Metabolic therapy for atrial fibrillation

Atrial Fibrillation (AF) is the most common arrhythmia in the United States (US) with an estimated prevalence of 5 million and is expected to increase to 12 million by 2030. AF poses a substantial public health burden in the US with an estimated annual cost of $6 billion. AF is associated with an increased risk of stroke, heart failure,

cardiovascular mortality, and significantly impairs quality of life in most patients. Restoration and maintenance of sinus rhythm with antiarrhythmic agents and catheter ablation remains the cornerstone treatment in symptomatic AF patients. The long-term recurrence of AF with anti-arrhythmic agents remains unacceptably high and moreover, their safety profile is suboptimal as they have a narrow therapeutic

window. While catheter ablation is more effective in restoring sinus rhythm, the recurrence rates following ablation still ranges from 30% to 50% in persistent AF, often leading to a second procedure. AF is a progressive disease with many patients progressing from paroxysmal AF to persistent AF and eventually longstanding persistent AF leading to permanent AF. Whilst this observation was initially considered

to be part of the arrhythmic process, recent data suggest that the likelihood of progression to more persistent forms of AF, are determined by uncontrolled cardiometabolic risk factors including obesity, diabetes mellitus (DM), metabolic syndrome, alcohol abuse and hypertension. Recently, several studies have reported positive

impact of cardiometabolic risk factor modification with incident AF (primary prevention), but fewer studies have examined the relationship with the burden of AF in patients with pre-existing AF (secondary prevention). These findings suggest that a new paradigm for AF management (primary and secondary prevention) should

include a new pillar targeting lifestyle and cardiometabolic risk factors. There have been significant recent advances in the development of cardiometabolic drugs, which are FDA-approved to treat metabolic conditions such as obesity and DM. There is a critical need to investigate the clinical effectiveness of management of

cardiometabolic risk factors with new cardiometabolic drugs including Glucagon-Like Peptide 1 Receptor Agonists (GLP1-RA) and Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) in secondary prevention of AF. Accordingly, we aim to we perform comparative effectiveness research investigating the role of new

cardiometabolic agents including GLP-1RA, SGLT2i and repurposing potential of metformin alongside bariatric surgery in reduction of AF burden. We will be using the Veteran Affairs nationwide electronic healthcare records (VA-EHR) which provides a unique opportunity to perform CER of AF at the population level due to the availability

of long term follow data (> 600,000 AF patients with ~7-years of follow up) with minimal missingness in follow up. The results from this R21 are likely to yield substantive new insights into the role of cardiometabolic agents and bariatric surgery in the reducing the burden AF and provide hypothesis generating findings which may

eventually lead to the design of new pragmatic clinical trials in secondary prevention of AF.