Semaglutide for Metabolic Intervention and Adipose Loss to Treat Atrial Fibrillation
Overview
- Phase
- Phase 3
- Intervention
- Semaglutide
- Conditions
- Overweight or Obesity
- Sponsor
- University of Chicago
- Enrollment
- 200
- Locations
- 2
- Primary Endpoint
- Time to first AF event detected by routine outpatient monitoring
- Status
- Recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
The goal of the study is to learn how a weight loss medication called semaglutide, which is used to treat obesity, in addition to standard AF treatment might affect AF, atrial fibrillation severity, and whether it changes the risk of atrial fibrillation recurring after standard AF treatments.
Detailed 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age 18-75 years
- •BMI greater than or equal to 30 kg/m2
- •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)
- •Ability to provide informed consent before any trial-related activities.
- •Patients with type 2 diabetes mellitus (T2DM) will be included:
- •If HbA1c (glycated hemoglobin) is less than or equal to 10 %
- •If the subject is taking basal insulin only or oral hypoglycemic agents or a combination of those.
- •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
- •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:
Exclusion Criteria
- •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
- •Current antiobesity medication use or use within the last 90 days prior to screening
- •A self-reported change in body weight of \> 5 kg (11 lb.) within 30 days before screening
- •History of bariatric surgery
- •History of type I diabetes mellitus
- •Current use of prandial insulin
- •Hospitalization for unstable angina, or TIA (Transient ischemic attack) \< 30 days prior to screening
- •Pulmonary embolism \< 90 days before screening
- •MI (myocardial infarction), stroke, etc. \< 90 months prior to screening
- •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
Arms & Interventions
Semaglutide
Participants will have a 2 in 3 chance of receiving semaglutide (2.4 mg).
Intervention: Semaglutide
Placebo
Participants will have a 1 in 3 chance of receiving placebo.
Intervention: Placebo
Outcomes
Primary Outcomes
Time to first AF event detected by routine outpatient monitoring
Time Frame: Baseline to Week 68
Defined by length of time detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
Change from baseline in AF burden detected by routine outpatient monitoring.
Time Frame: Baseline to Week 68
Defined as the percentage of time spent in atrial fibrillation as detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
Secondary Outcomes
- Weight loss(Baseline to Week 68)
- Change in waist circumference(Baseline to Week 68)
- Change in epicardial and/or pericardial adipose tissue volume(Baseline to Week 68)
- Change in left and right ventricular size (mass)(Baseline to Week 68)
- Change in left and right ventricular size (volume)(Baseline to Week 68)
- Change in left and right ventricular function (ejection fraction)(Baseline to Week 68)
- Change in left ventricular strain(Baseline to Week 68)
- Change in left ventricular diastolic parameters(Baseline to Week 68)
- Change in LV (left ventricular) myocardial fibrosis(Baseline to Week 68)
- Change in sympathetic activity and in circulating cytokines and adipokines(Baseline to Week 68)
- Change in Autonomic tone as determined by heart rate variability(Baseline to Week 68)
- Changes from baseline through Week 68 of Atrial conduction times(Baseline to Week 68)
- Changes in Body mass composition(Baseline to Week 68)
- Changes in Metabolic effects(Baseline to Week 68)
- Left atrial and myocardial stress(Baseline to Week 68)
- Changes from baseline through Week 68 of novel Patient Reported Outcome Assessment.(Baseline to Week 68)