Overview

This multicenter, randomized, double-blind, placebo-controlled trial aims to evaluate the effect of mazdutide, a dual GLP-1/GCG receptor agonist, on coronary plaque progression assessed by coronary computed tomography angiography (CCTA) in patients with coronary atherosclerosis and overweight or obesity. The primary endpoint is the change in total non-calcified plaque volume (NCPV) from baseline to week 52. Secondary endpoints include changes in pericoronary adipose tissue inflammation (fat attenuation index, FAI), plaque composition, metabolic parameters, inflammatory biomarkers, and clinical outcomes. A substudy will include 18F-NaF PET/CT imaging.

Eligibility

Inclusion Criteria:

1. Age ≥ 18 years
2. BMI ≥ 28 kg/m2 or BMI≥ 24kg/m2 with at least one of the following conditions: dyslipidemia, metabolic associated fatty liver disease, hypertension, prediabetes, type 2 diabetes mellitus, or obesity-related obstructive sleep apnea syndrome (at screening or within 6 months prior to screening).
3. Coronary stenosis 30-70% confirmed by CAG or CCTA within 3 months prior to enrollment.
4. Signed informed consent
5. Willing to comply with follow-up

Exclusion Criteria:

1. History or evidence of the following :
   1. A history of severe hypoglycemia, or recurrent symptomatic hypoglycemia (≥2 episodes) within the past six months
   2. Severe heart disease as determined by the investigator, including coronary artery disease that has undergone or is planned for coronary artery bypass grafting or percutaneous coronary intervention, valvular heart disease requiring valve repair or replacement, heart transplantation, severe heart failure (NYHA III-IV) or cardiogenic shock, or a known history of left ventricular ejection fraction ≤30%
   3. A hemorrhagic/ischemic stroke or transient ischemic attack within six months prior to screening
   4. A history of acute or chronic pancreatitis, gallbladder/bile duct disease, or pancreatic injury
   5. Presence of severe diseases such as malignant tumors, lymphoma, liver cirrhosis, HIV-positive status, etc., with an expected survival of less than 2 years
   6. Contraindications to GLP-1/GCG dual receptor agonists, such as hypersensitivity or severe intolerance
   7. A personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2
2. Use of the following medications or treatments prior to screening :
   1. Use of weight-affecting medications (e.g., systemic steroids, tricyclic antidepressants, psychiatric/sedative medications, etc.) within three months prior to screening
   2. Use of GLP-1 RA or GIP/GLP-1 RA (exposure to investigational drugs) within three months prior to screening
   3. Participation in other clinical trials (exposure to investigational drugs) within three months prior to screening
   4. Known clinically significant abnormal gastric emptying or current use of medications that directly affect gastrointestinal motility
3. Laboratory test results meeting any of the following criteria at screening (repeat testing within one week is permitted if there is a clear reason, and the reason for retesting must be documented by the investigator)
   1. Serum calcitonin ≥50 ng/L (pg/mL)
   2. ALT/AST \>3.0 × ULN
   3. eGFR \<30 mL/min/1.73m²
   4. Abnormal thyroid function (TSH \>6 mIU/L or \<0.4 mIU/L)
4. Pregnancy, planned pregnancy, or breastfeeding
5. Contraindications to CCTA, including severe allergy to iodine contrast agents, presence of cardiac implantable electronic devices or other metal implants that may affect image analysis
6. Inability to complete the study or comply with study requirements as determined by the investigator Exclusion criteria for the PET-CT substudy: All exclusion criteria of the main study, as well as contraindications to PET-CT examination