GLP-1s May Prevent Incident AF, Series of Studies Shows

CHICAGO, IL—Glucagon-like peptide-1 (GLP-1) receptor agonists may reduce the risk of incident atrial fibrillation (AF) and other cardiovascular outcomes irrespective of diabetes status and body weight, several observational studies suggest.

In four separate analyses presented last week at Heart Rhythm 2026, use of the agents—and tirzepatide (Mounjaro and Zepbound; Eli Lilly), a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors—was associated with a 33% to 47% lower relative risk of developing AF in individuals without a prior history of the arrhythmia.

The finding appeared to be consistent in patients with or without diabetes and across body mass index (BMI) categories.

Sana Al-Khatib, MD (Duke University Medical Center, Durham, NC), incoming president of the Heart Rhythm Society, stressed that these are observational studies, which are subject to confounding and selection bias and cannot be used to establish a causal relationship between GLP-1 receptor agonists and a reduction in AF risk.

“To be able to answer that question definitively, we certainly need a randomized clinical trial,” Al-Khatib commented to TCTMD.

But in the meantime, she added, “of course we have to take care of patients, and the patients are going to ask us these questions. We have to tell them what we think. And based on the collective evidence, I think there is a pretty good signal that GLP-1s are associated with a reduction in the risk of atrial fibrillation.”

Primary Prevention of AF

Previously, the observational TRANSFORM-AF study indicated that GLP-1 receptor agonist therapy may be useful for secondary prevention of AF, showing that the agents were associated with a lower risk of AF-related events over several years of follow-up in patients with active AF, obesity, and type 2 diabetes. In addition, a small trial called LEAF showed that the GLP-1 receptor agonist liraglutide, when added to risk factor modification, boosted freedom from atrial fibrillation/flutter in patients with obesity who were undergoing AF ablation in the absence of significant weight loss.

There has been limited evidence the potential impact of GLP-1s on the primary prevention of AF, and that question was tackled by several studies presented at Heart Rhythm 2026 that included a mix of patients with or without diabetes or obesity.

In a single-center retrospective cohort of 12,812 patients started on a GLP-1 receptor agonist who were propensity-matched to an equal number who were not taking one of the medications (mean age about 56 years, 68% women), the cumulative incidence of AF was lower and overall survival was greater in those treated with a GLP-1 (P < 0.001 for both).

An analysis accounting for the competing risk of death provided similar findings, which “supports a true protective association of GLP-1 therapy not explained by residual bias,” Kenneth Bilchick, MD (University of Virginia, Charlottesville), reported.

The lower incident AF risk associated with GLP-1 therapy (HR 0.67; 95% CI 0.57-0.79) was consistent across weight-change group, including among patients who gained weight during follow-up, “suggesting that the benefit is independent of weight loss,” Bilchick said.

Kevin Maymi-Quintana, MD (Boston Medical Center, MA), reported on a retrospective cohort study that used data from the TriNetX database on nondiabetic adults with obesity but without a history of atrial fibrillation/flutter.

Among 113,471 pairs of patients with and without exposure to GLP-1 therapy after propensity score matching (mean age about 50 years; 72% women), the rate of incident AF was 0.7% in the former group and 1.3% in the latter (HR 0.60; 95% CI 0.55-0.66). The finding was consistent in 30- and 90-day landmark analyses.

“These findings support a potential role of metabolic modulation in atrial fibrillation prevention,” Maymi-Quintana said.

The results were similar in another analysis of the TriNetX database focused on patients with chronic kidney disease that was presented by Ninad Khandekar, MBBS (Rochester General Hospital, NY). Among 37,768 propensity-matched pairs of patients (mean age about 67 years; 55% women), there was a much lower rate of incident AF among GLP-1 users (6.9% vs 12.4%; HR 0.59; 95% CI 0.56-0.62). There were also significantly lower risks of AF-related events (ablation, left atrial appendage occlusion, cardioversion, or pacemaker implantation), antiarrhythmic drug use, and heart failure exacerbation. Subgroup analyses showed largely consistent relationships in patients without diabetes or obesity.

Finally, a TriNetX analysis presented by Aseed Mestarihi, MD (University of Central Florida, Orlando), that included 350,241 propensity-matched pairs of nondiabetic adults with obesity (mean age 48 years; 77% women), provided similar results. The rate of incident AF through 5 years of follow-up was 1.1% in those using GLP-1 receptor agonists and 2.0% in those who were not (risk ratio 0.53; 95% CI 0.51-0.55).

There were also significantly lower risks of heart failure (risk ratio 0.61; 95% CI 0.59-0.64), stroke/systemic embolism (risk ratio 0.51; 95% CI 0.49-0.53), and ischemic heart disease (risk ratio 0.70; 95% CI 0.78-0.80) in patients using the medications.

Open Questions

Varun Sundaram, MD, PhD (University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH), who led the TRANSFORM-AF study and moderated the session focused on GLP-1s, highlighted areas that require additional research, including which doses of the medications—the lower ones for diabetes or the higher ones for weight loss—are needed to derive potential reductions in AF risk.

It’s also unclear, several speakers indicated, what mechanisms might explain a potential impact of GLP-1 receptor agonists on preventing AF if it’s more than just weight loss.

Bilchick described several possibilities, including direct cardiac effects stemming from GLP-1 receptors expressed in cardiomyocytes, gradual modification of the atrial substrate over time, improvements in glycemic control and systemic inflammation, or effects on epicardial adipose tissue.

Sundaram and others noted that randomized trials to confirm any effects of GLP-1 receptor agonists on AF will be needed to make definitive changes to practice, though there could be challenges with doing so.

Because GLP-1s are now approved for weight loss, it would be difficult to randomize a patient who qualified for treatment based on their BMI to placebo, Sundaram said.

Bilchick added that cost issues could come into play “because there are ethical issues in terms of treating people equally [and] in terms of whether they can pay or not.” He agreed, however, that “in order to move the needle, we do need more-rigorous data and then also studies that evaluate different doses on these effects.”