Results from the observational TRANSFORM-AF study presented at Heart Rhythm 2025 suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may offer a new approach for secondary prevention of atrial fibrillation (AF) in patients with obesity and type 2 diabetes.
The multicenter study found that patients with active AF who initiated a GLP-1 receptor agonist had a 13% lower risk of AF-related events (HR 0.87; 95% CI 0.68-0.96) compared to those taking other diabetes medications over a median follow-up of 3.2 years.
"The whole premise of this study is that the residual risk of AF, even post-ablation, is not trivial, and it's quite significant. Almost one-third of them having recurrence within a year," explained lead investigator Varun Sundaram, MD, PhD, from University Hospitals Harrington Heart & Vascular Institute in Cleveland.
Study Design and Population
TRANSFORM-AF analyzed data from 170 Veterans Affairs medical centers across the United States. Researchers identified 2,510 patients with type 2 diabetes, a body mass index (BMI) greater than 30 kg/m², and active AF treated with anticoagulation.
The study population was predominantly male (98%) with a median age of 74 years in the GLP-1 group and 67 years in the comparator group, which received either dipeptidyl peptidase-4 (DPP-4) inhibitors or sulfonylureas. Patients in the GLP-1 group (n=1,226) had a higher burden of both cardiovascular and non-cardiovascular comorbidities compared to the control group (n=1,284).
Active AF was defined as having a hospitalization with a primary diagnosis of AF, undergoing cardioversion or ablation, or consistently using antiarrhythmic agents in the year prior to starting treatment.
Key Findings
After inverse probability of treatment weighting to balance baseline characteristics, patients on GLP-1 receptor agonists demonstrated a significantly lower risk of AF-related events, including:
- Hospitalization for AF
- Cardioversion
- Ablation
- All-cause mortality
An analysis accounting for the competing risk of mortality showed a similarly lower risk of AF-related events in the GLP-1 group (HR 0.85; 95% CI 0.61-1.03).
Notably, patients with the highest BMI (>40 kg/m²) appeared to derive the greatest benefit from GLP-1 therapy, although the interaction did not reach statistical significance.
Modest Weight Loss, Significant Benefits
Interestingly, the clinical benefits occurred despite only modest differences in weight loss between the treatment groups. Patients on GLP-1 receptor agonists achieved 14.1% weight loss compared to 10.9% in the control group (P = 0.0001).
This relatively small difference in weight reduction raises questions about potential pleiotropic effects of GLP-1 drugs beyond weight management. Dr. Sundaram noted that the medications were used at doses indicated for diabetes management rather than the higher doses typically prescribed for weight loss.
"It is possible with [higher] weight-loss doses and the newer GLP-1 analogs like tirzepatide, which [results in] profound weight loss, you could have a greater effect in the secondary prevention of atrial fibrillation," Sundaram suggested.
Clinical Implications
Heart Rhythm Society President Kenneth Ellenbogen, MD, from Virginia Commonwealth University, called the findings "really important information" and noted that GLP-1 receptor agonists could be "just one more way to decrease the risk of A-fib in the future."
"There's no question that there's a component to A-fib that's metabolic, that's related to obesity," Ellenbogen said, pointing to prior research showing that gastric bypass surgery in patients with obesity leads to significant reductions in AF incidence.
Sanjeev Saksena, MD, from Rutgers Health Robert Wood Johnson Medical School, who discussed the results after the presentation, suggested the findings could represent "a pivotal change possible in our therapy of heart rhythm disorders."
"It turns our focus to fundamental mechanisms for obesity and atrial fibrillation, something we have not done a lot of in our time," Saksena added. "The focus is now on the AF substrate and the comorbidity issues."
Study Limitations and Future Directions
The researchers acknowledged several limitations of their analysis, including its observational design, potential for unmeasured confounding, lack of data on GLP-1 receptor agonist dosing, and the predominantly male study population.
Dr. Sundaram emphasized that the findings should be considered hypothesis-generating, noting that a definitive randomized trial would face significant challenges. Such a trial would require randomizing some patients with obesity to forego GLP-1 receptor agonist treatment, raising ethical concerns, and would need long follow-up to examine the impact of modifying obesity as a risk factor.
For now, Sundaram recommends clinicians "consider managing obesity along with managing atrial fibrillation through ablations and drugs" and "consider using GLP-1 receptor agonists along with the conventional therapy for AF."
Broader Cardiovascular Benefits
The potential role of GLP-1 receptor agonists in AF management adds to the growing evidence of cardiovascular benefits associated with this drug class. Previous studies have demonstrated reductions in heart failure hospitalizations and cardiovascular death with these medications.
As research continues to elucidate the complex relationship between metabolic health and cardiac arrhythmias, GLP-1 receptor agonists may emerge as an important tool in comprehensive AF management strategies that address both the electrical and metabolic components of the disease.
