Individuals with T2DM have a two-fold excess risk of cardiovascular (CV) events compared with their non-diabetic counterparts.

Although it is the primary cause of death in T2DM, there is no significant evidence that intensive glucose lowering reduces CV events. Multiple Cardiovascular Outcome Trials have suggested CV safety and benefit with the new class hypoglycemic agents - glucagon-like peptide 1 receptor agonists (GLP-RAs) in patients with DM and a high CV risk profile with a mechanism not directly dependent on their glucose-lowering effect. Varies theories regarding the mechanism of action of GLP-RAs on reducing CV events have been proposed, including reducing inflammation, protection of ischemia/reperfusion injury, and improvement in endothelial dysfunction but the effects of these new agents on in-vivo atherosclerotic plaque burden is currently unproven.

The investigators hypothesize that compared with placebo, 1-year treatment with the oral GLP-RA "Semaglutide" will result in a regression of necrotic core within potentially vulnerable coronary plaques (identified using the novel method "Plaque Maps" analysis on CT Coronary Angiography) in patients with raised HbA1c (>5.7%) after acute coronary syndromes (ACS).

Methods: One hundred forty patients admitted with ACS and have raised HbA1c >5.7% will be enrolled in the trial and randomized in a 1:1 blinded fashion to receive conventional therapy and initiation of Semaglutide or conventional therapy plus placebo.

All patients will have a CT Coronary Angiography with Plaque Map analysis of atherosclerotic burden, plaque composition and presence of potentially vulnerable plaque morphology at baseline prior to therapy initiation and following 12 months of treatment. In addition, to help elucidate the potential mechanisms of any anti-atherosclerotic effects, patients will have a non-invasive assessment of vascular function assessed by aortic pulse wave velocity and comprehensive biomarker analysis of inflammation, atherogenesis and oxidative stress.

Inclusion Criteria:

• HbA1c > 5.7% (39 mmol/mol)

• Patients presented with a clinical diagnosis of ACS comprising detection of a rise and/or fall of cardiac troponin (cTn) with at least one value above the 99th percentile and with at least one of the following:

  1. Symptoms of acute myocardial ischemia;
  2. New ischemic electrocardiographic (ECG) changes (ST-T wave changes or new LBBB);
  3. Development of pathological Q waves;
  4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic aetiology;
  5. Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy

Exclusion Criteria:

• Type 1 DM
• Left ventricular ejection fraction <40%
• Heart failure classified as being in New York Heart Association (NYHA) Class III-IV.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation.
• History of renal insufficiency with estimated glomerular filtration rate <30mL/min/1.73m2
• A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• History of treatment with GLP-1 within 90 days before screening
• Current use of SGLT-2 inhibitors within 30 days of screening
• Known or suspected hypersensitivity to Semaglutide or related products.
• Female who is pregnant, breastfeeding or intends to become pregnant, or is of child-bearing potential and not using a highly effective contraceptive method.
• Current enrolment in any other clinical trial within 30 days from screening