Coronary Artery Disease, Type2 Diabetes
Conditions
Keywords
Epicardial Fat
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.
Interventions
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).
DRUGmatching 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).
Sponsors
Novo Nordisk A/S
University of Miami
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
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.
Intervention model description
Double-blind, parallel group, placebo controlled study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| EAT Inflammation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EAT Thickness | Baseline and up to 12 weeks | Change from baseline in EAT thickness as measured via ultrasound in mm |
| SAT Inflammation | Up to 12 weeks | SAT adipogenesis and inflammation as measured by miRNA expression (miR16-miR155-miR181a), from SAT samples collected during CABG after up to 12 weeks of treatment with either liraglutide or placebo. miRNA 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. |
| Epicardial Adipose Tissue Glucagon Like 1 Receptor (EAT-GLP-1R) | Up to 12 weeks | Gene expression of receptors or GLP-1 within EAT, expressed as cycle threshold (ct) units. The PCT Ct (cycle threshold) value refers to the number of cycles needed to replicate enough RNA to be detected |
Countries
United States
Participant flow
Recruitment details
Participants were recruited among the outpatient population who routinely referred to the University of Miami, Division of Cardiothoracic Surgery, and/or the Division and/or Division of Endocrinology, Diabetes and Metabolism outpatient clinics who required elective coronary artery bypass graft (CABG) surgery regardless of their participation in the study during COVID-19 pandemic
Participants by arm
| Arm | Count |
|---|---|
| Study Group Study group was started on liraglutide in addition to current standard treatment for diabetes and CAD for 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), or maximum tolerated dose (MTD). | 19 |
| Control Group Control group received placebo pens in addition to current treatment for a minimum of 4 weeks up to 12 weeks 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). Patients continued placebo up to the day before CABG | 19 |
| Total | 38 |
Baseline characteristics
| Characteristic | Control Group | Total | Study Group |
|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 11 | 64.5 years STANDARD_DEVIATION 9.5 | 63.7 years STANDARD_DEVIATION 7 |
| Body Mass Index (BMI) | 32.1 kg/m^2 STANDARD_DEVIATION 6.8 | 32.4 kg/m^2 STANDARD_DEVIATION 6.4 | 32.7 kg/m^2 STANDARD_DEVIATION 6.1 |
| Hemoglobin A1c (HbA1c) | 7.2 %HbA1C STANDARD_DEVIATION 1.3 | 7 %HbA1C STANDARD_DEVIATION 1.2 | 6.9 %HbA1C STANDARD_DEVIATION 1.1 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Male | 15 Participants | 30 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 6 / 19 | 2 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
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.
Time frame: Up to 12 weeks
Population: EAT fat samples could not be collected in 8 patients (5 in the liraglutide group and 3 in the placebo group) due to surgical circumstances and surgeon's decision during the CABG and in 2 patients (1 in the liraglutide and 1 in the placebo group) who eventually decided not to have surgery despite the clinical indications.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Study Group | EAT Inflammation | miR155 | 0.39 ct (cycle threshold) | Standard Deviation 0.42 |
| Study Group | EAT Inflammation | IL6 | 0.8 ct (cycle threshold) | Standard Deviation 0.16 |
| Study Group | EAT Inflammation | miR181-a | 0.32 ct (cycle threshold) | Standard Deviation 0.42 |
| Study Group | EAT Inflammation | TNF-a | 0.57 ct (cycle threshold) | Standard Deviation 0.14 |
| Study Group | EAT Inflammation | miR16 | 0.70 ct (cycle threshold) | Standard Deviation 0.6 |
| Control Group | EAT Inflammation | TNF-a | 0.12 ct (cycle threshold) | Standard Deviation 0.05 |
| Control Group | EAT Inflammation | miR16 | 1.4 ct (cycle threshold) | Standard Deviation 2.3 |
| Control Group | EAT Inflammation | miR155 | 0.25 ct (cycle threshold) | Standard Deviation 0.43 |
| Control Group | EAT Inflammation | miR181-a | 0.25 ct (cycle threshold) | Standard Deviation 0.43 |
| Control Group | EAT Inflammation | IL6 | 0.5 ct (cycle threshold) | Standard Deviation 0.14 |
Secondary
EAT Thickness
Change from baseline in EAT thickness as measured via ultrasound in mm
Time frame: Baseline and up to 12 weeks
Population: EAT thickness ultrasound measurement could not be performed after the CABG due to COVID-19 hospital restrictions
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Group | EAT Thickness | 11.8 mm | Standard Deviation 2.1 |
| Control Group | EAT Thickness | 10 mm | Standard Deviation 2 |
Secondary
Epicardial Adipose Tissue Glucagon Like 1 Receptor (EAT-GLP-1R)
Gene expression of receptors or GLP-1 within EAT, expressed as cycle threshold (ct) units. The PCT Ct (cycle threshold) value refers to the number of cycles needed to replicate enough RNA to be detected
Time frame: Up to 12 weeks
Population: Data was not collected due to due to technical difficulties and decision of the cardiac surgeon during the CABG surgery.
Secondary
SAT Inflammation
SAT adipogenesis and inflammation as measured by miRNA expression (miR16-miR155-miR181a), from SAT samples collected during CABG after up to 12 weeks of treatment with either liraglutide or placebo. miRNA 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.
Time frame: Up to 12 weeks
Population: Fat samples could not be collected in 8 patients (5 in the liraglutide group and 3 in the placebo group) due to surgical circumstances and surgeon's decision during the CABG and in 2 patients (1 in the liraglutide and 1 in the placebo group) who eventually decided not to have surgery despite the clinical indications.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Study Group | SAT Inflammation | miR16 | 0.08 ct (cycle threshold) | Standard Deviation 0.11 |
| Study Group | SAT Inflammation | miR155 | 0.06 ct (cycle threshold) | Standard Deviation 0.11 |
| Study Group | SAT Inflammation | miR181a | 0.12 ct (cycle threshold) | Standard Deviation 0.24 |
| Control Group | SAT Inflammation | miR16 | 0.17 ct (cycle threshold) | Standard Deviation 0.36 |
| Control Group | SAT Inflammation | miR155 | 0.04 ct (cycle threshold) | Standard Deviation 0.07 |
| Control Group | SAT Inflammation | miR181a | 0.07 ct (cycle threshold) | Standard Deviation 0.16 |