Maridebart Cafraglutide in Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Obesity

Inclusion Criteria

• Age ≥ 18 years at the time of informed consent.
• BMI ≥ 30.0 kg/m\^2 at randomization.
• HF diagnosed for at least 30 days with New York Heart Association (NYHA) Class II-IV at the time of informed consent.
• Managed with HF standard of care therapies.
• Left ventricular ejection fraction (LVEF) of > 40% within 12 months before randomization.

Exclusion Criteria

• History of any of the following within 60 days prior to or during screening: Type I (spontaneous) MI, valvular replacement or repair, coronary revascularization, coronary artery bypass graft surgery or other major cardiovascular surgery, stroke.
• HF due to: hypertrophic cardiomyopathy, infiltrative cardiomyopathy, active or chronic myocarditis, constrictive pericarditis, cardiac tamponade, arrhythmogenic right ventricular or left ventricular cardiomyopathy/dysplasia, uncorrected primary valvular heart disease, clinically significant congenital heart disease.
• Hospitalized with acute decompensated HF at the time of or during the screening period.
• Type 1 diabetes mellitus, or any type of diabetes with the exception of T2DM or history of gestational diabetes.
• For participants with a prior diagnosis of T2DM (including those diagnosed during screening):

• HbA1c > 10.0% (86 mmol/mol) at screening
• Uncontrolled diabetes requiring immediate therapy
• 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 or presence of either proliferative diabetic retinopathy, or diabetic maculopathy, or severe non-proliferative diabetic retinopathy; or currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema.
• SBP ≥ 180 mmHg during the screening period, or on three or more blood pressure-lowering drugs with a SBP > 160 mmHg during the screening period (including day 1 prior to randomization).
• History of chronic pancreatitis or acute pancreatitis in the 180 days before screening or during the screening period.
• Any personal lifetime history of, or family history(first-degree relative[s]) of medullary thyroid carcinoma or MEN-2.
• eGFR \< 20 mL/min/1.73 m\^2 (CKD-EPI creatinine (Cr)-cystatin C equation) or receiving dialysis at screening.
• Calcitonin ≥ 50 ng/L (pg/mL) at screening.
• Acute or chronic hepatitis.
• Any of the following psychiatric history:

• History of unstable major depressive disorder or other severe psychiatric disorder within 2 years prior to screening or during the screening period
• Lifetime history of suicide attempt
• History of non-suicidal self-injury within 5 years prior to screening or during the screening period.
• History of any other condition that, in the opinion of the investigator, may preclude the participant from following the protocol and completing the trial.
• 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 prior to or during the screening period or planned use during the conduct of the trial.