Glucagon-Like Peptide-1 Receptor Agonists: A New Frontier in Atrial Fibrillation Treatment
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EP LAB DIGEST. 2025;25(3):1,24-26.
Linda Moulton, RN, MS
Faculty: Order and Disorder EP Training Program, Critical Care ED/CCE Consulting, Calistoga, California
Atrial fibrillation (AF) is the most common atrial arrhythmia in adults. Patients with diabetes mellitus (DM) are at increased risk for arrhythmias, and AF is highly prevalent in DM. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have received attention for their role in weight loss for patients with AF and their possible role in reducing the incidence of AF and other cardiac disease outcomes in the type 2 diabetes (T2D) population. This second result is believed to be due in part to the reduction of the adipose fat surrounding the heart.1-4 This paper will review the characteristics of epicardial adipose tissue (EAT), the impact of EAT on AF, the action of GLP-1RAs to alter that fat, issues related to drug side effects, and the care of those receiving GLP-1RAs.
Adipose Tissue and the Heart
There are 3 types of adipose tissue around the heart: epicardial, pericardial, and paracardial. The pericardial adipose tissue is found between the visceral and parietal pericardium. Outside the parietal pericardium is the paracardial adipose tissue. The EAT is found between the myocardium and visceral layer of pericardium.
EAT and the coronary arteries have a shared circulation because there is no muscle fascia to separate them. This shared microcirculation allows a crossover of substances from vessels to tissue and vice versa, possibly creating an undesired effect in either.5 This cross talk affects myocardial mechanical properties and adipose tissue expansion, and is probably driven in part by atrial natriuretic peptide (ANP), which is secreted by the myocardium.
EAT is found in the atrioventricular (AV) and interventricular grooves.6 EAT lies on cardiomyocytes and can penetrate the tissue with fatty infiltrates.7 Fatty acid synthesis, rate of incorporation of fatty acid into EAT, and rate of fatty acid breakdown are all higher in epicardial fat.8,9 The volume of EAT is related to structural remodeling and electrical remodeling, and changes in metabolism promote these. It is a gradual process with increasing fibrosis, and is directly associated with atrial conduction, AF initiation, and AF maintenance.10,11
Measurement of EAT
EAT can be measured by various cardiac imaging techniques. Thickness can be evaluated with standard 2-dimensional echocardiography. The EAT location is usually identified as the echo-free space between the outer wall of the myocardium and visceral layer of the pericardium. EAT may also appear as an echo-dense space when inflammation or large amounts of EAT are present.6 Other imaging techniques that are useful include 3-dimensional echocardiography, cardiac multidetector computed tomography, and cardiac magnetic resonance imaging. These tools can measure fat thickness, volume, density, and inflammatory state as well as help predict and stratify risk.12,13
What Is the Relationship Between EAT and Weight?
Opinion seems to vary on this relationship. Regional, visceral, and organ-specific adiposity seem to play a stronger role in the development of cardiovascular disease than obesity alone.8,11,12,14 There is growing evidence that obesity is not always related to an unfavorable cardiometabolic profile or bad cardiovascular outcomes. It has also been suggested that there could be adaptive morphological and functional changes at play in some individuals, preventing EAT from growing in volume. Iacobellis and Sharma believe that there needs to be a redefinition of obesity based on regional fat distribution indices instead of body mass index (BMI).14
EAT, AF, and Ventricular Arrhythmias
Coronary and left atrial EAT are implicated in AF and ventricular arrhythmias. Studies have looked at the relationship between the thickness of EAT and the presence of AF. Work by Shingu et al supported the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF.15 The Framingham Heart Study found that pericardial fat was associated with AF.16 Nascimento Matos et al17 found pericardial fat volume to be a strong predictor of AF relapse after PVI.
The overproduction of catecholamines and impairment of normal autonomic regulation of the heart, caused by excess EAT, may lead to ventricular arrhythmias (VAs). Locally, EAT thickness correlates with cardiac sympathetic denervation and norepinephrine overproduction, a negative feedback effect, causing functional and anatomical denervation.18 A variety of studies have looked at the relationship between EAT and VT recurrence after ventricular tachycardia (VT) ablation. EAT was an independent predictor of post-ablation recurrence and BMI was not related to this finding.19-21 This suggests that measurement of EAT may be helpful for risk stratification prior to VT ablation and that the BMI relationship needs more study.
GLP-1RAs and the Heart
To understand the impact of GLP-1RAs on AF, one must look at the role of GLP-1 in the body. GLP-1 is a peptide hormone secreted by pancreatic islets, and it targets the GLP-1 receptors. These receptors are present in pancreatic islets (alpha, beta, and delta cells) as well as in atrial tissue.22 GLP-1 is secreted by the gut in response to food intake, and it stimulates insulin secretion in pancreatic beta cells. By triggering insulin release, it blocks glucagon secretion and prevents more glucose from entering the circulation. GLP-1 also slows stomach emptying and increases satiety. GLP-1RAs mimic these actions and reduce oxidative stress, inflammation, and autonomic nervous system modulation.1 In addition, these drugs improve myocardial metabolism when risk factors are present, and therefore, lower the incidence of AF.
GLP-1RAs were initially used in T2D for blood sugar control, but their use has expanded to weight loss. For many patients with AF, being overweight has been a factor in the inability to successfully decrease or diminish the presence of AF, so these drugs offer some hope. Other potential benefits of these drugs are lowered blood pressure, reduced risk of kidney disease, improved lipid disorders, and improvement in fatty liver disease. Recently, the United States Food and Drug Administration (FDA) approved use of some of the GLP-1RAs for cardiovascular risk reduction.
Clinical Trials for Safety and Efficacy
Many studies have reported on the use of GLP-1RA for AF reduction. Studies focused on drug safety have found that GLP-1RAs were not associated with a higher risk of arrhythmias according to 1 clinical trial, 1 Medline search, and 2 meta-analyses comparing risk for all arrhythmia types, thereby establishing the safety of GLP-1RA administration in arrhythmia patients.23-26
Whether or not these drugs are effective in the prevention of AF has been challenged in at least one study. Using the TriNetX database (2014-2023), Satti et al27 looked at the effects of GLP-1RAs on patients within 1 year before ablation for AF and compared them to those not on the drug. No significant differences were found in the need for cardioversion, new antiarrhythmic drug therapy, or redo ablation. The risk for stroke did not differ. The study concluded that preprocedural use of GLP-1RAs did not exert a protective effect.
An observational cohort study evaluated individuals with obesity and without T2D. The 2 subject groups included those new to GLP-1RAs versus those not receiving them.28 GLP-1RA treatment was associated with significantly lower risk of all-cause mortality, ischemic heart disease, HF, arrhythmias, hypertension, stroke, and AF. Huang et al believe this represented a protective effect that may offer a comprehensive approach to obesity and comorbidities.
Another study using the TriNetX database looked at the possible benefit of GLP-1 agonist use in patients with T2D undergoing AF ablation (2015-2022). Sheth et al29 found that patients taking GLP-1 agonists had a significantly reduced composite risk of postprocedural cardioversion, new antiarrhythmic drug therapy, and repeat AF ablation. At 12 months, these patients had overall lower mortality, fewer AF readmissions, and fewer HF readmissions compared to those not on the drug. There was no difference in ischemic stroke rate.
A retrospective analysis by Tabaja et al30 evaluated data from a prospective AF ablation registry (2018-2022). Use of GLP-1RA was defined as any sustained administration for longer than 6 months that started within 3 months prior to or after ablation. Sixty patients were matched 1:1 with others based on age, sex, AF type, BMI, and CHADS2 score. Freedom from arrhythmia recurrence over 1 year of follow-up was 83% for the treatment group versus 72% for the nontreatment group (P=.03). Weight reduction was considered an independent predictor for AF-free survival.
Three meta-analyses reviewing a total of 34 trials found a reduction in AF recurrence post-AF ablation with GLP-1RAs.2,31,32
GLP-1RAs Most Commonly Prescribed for the Cardiovascular Patient
The primary GLP-1RA drug being used in these trials is semaglutide injection. There are 2 GLP-1RAs on the market that are administered primarily as a subcutaneous injection. Ozempic (Novo Nordisk, Inc) is approved by the US FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2D, and to reduce the risk of major adverse cardiovascular events in adults with T2D and established cardiovascular disease.33 It is administered once a week. There is also an oral version that is taken daily. Wegovy (Novo Nordisk, Inc) is approved in combination with a reduced caloric diet and increased physical activity to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight, and reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 12 years and older with obesity as well as overweight adults with the presence of at least 1 weight-related comorbid condition.34
Side Effects
The most common side effects of GLP-1RAs include loss of appetite, nausea, vomiting, constipation, abdominal pain, and diarrhea (more likely to start at the beginning of treatment or when the dose is increased). Others include dizziness, mild tachycardia, infections, headaches, indigestion, bowel obstruction, dehydration, electrolyte abnormality, and kidney failure. Locally, there may be temporary mild itchiness or redness at injection sites.
Severe but rare side effects include pancreatitis, medullary thyroid cancer, acute kidney injury, and worsened diabetic retinopathy. Risks may include allergic reactions, hypoglycemia, and anaphylaxis. The drug is not to be used during pregnancy (contraception should be used); also, it should not be used if medullary thyroid cancer or C-cell tumors, or a family history of this, is present, or in multiple endocrine neoplasia syndrome type 2.
Patients should report the following to care providers: pancreatic or kidney problems, diabetic retinopathy, gallbladder problems, jaundice, fever, clay-colored stools, changed vision, low blood sugar, new lumps or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath.
A couple of studies have looked at additional concerns related to GLP-1RAs. A meta-analysis by Monami et al35 reviewing 113 trials found GLP-1RAs to be safe for pancreatitis but were associated with an increased risk of cholelithiasis. A surgical meta-analysis found that patients on GLP-1RAs experienced delayed gastric emptying and risk of aspiration compared to controls. Those on GLP-1RAs had an increased incidence of gastrointestinal symptoms and increased risk of residual gastric content in spite of fasting adherence preprocedure. However, GLP-1RA patients did experience improved glycemic control and a decreased rate of rescue insulin administration.36
Patient Care Issues
A couple of topics are of increased importance for those who are started on these drugs. Subcutaneous administration and injection technique may need to be taught. Administration locations include the belly, outer thigh, upper buttocks, and back of arms.
Lifestyle and dietary modifications, regular exercise, and possibly behavior modification should be started, as weight loss will be more successful as a result. If a surgical procedure is planned, fasting time should be adjusted accordingly.
Due to the popularity of these drugs, there is an ongoing shortage. The World Health Organization has warned of a rise in counterfeit versions found in the United Kingdom, Brazil, and the United States. So far, 9 reports of adverse events have been reported. These medications should only be purchased from state-licensed pharmacies.37
Azizi et al38 discussed how the demonstrated efficacy of semaglutide in reducing cardiovascular mortality is an important addition to improving the health of the population. However, drug cost is an issue, leading to a disparity in accessibility. This tends to worsen the global health equity gap for the treatment of obesity. They suggest a reduction of the price of these drugs in the United States, as occurred with some drugs in the Inflation Reduction Act of 2022.
Summary
GLP-1RAs offer the promise of weight loss plus reduced incidence of AF. This is an exciting and dynamic area of development that requires continued attention.
Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest and reports no conflicts of interest regarding the content herein.
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