GLP-1 Drugs May Have Role in Secondary Prevention of AF

SAN DIEGO, CA—Glucagon-like peptide-1 (GLP-1) receptor agonists may be useful for secondary prevention of atrial fibrillation (AF) in patients with obesity and type 2 diabetes, new results from the observational TRANSFORM-AF study suggest.

Patients with active AF who initiated a GLP-1 receptor agonist had a lower risk of AF-related events over several years of follow-up compared with those taking other medications for their diabetes (HR 0.87; 95% CI 0.68-0.96), researchers reported here at Heart Rhythm 2025.

This was seen despite only modest differences in weight loss between groups, raising questions about potential pleiotropic effects of the GLP-1 drugs, which were used at doses indicated for diabetes management, said investigator Varun Sundaram, MD, PhD (University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH). “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.”

These findings should be considered hypothesis-generating, said Sundaram, but he added that conducting a definitive randomized trial to explore this question would be challenging. It would require randomizing some patients with obesity to no treatment with a GLP-1 receptor agonist, raising ethical concerns, and would require long follow-up to examine the impact of modifying obesity as a risk factor. Even if such a trial were designed, it would be difficult to prevent crossover between treatment arms.

For now, “we should consider managing obesity . . . along with managing atrial fibrillation through ablations and drugs,” Sundaram said. “Consider using GLP-1 receptor agonists along with the conventional therapy for AF.”

Heart Rhythm Society President Kenneth Ellenbogen, MD (Virginia Commonwealth University, Richmond), told TCTMD that use of these agents will be “just one more way to decrease the risk of A-fib in the future. I think this is really important information.”

He noted that prior research has shown that gastric bypass surgery in patients with obesity leads to a significant drop in the incidence of AF. It’s not clear, he added, whether that is due to weight loss, a reduction in sleep apnea, or some other mechanism.

“But there’s no question that there’s a component to A-fib that’s metabolic, that’s related to obesity,” Ellenbogen said.

He said that because GLP-1 receptor agonists have been shown to result in less AF, there use “is a clinically important thing to do for our patients,” who remain at risk for recurrent AF even after catheter ablation. Therefore, these medications could be combined with lifestyle modification, including losing weight and increasing physical activity, he suggested.

Though Ellenbogen said “we’re going to need randomized data” to convince insurance companies to pay for GLP-1 receptor agonists, he pointed out that “we have a lot of prospective data on these drugs in patients where it shows their risk of heart failure and their risk of cardiovascular death goes down.”

The TRANSFORM-AF Study

Sundaram noted that after catheter ablation for AF, there remains a residual risk of AF that increases over time, which “could possibly reflect progressive atrial substrate remodeling that persists despite initial procedural success.” One plausible reason for this remodeling could be suboptimally managed cardiometabolic risk factors like obesity, which affects up to half of patients undergoing catheter ablation for AF, he said.

GLP-1 receptor agonists have proven to be effective for weight loss but “we don’t know what the long-term outcomes are of targeting this risk factor . . . in terms of secondary prevention of atrial fibrillation,” Sundaram said.

Consider using GLP-1 receptor agonists along with the conventional therapy for AF. Varun Sundaram

TRANSFORM-AF was a pharmacoepidemiologic study involving 170 Veterans Affairs medical centers in the United States. They identified patients with type 2 diabetes, a body mass index (BMI) greater than 30 kg/m², and active AF treated with anticoagulation. Active AF was defined as having a hospitalization with a primary diagnosis of AF, undergoing cardioversion or ablation for the arrhythmia, or consistently using antiarrhythmic agents in the year prior to starting treatment with a GLP-1 receptor agonist, a dipeptidyl peptidase-4 (DPP-4) inhibitor, or a sulfonylurea.

The analysis included 1,226 patients (median age 74.0 years; 98% men) starting a GLP-1 receptor agonist and 1,284 (median age 67.0; 98% men) initiating one of the other classes of medications. Those in the former group had a higher burden of both cardiovascular and noncardiovascular comorbidities.

After inverse probability of treatment weighting to balance baseline characteristics between the two groups, patients on GLP-1 receptor agonists had a lower risk of AF-related events (hospitalization for AF, cardioversion, ablation, or all-cause mortality) compared with patients on the other diabetes medications through a median follow-up of 3.2 years.

Although the interaction wasn’t statistically significant, there appeared to be a greater advantage for the GLP-1 drugs among patients with the highest BMI (> 40 kg/m²).

An analysis that accounted 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).

Weight loss was only modestly higher with GLP-1 receptor agonists than with DPP-4 inhibitors/sulfonylureas (14.1% vs 10.9%; P = 0.0001).

A Pivotal Change?

Sundaram acknowledged the limitations of the study, including the observational design, the potential for unmeasured confounding, the lack of data on the dose of GLP-1 receptor agonists, and the fact that nearly all the participants were men (since the study used data from the Veterans Affairs system).

Nonetheless, Sanjeev Saksena, MD (Rutgers Health Robert Wood Johnson Medical School, New Brunswick, NJ), who discussed the results after Sundaram’s presentation, said, “I’m pleased to comment on this study because it is not very often that I’m at a session where I see a pivotal change possible in our therapy of heart rhythm disorders. And we may be witnessing one such moment now.”

He pointed to evidence of a link between atrial myopathy and obesity, with research indicating that left atrial dysfunction can be improved with weight loss. “So here is a piece that now connects to what we are talking about at this point,” Saksena said.

It is not very often that I’m at a session where I see a pivotal change possible in our therapy of heart rhythm disorders. Sanjeev Saksena

He noted some additional limitations of the TRANSFORM-AF analysis but also underscored its strength. “It turns our focus to fundamental mechanisms for obesity and atrial fibrillation, something we have not done a lot of in our time,” said Saksena. “The focus is now on the AF substrate and the comorbidity issues.”

Citing research showing that only a minority of patients with newly diagnosed AF undergo catheter ablation, Saksena argued that “public health demands preventative, upstream, comorbidity-focused therapy in AF” and called for future RCTs to address these questions.