Liraglutide Effects on Epicardial Fat Inflammatory Genes
Liraglutide Effects on Epicardial Fat Inflammatory Genes
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.
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)