Semaglutide for Metabolic Intervention and Adipose Loss to Treat Atrial Fibrillation

Recruitment Status
RECRUITING
(See Contacts and Locations)Verified October 2025 by University of Chicago
Sponsor
University of Chicago
Information Provided by (Responsible Party)
University of Chicago
Clinicaltrials.gov Identifier
NCT06499857
Other Study ID Numbers:
IRB23-0889
First Submitted
April 23, 2024
First Posted
July 14, 2024
Last Update Posted
November 13, 2025
Last Verified
October 2025

ClinicalTrials.gov processed this data on November 2025. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

Obesity and atrial fibrillation (AF) pose a significant burden on healthcare systems worldwide. Obesity is an established independent risk factor for both the development of AF, as well as increased disease severity and adverse outcomes. According to a meta-analysis of 51 studies involving 60,000 individuals, every 5-unit increment in BMI confers an additional 19%-29% risk of incident AF, a 10% risk of post-operative AF, and a 13% risk of post-ablation AF. The estimated prevalence of AF in the United States is approximately 5.2 million, and is expected to increase to 12.1 million by the year 2030, likely explained by mirroring the growth of the obesity epidemic. While many associations have been made, the underlying pathophysiological mechanisms linking obesity and AF are incompletely understood.

Two large longitudinal cohort studies demonstrated that obesity contributes to disease progression to persistent or permanent forms of AF. Importantly, significant weight loss achieved by bariatric surgery has been associated with a reduction in the risk of new-onset AF by 29% in the prospective matched cohort Swedish Obese Study. Weight loss achieved with intensive lifestyle modification has also been shown to impact AF burden. However, these studies have not systematically investigated the biological mechanisms underlying weight loss and AF.

The novelty of the proposed study is that it will be the first to examine the impact of weight loss with semaglutide 2.4 mg on biological signaling and cardiac remodeling in relation to reductions in AF burden. Additionally, the proposed study will be the first to evaluate the effect of pharmacological weight loss on the risk of arrhythmia recurrence, combined with antiarrhythmic drugs (AAD) and/or catheter ablation (CA), which are the current first-line strategies for rhythm maintenance in patients with obesity. That is relevant as obesity is a chronic and relapsing health condition as demonstrated in multiple large intensive lifestyle modification studies which show a significant weight loss in the short term but minimal weight reduction in the long-term follow up. Pharmacotherapy has been shown to be superior to lifestyle modification to achieve larger and maintained weight loss.

Therefore, The investigators propose the first-ever double-blinded placebo controlled randomized clinical study to assess the efficacy and impact of an anti-obesity medication on atrial fibrillation in patients receiving contemporary therapies for atrial fibrillation.

Condition or DiseaseIntervention/Treatment
Overweight or ObesityAtrial Fibrillation
Drug: SemaglutideDrug: Placebo

Study Design

Study TypeInterventional
Actual Enrollment200 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingTriple
Primary PurposeTreatment
Official TitleSemaglutide for Metabolic Intervention and Adipose Loss to Treat Atrial Fibrillation
Study Start DateApril 13, 2025
Actual Primary Completion Date1yr 6mos from now
Actual Study Completion Date2yrs 1w from now

Groups and Cohorts

Group/CohortIntervention/Treatment
Semaglutide
Participants will have a 2 in 3 chance of receiving semaglutide (2.4 mg).
Drug: Semaglutide
3ml pen-injector containing semaglutide 3.0mg/ml solution for subcutaneous use.
Placebo
Participants will have a 1 in 3 chance of receiving placebo.
Drug: Placebo
3ml pen-injector containing placebo solution for subcutaneous use.

Outcome Measures

Primary Outcome Measures
  1. Time to first AF event detected by routine outpatient monitoring
    Defined by length of time detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
  2. Change from baseline in AF burden detected by routine outpatient monitoring.
    Defined as the percentage of time spent in atrial fibrillation as detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
Secondary Outcome Measures
  1. Weight loss
    Change in Weight (kilograms) measured.
  2. Change in waist circumference
    Change waist circumference (cm) measured.
  3. Change in epicardial and/or pericardial adipose tissue volume
    Decrease measured by Cardiovascular magnetic resonance
  4. Change in left and right ventricular size (mass)
    Change in left and right ventricular size derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
  5. Change in left and right ventricular size (volume)
    Change in left and right ventricular size derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
  6. Change in left and right ventricular function (ejection fraction)
    Change in left and right ventricular function derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
  7. Change in left ventricular strain
    Change in left ventricular strain derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
  8. Change in left ventricular diastolic parameters
    Change in left ventricular strain diastolic parameters measured by cardiovascular magnetic resonance
  9. Change in LV (left ventricular) myocardial fibrosis
    Decrease in LV (%)myocardial fibrosis burden as measured by changes in native myocardial T1 times (milliseconds) measured by Cardiovascular magnetic resonance
  10. Change in sympathetic activity and in circulating cytokines and adipokines
    Decrease in systemic inflammation as measured by the levels of circulating cytokines and adipokines such as \[CRP(C-reactive protein), TNF(Tumor necrosis factor), IL-6 (Interleukin 6), IL-1 alpha beta IL-8, IL-10, 16-18 monocyte chemoattractant protein (MCP-1), VEGF (Vascular endothelial growth factor)\] (pg/mL) and adipokines (leptin, adiponectin, resistin, and visfatin) (pg/mL).
  11. Change in Autonomic tone as determined by heart rate variability
    HRV (milliseconds) will measured from baseline to Week 68 by outpatient rhythm monitoring
  12. Changes from baseline through Week 68 of Atrial conduction times
    Estimated by simple P wave duration (milliseconds) measured by 12-lead ECG
  13. Changes in Body mass composition
    Change in Body mass composition (percentage) measured by bio-impedance
  14. Changes in Metabolic effects
    Metabolic effects measured by CMP/HgA1C (mg/dL and %)
  15. Left atrial and myocardial stress
    Change measured by Serum BNP (pg/mL), which reflects left atrial and myocardial stress
  16. Changes from baseline through Week 68 of novel Patient Reported Outcome Assessment.
    Detection of within-patient changes on impact of health on an individual's everyday life reported in a novel Patient-Reported Outcome Assessment between baseline and Week 68.

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
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 expected within 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: 1. If HbA1c (glycated hemoglobin) is less than or equal to 10 % 2. If the subject is taking basal insulin only or oral hypoglycemic agents or a combination of those. 3. Patients on SGLT2-inhibitors and TZDs (Thiazolidinedione) will be included if they have been on a stable dose of these medications for at least 6 months 4. The following protocol will be adopted to adjust insulin secretagogues (sulfonylureas or meglitinides) and insulin during the study (adapted from the Look 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 \[insulin secretagogues (sulfonylureas or meglitinides) and basal insulin\] by 0-50 %
3 blood sugars 80-100 mg/dl- reduce meds \[insulin secretagogues (sulfonylureas or meglitinides) and basal insulin\] by 25-75%
3 blood sugars \<80 mg/dl \> 2 x week or severe hypoglycemia or symptomatic hypoglycemia- reduce meds \[insulin secretagogues (sulfonylureas or meglitinides) and basal insulin\] 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 to screening 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 before screening 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 days prior 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 Per Liter) at screening 11. Active malignancy 12. Active enrollment in another investigational study that includes any kind of intervention 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 Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 19. A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in WEGOVY 20. Chronic inflammatory conditions requiring immunosuppression and/or on glucocorticoids 21. Previous participation in this trial (received at least one dose of study drug or placebo) 22. Pregnant, breast-feeding or planning pregnancy

Contacts and Locations

Sponsors and CollaboratorsUniversity of Chicago
Locations
The University of Arizona College of Medicine- Phoenix | Phoenix Arizona, United States, 85004University of Chicago | Chicago Illinois, United States, 60637
Investigators
Principal Investigator: Silvana Pannain, MD, University of Chicago