Effect of Oral Semaglutide on Epicardial and Pericoronary Adipose Tissues in Type 2 Diabetes After Myocardial Infarction

TITLE: Effect of Oral Semaglutide on Epicardial and Pericoronary Adipose Tissues in Type 2 Diabetic Patients After Myocardial Infarction.

OBJECTIVE: This randomized, placebo-controlled study primarily aims to demonstrate the effect of oral semaglutide on pericardial and pericoronary adipose tissues, atherosclerotic plaque, and the vascular lumen in patients with T2D after myocardial infarction through CCT and CTA analysis, with a secondary objective of analyzing anthropometric markers, cardiac markers, and insulin resistance.

MATERIAL AND METHODS: Equipment: Cardiac Computed Tomography (CCT) and Echocardiography: A standard CTA protocol using a 320 detector-row scanner (Aquillion ONE, Canon Medical Systems, Ottawa, Japan), including coronary calcium score (CCS) and CTA, will be performed. To achieve a heart rate < 65 bpm during acquisition, patients will receive oral metoprolol (50-100 mg) or intravenous metoprolol (up to 15 mg in 5 mg increments). Fast-acting sublingual nitrate (2.5-5 mg) will also be administered to all patients before scanning. After CCS acquisition, ECG-triggered CTA will be performed with 70 mL of non-ionic contrast (Iopromide 370 mg iodine/mL, Bayer Schering Pharma, Berlin, Germany), injected intravenously at 5.0 mL/s, followed by 30-40 mL of saline. The CTA parameters are as follows: collimation 0.5 mm, rotation time 400 ms, tube voltage and current 100-120 kV and 250-550 mA, adjusted to body mass index. To be performed during Visits 1 and 2:

• Coronary Computed Tomography Angiography (CTA) in the proximal segment of the right coronary artery and/or anterior descending coronary artery.
• Cardiac Markers: Troponin I, CK-MB, C-Reactive Protein, Interleukin 6.
• Metabolic Markers: Measurement of neck circumference, hepatic steatosis (Abdominal Ultrasound), Fasting Glycemia, HbA1c, Basal Insulin and HOMA-IR, Cystatin C, Total Cholesterol and Fractions, Uric Acid, TSH and Free T4.
• Anthropometric and Clinical Markers: Body Weight, Body Mass Index (BMI) = weight / height², Abdominal Waist (AW), AW/Height Ratio, Blood Pressure, and Heart Rate.

STUDY DESIGN: Prospective, placebo-controlled, double-blind, single-center randomized study with 4 phases: First phase: Screening of chronic patients who had AMI with T2D for more than 1 month and less than 6 months in the InCor database, according to inclusion criteria. The patient will be called for Visit 1 (inclusion). If the screening is successful, the patient will be fully informed about this study and will read and freely sign the Informed Consent Form (ICF). After this, a clinical consultation will be conducted, anthropometric data, blood pressure, and heart rate will be measured, and the exams of CCT, CTA, Abdominal Ultrasound, Echocardiography, and other markers described will be ordered to enter the 1st phase of the study and receive randomized oral semaglutide/placebo treatment on the day of Visit 1. Randomization: The start of randomization will be considered as day one. The other phases will be counted from the start of randomization. Phone calls during the 2nd and 3rd phases will ask the following questions: 1) Is the patient using the medication correctly? If not, the patient will be invited for an extra visit. 2) Is the patient experiencing any Adverse Events (AE)? If yes, the patient will be invited for an extra visit. 4th Phase (Visit 2): It will be asked if the patient used the medication/placebo correctly, if any AE occurred, a clinical consultation will be conducted, and the exams of CCT, CTA, Abdominal Ultrasound, Echocardiography, and other described markers will be ordered.

STATISTICAL ANALYSIS: Qualitative characteristics will be described according to the groups using absolute and relative frequencies, and the association between groups will be verified at Visit 1 using chi-square tests or exact tests. Quantitative characteristics will be described according to the groups using summary measures (mean, standard deviation, median, minimum, and maximum) and compared at baseline using Student's t-test or Mann-Whitney tests according to the probability distribution of the data. The characteristics of interest will be described according to the groups throughout the follow-up using summary measures and compared between groups and evaluation moments using generalized estimation equations with appropriate distributions and linkages, followed by Bonferroni multiple comparisons when necessary. IBM-SPSS for Windows version 22.0 software will be used for the analysis, and Microsoft Excel 2010 software will be used for data tabulation. Tests will be performed with a significance level of 5%.

Inclusion criteria

Male or female patient aged 50 years or older at the time of screening, diagnosed with type 2 diabetes and with a previous acute myocardial infarction more than 2 and less than 9 months ago, with the following conditions:

• Signed Informed Consent Form.
• BMI ≥ 25 and < 40 kg/m².
• The following glucose-lowering agents are permitted: any insulin, insulin analogs, sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, and SGLT-2 inhibitors (iSGLT2).
• Patients using iSGLT2 will not be excluded because they receive this medication at no cost at InCor with benefits for the treatment of type 2 diabetes. Furthermore, there would be an impact on ethical issues and the control of this prescription in other clinics. Thus, we will list the patients using SGLT2 inhibitors and statistically evaluate the comparison with the group that did not use this medication.

Exclusion criteria

• Patients with type 1 diabetes.
• Type 2 diabetes currently or previously treated (within 90 days prior to screening) with any GLP-1RA and DPP-4 inhibitor.
• Those not properly treated for previously diagnosed hypothyroidism.
• Diagnosed with NYHA class IV heart failure.
• Myocardial infarction more than 9 months after diagnosis.
• Any of the following: myocardial infarction, stroke, or hospitalization for unstable angina or transient ischemic attack within 60 days before screening.
• Any contraindication present in the package insert for the use of GLP1-RA or Oral Semaglutide.
• Desire to become pregnant.
• Previous history of pancreatitis (acute or chronic).
• Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.
• History of major surgical procedures involving the stomach, potentially affecting the absorption of the test product (e.g., subtotal and total gastrectomy, vertical gastrectomy, gastric bypass surgery).
• Planned and known coronary, carotid, or peripheral arterial revascularization on the day of screening.
• Chronic or intermittent hemodialysis, peritoneal dialysis, or severe renal insufficiency (corresponding to eGFR < 30 mL/min/1.73 m²) - due to CT specifications reported below.

History or presence of malignant neoplasm in the last 5 years (except basal cell and squamous cell skin cancer and carcinoma in situ).

• History of diabetic ketoacidosis.
• Participation in another clinical trial investigating a drug.
• Participation in a clinical trial specifically evaluating stent(s) will be allowed.
• Uncontrolled systemic arterial hypertension with multiple antihypertensive agents.
• Any disorder that, in the opinion of the researcher, may compromise patient safety or protocol compliance.