Cardiac and Metabolic Effects of Semaglutide in Heart Failure With Preserved Ejection Fraction

Inclusion Criteria: * BMI ≥ 30.0 kg/m2. * NYHA Class II-IV. * LVEF ≥ 50 % within the preceding year. * No hospitalizations due to heart failure in the preceding 30 days. * At least one of the following: 1. Mean PCWP ≥ 15 mmHg or left ventricular end diastolic pressure (LVEDP) ≥ 15 mmHg documented during catheterization at rest, or PCWP or LVEDP ≥ 25 mmHg documented during catheterization at exercise. 2. If BMI \< 35.0: NT-proBNP ≥ 220 pg/mL (for patients with sinus rhythm) or NT-proBNP ≥ 660 pg/mL (for patients with persistent/permanent atrial fibrillation); if BMI ≥ 35.0: NT-proBNP ≥ 125 pg/mL (for patients in sinus rhythm) or NT-proBNP ≥ 375 pg/mL (for patients with persistent/ permanent atrial fibrillation) at screening (NT-proBNP analyzed by the central laboratory) in combination with at least one of the following (documented by echocardiography within 12 months prior to or at screening): i. Septal é \< 7 cm/sec or lateral é \< 10 cm/sec or average E/é ≥ 15. ii. PA systolic pressure \> 35 mmHg. iii. Left atrial (LA) enlargement (LA width ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20.0 cm2 or LA volume ≥ 55 mL or LA volume index ≥ 29 mL/m2). iv. LV hypertrophy with septal thickness or posterior wall thickness ≥ 1.2 cm 3. Hospitalization with a primary diagnosis of decompensated heart failure which required intravenous (IV) loop diuretic treatment, within the previous 12 months in combination with at least two of the following (documented by echocardiography within 12 months prior to or at screening): i. Septal é \< 7 cm/sec or lateral é \< 10 cm/sec or average E/é ≥ 15. ii. PA systolic pressure \> 35 mmHg. iii. LA enlargement (LA width ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20.0 cm2 or LA volume ≥ 55 mL or LA volume index ≥ 29 mL/m2). iv. LV hypertrophy with septal thickness or posterior wall thickness ≥ 1.2 cm. v. Ongoing use of diuretic therapy for at least 30 days prior to screening. Exclusion Criteria: Cardiovascular-related: * Myocardial infarction, stroke, hospitalization for heart failure, unstable angina pectoris or transient ischemic attack within 30 days prior to the day of screening. * Systolic blood pressure \> 160 mmHg at screening. * Planned coronary, carotid or peripheral artery revascularization. * Any other condition judged by the investigator to be the primary cause of dyspnea (such as heart failure due to restrictive cardiomyopathy or infiltrative conditions (e.g., amyloidosis), hypertrophic obstructive cardiomyopathy, primary pulmonary arterial hypertension, chronic obstructive pulmonary disease, right heart failure due to pulmonary disease, complex congenital heart disease, anemia, or more than moderate mitral or aortic heart valve disease). * Amyloid cardiomyopathy may be present in 5-15% of patients presenting with the clinical syndrome of HFpEF,60-62 and patients with amyloid may respond differently to WL intervention. To enhance the scientific rigor of the trial by ensuring a homogenous population of true primary HFpEF, we will carefully evaluate for the presence of amyloid using the approach outlined in a recent scientific statement from the AHA,63 which is also consistent with our current clinical practice. * Specifically, potential participants will be evaluated for clues or risk factors for underlying cardiac amyloid including intolerance to antihypertensives, hypotension, orthostatic intolerance, persistent low-grade elevation in troponin, low QRS voltage on ECG, unexplained AV block or prior pacemaker, unexplained LV or RV wall thickening, impaired LV global longitudinal strain with apical sparing by echocardiography, family history of cardiomyopathy, neuropathy, autonomic dysfunction, carpal tunnel syndrome, lumbar spinal stenosis, family history of polyneuropathy, or black race. Patients with these risk factors will undergo screening evaluation for amyloid prior to consent in CAMEO-SEMA as part of best clinical practice. This includes screening for monoclonal light chain as first step, followed by hematology consultation if the screen is positive. Patients with risk factors but no monoclonal light chain will then undergo Tc-99m-PYP scan to rule out cardiac amyloid. Obesity-related: * Bariatric surgery prior to screening within 5 years of screening or planned bariatric surgery within the trial time course. * A self-reported change in body weight \> 5 kg (11 lbs) within 90 days before screening irrespective of medical records. Glycemia-related: * HbA1c ≥ 10.0% based on latest available value from medical records, not older than 3 months * History of type 1 diabetes (history of gestational diabetes is allowed). * Treatment with any GLP-1 receptor agonist within 90 days prior to the day of screening. General health and safety: * Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma. * Presence of acute pancreatitis within the last 180 days prior to screening. * History or presence of chronic pancreatitis. * End-stage renal disease or chronic or intermittent hemodialysis or peritoneal dialysis. * Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal and squamous cell cancer and any carcinoma in-situ are allowed. * Known or suspected hypersensitivity to trial product(s) or related products. * Participation in any clinical trial of an approved or non-approved device for the treatment of heart failure or obesity within 30 days before screening. * Receipt of any investigational medicinal product within 30 days before screening. * Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method. * Major surgery scheduled for the duration of the trial, affecting walking ability in the opinion of the investigator. * Any disorder, including severe psychiatric disorder, suicidal behavior within 90 days before screening, and suspected drug abuse, which in the investigator´s opinion might jeopardize subject´s safety or compliance with the protocol.