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

Eligibility Criteria

• * Age ≥ 18 years.
• * BMI ≥ 30 kg/m\^2.
• * HF diagnosed for at least 30 days before screening with New York Heart Association (NYHA) Class II-IV.
• * Managed with HF standard of care therapies.
• * Left ventricular ejection fraction (LVEF) of \> 40%.
• * Elevated NT-proBNP.
• * Participants must have at least one of the following:
• 1. Structural heart disease OR
• 2. Documented hospitalization with a primary diagnosis of decompensated HF within 12 months before randomization OR
• 3. Evidence of elevated filling pressures within 12 months before randomization.
• * History of any of the following within 60 days before 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 myocarditis, constrictive pericarditis, cardiac tamponade, arrhythmogenic right ventricular or left ventricular cardiomyopathy/dysplasia, or uncorrected primary valvular heart disease, or clinically significant congenital heart disease.
• * Any lifetime history of LVEF ≤ 40%.
• * Currently hospitalized with acute decompensated HF or hospitalization with a primary diagnosis of decompensated HF within 30 days before screening.
• * 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 at screening:
• 1. HbA1c \> 10.0%
• 2. Uncontrolled diabetes requiring immediate therapy
• 3. History of diabetic ketoacidosis or hyperosmolar state/coma
• 4. One or more episodes of severe hypoglycemia within 6 months before screening and/or history of hypoglycemia unawareness
• 5. History of proliferative diabetic retinopathy, diabetic maculopathy, or severe non-proliferative diabetic retinopathy.
• * SBP ≥ 180 mmHg , or on three or more blood pressure-lowering drugs with a SBP \> 160 mmHg.
• * History of chronic pancreatitis or acute pancreatitis in the 180 days before screening.
• * Family (or personal) history 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:
• 1. History of unstable major depressive disorder or other severe psychiatric disorder within 2 years before screening
• 2. Lifetime history of suicide attempt
• 3. History of non-suicidal self-injury within 5 years before screening.
• * History of any other condition that, in the opinion of the investigator, may preclude the participant from following the protocol and completing the study.
• * 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 study.