behind this effect. However, no in vivo human studies have been undertaken to test this hypothesis and it would be of significance to determine the precise mechanism since atherosclerosis has large prognostic impact in patients with type 2 diabetes.

The objective of this study is to evaluate the mechanism behind the anti-atherogenic effects of liraglutide.

In a randomized, placebo-controlled, double-blind, parallel trial we will included 100 patients with type 2 diabetes. Patients will be randomized 1:1 to an active treatment period of 26 weeks or placebo for 26 weeks.

The primary endpoint is change from baseline to week 26 in vascular inflammation, assessed by Flour Deoxy Glucose (FDG)-Positron Emission Tomography/Computed Tomography (PET/CT). FDG-PET/CT is currently the only clinically available technique for specific in vivo evaluation of vascular inflammation and for quantification of the effects of medical intervention on plaque inflammation. FDG-PET of arteries has been proven very reproducible and therefore has high power to show a treatment effect in a smaller group of patients.

A number of complementary methods exist that assess different steps in the atherogenesis like endothelial function (e.g. endo-PAT, glycocalyx measurement), artery wall thickening (e.g. carotid intima media thickness), or coronary atherosclerosis (e.g. coronary artery calcium score). For comparison these other methods will be included as secondary endpoints as they are generally more accessible and less expensive.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Given written informed consent
2. Male or female patients >50 years with type 2 diabetes (WHO criteria)
3. HbA1c ≥ 48 mmol/mol (6.5 %)
4. eGFR ≥ 30 ml/min/1.73 m2 (estimated by CKD-epi formula)
5. Stable glucose-lowering medication (excluding oral glucocorticoids, calcineurin inhibitors, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon like peptide-1 agonists and other agents, which in the investigator's opinion could interfere with the effect of liraglutide)for at least 4 weeks before the baseline PET/CT
6. Stable/no treatment of hypercholesterolemia 4 weeks before baseline PET/CT
7. Must be able to communicate with the investigator and understand informed consent.

Exclusion Criteria:

1. Type 1 diabetes mellitus
2. Chronic pancreatitis / previous acute pancreatitis
3. Known or suspected hypersensitivity to trial product(s) or related products
4. Treatment 90 days prior to screening with oral glucocorticoids, calcineurin inhibitors, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon like peptide-1 agonists and other agents, which in the investigator's opinion could interfere with the effect of liraglutide
5. Cancer or any other clinically significant disorder, except for conditions associated with type 2 diabetes history, which in the investigators opinion could interfere with the results of the trial
6. Clinical signs of diabetic gastroparesis
7. Previous bowel resection
8. Impaired liver function (transaminases > two times upper reference levels)
9. Inflammatory bowel disease
10. Weight >150 kg
11. Females of childbearing potential who are pregnant, breast-feeding, intend to become pregnant or are not using adequate contraceptive methods
12. Known or suspected abuse of alcohol or narcotics
13. Subjects with personal or family history of medullary thyroid carcinoma or a personal history of multiple endocrine neoplasia type 2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Liraglutide	Drug: Liraglutide; Liraglutid
Other: placebo	Drug: Placebo (for liraglutide); Placebo (for liraglutide)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in vascular inflammation	Change in vascular inflammation assessed by FDG PET/CT	baseline to week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Endothelial dysfunction	Change in endothelial dysfunction assessed with endo-PAT	baseline to week 26
Change in Endothelial dysfunction	Change in endothelial dysfunction, assessed as sublingual glycocalyx measurement	baseline to week 13 and 26
Coronary artery calcium score	Change coronary artery calcium score (absolute values)	baseline to week 26
Carotid intima media thickness	Change in carotid intima media thickness measured by ultrasound	baseline to week 26

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Autonomic nervous system function	Change in cardiovascular autonomic neuropathy indices	baseline to week 26

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet & Cluster for Molecular Imaging, University of Copenhagen, Denmark

Publications and helpful links

General Publications

• Zobel EH, Wretlind A, Ripa RS, Rotbain Curovic V, von Scholten BJ, Suvitaival T, Hansen TW, Kjaer A, Legido-Quigley C, Rossing P. Ceramides and phospholipids are downregulated with liraglutide treatment: results from the LiraFlame randomized controlled trial. BMJ Open Diabetes Res Care. 2021 Sep;9(1):e002395. doi: 10.1136/bmjdrc-2021-002395.
• Ripa RS, Zobel EH, von Scholten BJ, Jensen JK, Binderup T, Diaz LJ, Curovic VR, Hansen TW, Rossing P, Kjaer A. Effect of Liraglutide on Arterial Inflammation Assessed as [18F]FDG Uptake in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. Circ Cardiovasc Imaging. 2021 Jul;14(7):e012174. doi: 10.1161/CIRCIMAGING.120.012174. Epub 2021 Jun 30.

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2017
• Primary Completion (Actual): August 16, 2019
• Study Completion (Actual): August 16, 2019

Study Registration Dates

• First Submitted: December 7, 2017
• First Submitted That Met QC Criteria: February 22, 2018
• First Posted (Actual): February 28, 2018

Study Record Updates

• Last Update Posted (Actual): June 11, 2020
• Last Update Submitted That Met QC Criteria: June 11, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Inflammation; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: H-16044546

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No