Liraglutide Effects on Epicardial Fat Inflammatory Genes

NCT03260881 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 20170684
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

Epicardial adipose tissue (EAT) is the visceral fat of the heart. EAT could locally affect the coronary arteries through local secretion of pro-inflammatory cytokines. EAT plays a role in the development of the coronary artery disease (CAD). EAT is a highly enriched with genes involved in inflammation. Given its rapid metabolism and simple measurability, as first developed by Iacobellis, EAT serves as target for medications targeting the fat. Glucagon-like peptide-1 agonists (GLP-1A) are anti-diabetic medications with recently suggested cardio-protective properties. Liraglutide, a GLP-1A, has recently shown to reduce the cardiovascular risk. Iacobellis'group found that EAT thickness decreased by an unprecedented 36% after 12 weeks of treatment with liraglutide. Remarkably, Iacobellis'group found for the first time that human EAT express GLP-1 Receptor (GLP-1R). GLP-1A effects may be therefore visceral fat specific and target EAT. Based on these preliminary data, we hypothesize that treatment with liraglutide will significantly and rapidly reduce EAT inflammation. Decreased EAT inflammation can reduce the burden of the coronary plaques. We will test our hypothesis in a 12-week randomized, double-blind, placebo-controlled, interventional study in 40 patients with type 2 diabetes mellitus (T2DM), and CAD, with an acceptable glycemic control on their current diabetes regimen who require elective coronary artery bypass graft (CABG) regardless of their participation in the study. A minimum time frame of 3-week treatment will be considered to detect significant changes in the study endpoints. Inclusion criteria for body fat markers will rule out the confounding effect of different body fast distribution at baseline. Study subjects will be randomized in two groups of 20 patients to receive additional liraglutide or to remain on current treatment/ placebo prior to cardiac surgery. CAD subjects not allocated to liraglutide will be started on a supervised low-calorie diet (LCD) to achieve approximately 5% of weight loss after from a minimum of 3 weeks up to 12 weeks to avoid the confounding effect of weight loss on the study outcomes. Fat samples will be collected during cardiac surgery after up to 12 weeks of treatment either with liraglutide or placebo and processed for analysis of mRNA and protein expression of EAT and SAT inflammatory genes such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin 6 (IL-6), and GLP-1R.

Conditions

Type2 Diabetes; Coronary Artery Disease

Keywords

Epicardial Fat

Outcome Measures

Primary Outcomes (1)

• EAT Inflammation

  EAT adipogenesis and inflammation as measured by miRNA expression (miR16-miR155-miR181a), from peri-coronary EAT samples collected during CABG after up to 12 weeks of treatment with either liraglutide or placebo. Tumor Necrosis Factor (TNF)-Alpha and Interleukin (IL)-6 gene expression were also measured in a subsample of peri-coronary EAT samples. miRNA and gene expression will be expressed as cycle threshold (ct) units. The PCR ct (cycle threshold) value refers to the number of cycles needed to replicate enough RNA to be detected.

  Up to 12 weeks

Secondary Outcomes (3)

• EAT Thickness

  Baseline and up to 12 weeks

• SAT Inflammation

  Up to 12 weeks

• Epicardial Adipose Tissue Glucagon Like 1 Receptor (EAT-GLP-1R)

  Up to 12 weeks

Study Arms (2)

L-group

ACTIVE COMPARATOR

• L-group will be started on liraglutide. Liraglutide will be started and administered for from a minimum of 4 weeks up to 12 weeks prior to CABG with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). The dose of 1.8 mg daily will be maintained until the end of the 12-week study. Other and current diabetes treatment will be continued

Drug: Liraglutide Pen Injector [Victoza]

D-group

PLACEBO COMPARATOR

placebo will be administered in addition to current treatment prior to the CABG with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). D-group will be started on a supervised low calorie diet (LCD) to achieve approximately 5% of weight loss after from a minimum of 4 weeks up to 12 weeks.

Drug: matching liraglutide-placebo pre-filled pens

Interventions

Liraglutide Pen Injector [Victoza] DRUG

Study subjects will be randomized in two groups of 20 patients to receive additional liraglutide, (L-group) or to remain on current treatment or placebo (D-group).

L-group

matching liraglutide-placebo pre-filled pens DRUG

Study subjects will be randomized in two groups of 20 patients to receive additional liraglutide, (L-group) or to remain on current treatment or placebo (D-group).

D-group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• T2DM as defined by American Diabetes Association (ADA) criteria
• Adult patients with T2DM who are indicated to receive liraglutide, not as first-line therapy, in addition to diet and exercise to improve glycemic control
• Hemoglobin A1c (HbA1c) ≤ 9%
• Age ≥ 18 years old
• Body mass index (BMI) ≥ 27 Kg/m2 and/or waist circumference ≥ 102 cm (40 inches) in men and 88 cm (35 inches) in women, respectively.
• Clinically and angiographically stable CAD who requires CABG as part of the standard medical care, as CAD does not represent a contraindication for using liraglutide. The stability of the CAD further warranties that study patients will not be exposed to higher risk by using liraglutide

You may not qualify if:

• Patients with a personal or family history of medullary thyroid carcinoma or patients with Multiple Endocrine Neoplasia syndrome type 2
• Patients with a prior serious hypersensitivity reaction to liraglutide
• Other contra-indications to liraglutide in accordance with risks and safety information included in the latest updated prescribing information
• Type 1 diabetes, as defined by ADA criteria
• Current use of other GLP-1A, dipeptidyl peptidase 4 (DPP4) or Sodium Glucose transporters 2 (SGLT2) inhibitors, thiazolidinediones (TZDs), pramlintide and fixed prandial insulin.
• Patients with unstable CAD, assessed by the Cardiology team and defined as new onset angina, rest angina, rapidly increasing or crescendo angina
• History of diabetic ketoacidosis, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy; acute or chronic infective diseases, cancer or chemotherapy, history of pulmonary, renal or liver diseases, and drug abuse
• Patients with chronic and acute inflammatory conditions such as sepsis, rheumatoid arthritis, ectopic dermatitis, asthma, ulcerative colitis.
• Current use of systemic corticosteroids in the 3 months prior this study.
• Pregnant or breast-feeding women
• Females of childbearing potential who are not using adequate contraceptive methods (as required by local law or practice)

Sponsors & Collaborators

• University of Miami: lead
• Novo Nordisk A/S: collaborator

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

Location

MeSH Terms

Conditions

Coronary Artery Disease

Interventions

Liraglutide

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and Caveats

Overall, the study was greatly affected by the COVID-19 pandemic. Enrollment, clinical assessment, surgery schedule, fat sample collection were all impacted by COVID-19. Fat samples could not be collected or analyzed in all patients due to COVID-19 restrictions and surgical decisions during the standard of care CABG. Ultrasound EAT thickness could not be measured after the CABG due to COVID-9 restrictions.

Results Point of Contact

• Title: Dr Gianluca Iacobellis MD PhD Professor of Medicine
• Organization: University of Miami Miller School of Medicine

giacobellis@med.miami.edu

3052433636

Study Officials

• Gianluca Iacobellis, MD PhD

  University of Miami

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This will be a double-blind, parallel group, placebo controlled study. The method of allocation generation will be a computerized random-number generator. The sequence will be generated by the process of restricted randomization. Computer-based randomization process will be managed by the UM Research pharmacy.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Clinical

Model Details: Double-blind, parallel group, placebo controlled study.

Study Record Dates

• First Submitted: August 22, 2017
• First Posted: August 24, 2017
• Study Start: September 1, 2018
• Primary Completion: September 5, 2024
• Study Completion: September 5, 2024
• Last Updated: July 8, 2025
• Results First Posted: July 8, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)