This is a Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial evaluating the safety and efficacy of once-weekly semaglutide 2.4 mg in adult patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) who meet current clinical criteria for semaglutide treatment. A total of 826 participants will be randomized 1:1 to receive semaglutide or placebo as an add-on to standard-of-care, starting 3 months before TAVR and continuing for 24 months post-procedure. The primary endpoint is time to first occurrence of a composite of cardiovascular (CV) death, non-fatal myocardial infarction, non-fatal stroke or transient ischemic accident (TIA), and hospitalization for heart failure (HF). The study is event-driven and powered to detect a 20% relative risk reduction in primary outcome events. This trial aims to address the unmet need for medical therapies that improve outcomes in patients with severe AS following TAVR, with potential for direct clinical implementation.

Inclusion Criteria: Subjects are eligible to be included in the trial only if all of the following criteria apply:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
• Adults (≥18 years) undergoing TAVR for severe AS, and
• BMI ≥30 kg/m2, or
• BMI 27-30 kg/m2, AND at least one of the following:
• Dysglycemia (prediabetes or type 2 diabetes) ≥90 days prior to the day of screening with HbA1c of ≤ 10.0% as measured at the screening visit.
• Arterial Hypertension
• Hypercholesterolemia
• Obstructive sleep apnea
• History of stroke (ischemic or hemorrhagic)
• History of myocardial infarction
• Symptomatic peripheral artery disease (intermittent claudication with ankle-brachial index <0.85, peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease)

Exclusion Criteria:

• Treatment with an GLP-1 receptor agonist within the previous 90 days.
• Myocardial infarction, stroke, hospitalization for unstable angina or transient ischemic attack within the previous 60 days.
• Planned coronary, carotid or peripheral artery revascularization known on the day of screening.
• eGFR <25 mL/min/1.73 m² or intermittent hemodialysis or peritoneal dialysis.
• Presence of acute pancreatitis within the last 180 days prior to screening.
• History or presence of chronic pancreatitis.
• Self-reported change in body weight of >5 kg within 90 days before screening.
• Bariatric surgery prior to screening or planned bariatric surgery within the trial time course.
• 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 aortic stenosis 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.

This is a double-blind study. Participants, care providers, investigators, and outcome assessors will be blinded to treatment allocation. Semaglutide and placebo will be identical in appearance and administered in the same manner.