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.

Obesity prevalence has risen sharply, making elevated BMI a leading cause of global mortality and disability. Excess adiposity drives inflammation and coronary heart disease, highlighting an urgent need for effective pharmacological interventions to achieve sustained weight loss and reduce residual cardiovascular risk.

Non-calcified plaques represent a key high-risk feature for cardiovascular events. Inflammation serves as a key mechanism in the initiation and progression of non-calcified plaques. Furthermore, pericoronary adipose tissue (PCAT) attenuation, a non-invasive imaging biomarker of inflammation, demonstrates a significant positive correlation with non-calcified plaque burden (r = 0.55, P < 0.001). Individuals with baseline PCAT attenuation ≥ -75 Hounsfield units (HU) exhibit a three-fold increased risk of non-calcified plaque progression.

GLP-1RAs could offer hypoglycemic, weight-loss, and cardiovascular protective benefits. The mechanisms underlying their cardiovascular advantages are partially understood: beyond improving lipid metabolism and reducing blood glucose, they exert vascular protective effects by inhibiting systemic inflammatory responses and modulating the secretory function of PVAT. For instance, liraglutide has been shown to improve vascular endothelial function by reducing apoB levels, while semaglutide reduces epicardial adipose tissue volume.

Animal studies show glucagon (GCG) has distinct anti-inflammatory mechanisms from GLP-1. Mazdutide, the first approved GLP-1/GCG dual receptor agonist, combines GLP-1-mediated insulin secretion and appetite suppression with GCG-driven energy expenditure. Phase III trials demonstrate robust glycemic and weight benefits, plus reduced hs-CRP and liver fat. Thus, Mazdutide may offer superior potential over GLP-1 monotherapy in mitigating coronary plaque progression and inflammation.

Therefore, we propose a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of 52 weeks of Mazdutide treatment on CCTA-assessed non-calcified plaque volume (NCPV) in patients with coronary atherosclerosis and overweight or obesity.

PET-CT substudy: A subset of eligible patients will be enrolled into a sub-study, we aim to evaluate the efficacy of Mazdutide on plaque assessed by 18NaF PET/CT.

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
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