The primary objective of this trial is to demonstrate that maridebart cafraglutide is superior to placebo when given as an adjunct to standard of care with respect to reducing cardiovascular (CV) morbidity and mortality.

Inclusion Criteria

• Age ≥ 45 years at screening.

• BMI of ≥ 27.0 kg/m^2 at screening.

• History of Atherosclerotic Cardiovascular Disease (ASCVD) with a documented history of at least one of the following:

  • Prior MI (presumed atherothrombotic event due to plaque rupture/erosion).
  • Prior ischemic stroke (presumed due to atherosclerosis; may include ischemic stroke with hemorrhagic transformation).
  • Symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) < 0.9 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease.

Exclusion Criteria

• History of any of the following within 60 days before screening or between screening and randomization: MI, hospitalization for unstable angina, arterial revascularization (eg, coronary, cerebrovascular or peripheral) major cardiovascular surgery, stroke, or transient ischemic attack (TIA).

• New York Heart Association (NYHA) class IV HF during screening or hospitalization for HF within 60 days before screening or between screening and randomization.

• Type 1 DM, or any other type of diabetes with the exception of T2DM or prior gestational diabetes. Participants with a history of gestational diabetes should be stratified according to their current diabetes classification.

• For participants with T2DM (including those without a prior history of T2DM but with a HbA1c ≥ 6.5% during screening):

  • HbA1c > 10.0% (86 mmol/mol) at screening.
  • History of diabetic ketoacidosis or hyperosmolar state/coma within 12 months before randomization.
  • One or more episodes of severe hypoglycemia within 6 months before randomization and/or history of hypoglycemia unawareness.
  • History of proliferative diabetic retinopathy, diabetic maculopathy, severe non-proliferative diabetic retinopathy, or currently receiving or planning to receive treatment for diabetic retinopathy and/or diabetic macular edema.

• Use of any glucagon-like peptide-1 receptor agonist (GLP-1 RA), glucose-dependent insulinotropic polypeptide (GIP) agonists or antagonists, or amylin analogs within 90 days before randomization or planned use during the conduct of the trial.

• History of chronic pancreatitis or history of acute pancreatitis in the 180 days before screening or between screening and randomization.

• Family (first-degree relative[s]), or personal history of medullary thyroid carcinoma (MTC), or multiple endocrine neoplasia syndrome type 2 (MEN-2).

• Calcitonin ≥ 50 ng/L (pg/mL) at screening.

• Acute or chronic hepatitis; signs and symptoms of any liver disease other than metabolic dysfunction-associated steatotic liver disease, or alanine aminotransferase (ALT) > 3.0 x the upper limit of normal (ULN) during screening, or total bilirubin (TBL) > 1.8 x ULN during screening (for participants with a known diagnosis of Gilbert syndrome, direct bilirubin should be used instead of TBL).

• History of malignancy within the last 5 years before screening or between screening and randomization (except for the following treated with curative intent: non-melanoma skin cancer, breast ductal carcinoma in situ, cervical carcinoma in situ, or prostate cancer in situ).

• Participants of childbearing potential planning to become pregnant while on study or unwilling to use protocol-specified methods of contraception during treatment.

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Data sharing requests relating to this trial will be considered beginning 18 months after the trial has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe, or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this trial.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen trial/trials in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.