Semaglutide for Metabolic Intervention and Adipose Loss to Treat Atrial Fibrillation

Inclusion Criteria:

1. Age 18-75 years

2. BMI greater than or equal to 30 kg/m2

3. Paroxysmal AF or persistent AF, in whom catheter ablation (CA) for AF is expectedwithin 1 year (A group) or in whom catheter ablation is NOT expected within 1 year (M group)

4. Ability to provide informed consent before any trial-related activities.

5. Patients with type 2 diabetes mellitus (T2DM) will be included:

6. If HbA1c (glycated hemoglobin) is less than or equal to 10 %

7. If the subject is taking basal insulin only or oral hypoglycemic agents or acombination of those.

8. Patients on SGLT2-inhibitors and TZDs (Thiazolidinedione) will be included ifthey have been on a stable dose of these medications for at least 6 months

9. The following protocol will be adopted to adjust insulin secretagogues (sulfonylureas or meglitinides) and insulin during the study (adapted from theLook Ahead Study).

Patients will be asked to check their blood glucose (BG) 4 x day (before meals and at bed time) during the dose escalation and dose stabilization phases (weeks 0 to 20) and recommendation of dose adjustments will be immediately sent to their treating physician according to the dose adjustment scale below:

• 2 blood sugars <100 mg/dl- reduce meds [insulin secretagogues (sulfonylureas ormeglitinides) and basal insulin] by 0-50 %

• 3 blood sugars 80-100 mg/dl- reduce meds [insulin secretagogues (sulfonylureas ormeglitinides) and basal insulin] by 25-75%

• 3 blood sugars <80 mg/dl > 2 x week or severe hypoglycemia or symptomatichypoglycemia- reduce meds [insulin secretagogues (sulfonylureas or meglitinides) andbasal insulin] by 50-100 %

Randomization to treatment (active and placebo) will be stratified to balance patients with T2DM across the study arms. After completion of the trial a prespecified subgroup analysis of the patients enrolled affected by T2DM will be performed.

For women of child-bearing potential, use of appropriate contraception will be required.

In patients that are prescribed amiodarone, standard care practices will be implemented to evaluate for liver and thyroid side effects with baseline liver and thyroid function tests via blood draw and evaluation every 6 months.

Exclusion Criteria:

1. Current use of GLP-1 RA (glucagon-like peptide receptor agonists) or DPP4 (Dipeptidyl peptidase-4)-inhibitors or use within the last 90 days prior toscreening

2. Current antiobesity medication use or use within the last 90 days prior to screening

3. A self-reported change in body weight of > 5 kg (11 lb.) within 30 days beforescreening

4. History of bariatric surgery

5. History of type I diabetes mellitus

6. Current use of prandial insulin

7. Hospitalization for unstable angina, or TIA (Transient ischemic attack) < 30 daysprior to screening

8. Pulmonary embolism < 90 days before screening

9. MI (myocardial infarction), stroke, etc. < 90 months prior to screening

10. Uncontrolled thyroid disease: TSH (Thyroid-stimulating hormone) > 10.0 mIU/L (Milli-international Units Per Liter) or < 0.4 mIU/L (Milli-international Units PerLiter) at screening

11. Active malignancy

12. Active enrollment in another investigational study that includes any kind ofintervention

13. The receipt of any investigational drug within 90 days prior to this trial.

14. Inability to comply with study procedures

15. Acute pancreatitis < 180 days before screening

16. History or presence of chronic pancreatitis

17. CKD (Chronic Kidney Disease) stage 4 (GFR <30 ml/min)

18. A personal or family history of medullary thyroid carcinoma (MTC) or MultipleEndocrine Neoplasia syndrome type 2 (MEN 2)

19. A prior serious hypersensitivity reaction to semaglutide or to any of the excipientsin WEGOVY

20. Chronic inflammatory conditions requiring immunosuppression and/or onglucocorticoids

21. Previous participation in this trial (received at least one dose of study drug orplacebo)

22. Pregnant, breast-feeding or planning pregnancy