Effects of Liraglutide on Epicardial Fat Pro-Inflammatory Genes in Type 2 Diabetes and Coronary Artery Disease
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- EAT Inflammation
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
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
干预措施: Liraglutide Pen Injector [Victoza] (Drug)
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.
干预措施: matching liraglutide-placebo pre-filled pens (Drug)
结局指标
主要结局
EAT Inflammation
时间窗: Up to 12 weeks
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.
次要结局
- 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)
研究者
Gianluca Iacobellis
Professor of Clinical
University of Miami