Obesity & Overweight, Coronary Heart Disease
Conditions
Keywords
GLP-1RA, CCTA, Mazdutide, Obesity, Plaque, Overweight, Coronary Heart Disease
Brief summary
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.
Detailed description
Coronary atherosclerosis is the principal pathological substrate underlying most cardiovascular events and remains a leading cause of morbidity and mortality. Overweight and obesity are well-established independent risk factors that drive the development and progression of coronary atherosclerotic plaque, and thus represent critical modifiable targets for therapeutic intervention. Prior studies have shown that GLP-1 receptor agonists (GLP-1RAs) provide hypoglycemic, weight-loss, and cardiovascular protective benefits. 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 have demonstrated robust glycemic and weight benefits, along with reductions in hs-CRP and liver fat. Given that dual-receptor activation yields more robust metabolic improvements than single-receptor agonism, mazdutide may possess greater potential than GLP-1 monotherapy in suppressing coronary plaque progression. 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 inflammation assessed by 18F-NaF PET/CT.
Interventions
DRUGMazdutide
Mazdutide administered subcutaneously once weekly, starting at 2 mg for 4 weeks, then escalated to 4 mg for 4 weeks, and then to 6 mg thereafter until week 52.
DRUGPlacebo
Placebo administered subcutaneously once weekly, starting at 2 mg for 4 weeks, then escalated to 4 mg for 4 weeks, and then to 6 mg thereafter until week 52.
Sponsors
China National Center for Cardiovascular Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in total non-calcified plaque volume (NCPV) by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Change in RCA pericoronary fat attenuation index (RCA-FAI) by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in LAD pericoronary fat attenuation index (LAD-FAI) by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in LCX pericoronary fat attenuation index (LCX-FAI) by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in lesion pericoronary fat attenuation index (lesion-FAI) by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in total plaque volume (TPV) by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in percent atheroma volume (PAV) by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in low-attenuation plaque volumes by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in fibrous plaque volumes by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in fibrofatty plaque volumes by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in calcified plaque volumes by CCTA from baseline to 52 weeks | Baseline and 52 weeks |
| Change in total cholesterol from baseline to 52 weeks | Baseline and 52 weeks |
| Change in triglycerides from baseline to 52 weeks | Baseline and 52 weeks |
| Change in LDL-C from baseline to 52 weeks | Baseline and 52 weeks |
| Change in non-HDL-C from baseline to 52 weeks | Baseline and 52 weeks |
| Change in ApoB from baseline to 52 weeks | Baseline and 52 weeks |
| Change in HbA1c from baseline to 52 weeks | Baseline and 52 weeks |
| Changein fasting glucose from baseline to 52 weeks | Baseline and 52 weeks |
| Change in uric acid from baseline to 52 weeks | Baseline and 52 weeks |
| Change in Lp(a) from baseline to 52 weeks | Baseline and 52 weeks |
| Change in hs-CRP from baseline to 52 weeks | Baseline and 52 weeks |
| Change in IL-6 from baseline to 52 weeks | Baseline and 52 weeks |
| Change in TNF-α from baseline to 52 weeks | Baseline and 52 weeks |
| Change in body weight from baseline to 52 weeks | Baseline and 52 weeks |
| Change in waist circumference from baseline to 52 weeks | Baseline and 52 weeks |
| Change in waist-to-hip ratio from baseline to 52 weeks | Baseline and 52 weeks |
| Change in SBP from baseline to 52 weeks | Baseline and 52 weeks |
| Change in DBP from baseline to 52 weeks | Baseline and 52 weeks |
| Incidence of major adverse cardiovascular events (MACE) at 52 weeks | Baseline and 52 weeks |
Countries
China
Contacts
CONTACTXiao Wang
CONTACTFang Luo
PRINCIPAL_INVESTIGATORKe fei Dou
Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
PRINCIPAL_INVESTIGATORXiao Wang
Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
Outcome results
None listed