Semaglutide for the Reduction of Arrhythmia Burden in Overweight AF Patients

Inclusion Criteria: * Signed informed consent before any study-related activity * ≥ 18 years of age at the time of signing informed consent * Body mass index (BMI) ≥ 30 kg/m2 * Body mass index (BMI) ≥ 27 kg/m2 and at least 1 concomitant cardiometabolic risk factor (hypertension, dyslipidemia, or obstructive sleep apnea) * Symptomatic paroxysmal or early persistent atrial fibrillation (Paroxysmal AF: Self- terminating, in most cases within 48 hours up to 7 days. AF episodes that are cardioverted within 7 days with a documented 12 lead ECG showing sinus rhythm within the last 12 months; early persistent AF: AF episodes lasting longer than 7 days, including episodes that are terminated by cardioversion, either with drugs or by direct current cardioversion, after 7 days or more. Early persistent AF in this trial is defined as persistent AF with first-time electrical cardioversion (ECV) or a maximum of 1 previous ECVs.) Exclusion Criteria: * General exclusion criteria * Age ≥75 years * History of type 1 or 2 diabetes (history of gestational diabetes is allowed) * Known or suspected hypersensitivity to study medication or related products * Treatment with GLP-1 receptor agonists within the last 3 months before randomisation * Treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors * Alcohol/drug abuse * Pregnant or breastfeeding women * Fertile women not using chemical (tablet/pill, depot injection of progesterone, sub- dermal gestagen implantation, hormonal vaginal ring or transdermal hormonal patch) or mechanical (spirals) contraceptives * Active malignancy, unless in complete remission for ≥5 years * Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC) * Personal history of non-familial medullary thyroid carcinoma * Inflammatory bowel diseases * Acute or chronic pancreatitis * Obesity induced by other endocrinologic disorders (e.g. Cushing's Syndrome) * Current history of treatment with medications that may cause significant weight gain, within the last 3 months before screening, including systemic corticosteroids (except for a short course of treatment, i.e. 7-10 days), tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g. imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium) * Diet attempts using herbal supplements or over-the-counter medications within 3 months before screening * Current participation (or within the last 3 months) in an organised weight reduction programme or currently using or used within 3 months before screening: pramlintide, sibutramine, orlistat, zonisamide, topiramate, phentermine (either by prescription or as part of a clinical trial) * Severe chronic obstructive pulmonary disease * Uncontrolled treated/untreated hypertension (systolic \>180 mmHg and/or diastolic \>105 mmHg) * Previous or planned surgical treatment for obesity * Life expectancy \<2.5 years * Other concomitant disease or treatment that according to the investigator's assessment makes the subject unsuitable for study participation * Participation in any other clinical intervention trial * Previous participation in the SOCRATES-AF pilot study * Inability to sign informed consent * Exclusion criteria related to a cardiac condition * Previous or planned AF ablation * Previous use of continuous prophylactic class I or III antiarrhythmic drugs * Long-standing persistent or permanent AF * Overall clinical history of persistent AF ≥5 years * ECG suggestive of malignant ventricular arrhythmia * Prolonged corrected QT-interval (\>500 ms), unless caused by bundle branch block * Myocardial infarction (MI) within the last 3 months before screening * Coronary revascularization within the last 3 months before screening * Planned coronary revascularisation * Cardiac surgery within the last 12 months before screening * Obstructive hypertrophic cardiomyopathy * Clinically significant valvular heart disease * Left ventricular (LV) dysfunction (HFrEF with left ventricular ejection fraction (LVEF) \<45%) unless elicited by AF * Hospitalization due to decompensated heart disease within 30 days prior to randomization * Congestive heart failure (NYHA class IV) * Current myocardial or pericardial infection * Permanent pacemaker (PM) in use or implantable cardioverter defibrillator (ICD) * Patient cannot be prescribed non-vitamin K oral anticoagulant (NOAC) * perform physical exercise for medical or personal reasons * Exclusion criteria based on laboratory abnormalities * Liver disease with increased plasma alanine aminotransferase (ALAT) levels of more than three times the upper limit of normal * Renal dysfunction (eGFR \<30 ml/min), dialysis or kidney transplant * Clinically manifest thyroid dysfunction requiring therapy. After successful treatment of thyroid dysfunction, subjects may be enrolled, when thyroid function is controlled. * HbA1c \>6.5% measured at screening