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 riskfactor (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 arecardioverted within 7 days with a documented 12 lead ECG showing sinus rhythm withinthe last 12 months; early persistent AF: AF episodes lasting longer than 7 days,including episodes that are terminated by cardioversion, either with drugs or bydirect current cardioversion, after 7 days or more. Early persistent AF in this trialis defined as persistent AF with first-time electrical cardioversion (ECV) or amaximum 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 beforerandomisation
• 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 hormonalpatch) or mechanical (spirals) contraceptives
• Active malignancy, unless in complete remission for ≥5 years
• Family or personal history of multiple endocrine neoplasia type 2 (MEN2) orfamilial 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 weightgain, within the last 3 months before screening, including systemiccorticosteroids (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, andlithium)
• Diet attempts using herbal supplements or over-the-counter medications within 3months before screening
• Current participation (or within the last 3 months) in an organised weightreduction programme or currently using or used within 3 months before screening:pramlintide, sibutramine, orlistat, zonisamide, topiramate, phentermine (eitherby 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'sassessment 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 torandomization
• 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 ofmore 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 successfultreatment of thyroid dysfunction, subjects may be enrolled, when thyroid functionis controlled.
• HbA1c >6.5% measured at screening