Liraglutide Effects on Epicardial Fat Inflammatory Genes

Effects of Liraglutide on Epicardial Fat Pro-Inflammatory Genes in Type 2 Diabetes and Coronary Artery Disease

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 4-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 4 weeks up to 12 weeks to avoid the confounding effect of weight loss on the study outcomes. EAT samples will be collected during cardiac surgery and processed for analysis of mRNA and protein expression of EAT inflammatory genes such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin 6 (IL-6), and GLP-1R.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Type2 Diabetes
• Intervention / Treatment: Drug: Liraglutide Pen Injector [Victoza]; Drug: matching liraglutide-placebo pre-filled pens

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Gianluca Iacobellis, MD PhD; Phone Number: 3052433636; Email: giacobellis@med.miami.edu

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
      • Contact: Gianluca Iacobellis, MD PhD; Phone Number: 305-243-3636; Email: giacobellis@med.miami.edu
      • Principal Investigator: Gianluca Iacobellis, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: L-group; • 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]; 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).
Placebo Comparator: D-group; 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; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EAT inflammation	EAT inflammation as measured by mRNA and protein expression of Tumor Necrosis Factor (TNF)-Alpha and Interleukin (IL)-6 from blood sample.	from a minimum of 4 weeks up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EAT thickness	EAT thickness as measured via ultrasound	from a minimum of 4 weeks up to 12 weeks
SAT inflammation	Subcutaneous Adipose Tissue (SAT) inflammation as measured by mRNA and protein expression of Tumor Necrosis Factor (TNF)-Alpha and Interleukin (IL)-6 from blood sample	from a minimum of 4 weeks up to 12 weeks
EAT GLP-1R	EAT Glucagon-like Peptide-1 Receptor (GLP-1R) mRNA and protein expression from blood sample	from a minimum of 4 weeks up to 12 weeks

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: Novo Nordisk A/S
• Investigators: Principal Investigator: Gianluca Iacobellis, MD PhD, University of Miami

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2018
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: August 22, 2017
• First Submitted That Met QC Criteria: August 22, 2017
• First Posted (Actual): August 24, 2017

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Epicardial Fat
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Diabetes Mellitus; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Glucagon-Like Peptide-1 Receptor Agonists; Liraglutide
• Other Study ID Numbers: 20170684

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