GLP-1s Tied to Lower Atrial Fibrillation Risk; AACE 2026 Adds Semaglutide, Tirzepatide for Prediabetes

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 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. Separately, the 2026 AACE Algorithm for Management of Adults With Type 2 Diabetes now recommends semaglutide and tirzepatide as first-line options for prediabetes when appropriate.

The AF finding appeared to be consistent in patients with or without diabetes and across body mass index (BMI) categories. The 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,” the incoming president commented. In the meantime, based on the collective evidence, “there is a pretty good signal that GLP-1s are associated with a reduction in the risk of atrial fibrillation.”

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

In a retrospective cohort study using data from the TriNetX database on nondiabetic adults with obesity but without a history of atrial fibrillation/flutter, 113,471 pairs of patients with and without exposure to GLP-1 therapy after propensity score matching (mean age about 50 years; 72% women) showed an incident AF rate of 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. Another TriNetX analysis focused on patients with chronic kidney disease included 37,768 propensity-matched pairs (mean age about 67 years; 55% women) and found 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), along with significantly lower risks of AF-related events (ablation, left atrial appendage occlusion, cardioversion, or pacemaker implantation), antiarrhythmic drug use, and heart failure exacerbation. A third TriNetX analysis that included 350,241 propensity-matched pairs of nondiabetic adults with obesity (mean age 48 years; 77% women) provided similar results.

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.

The 2026 AACE Algorithm for Management of Adults With Type 2 Diabetes builds on the 2023 version and incorporates major new evidence with an updated complications-focused framework. MASLD and MASH are now recognized as key diabetes-related complications and appear throughout the document, alongside updated obesity and dyslipidemia guidance and a new diabetes classification pathway. The update is organized into 11 linked algorithms and incorporates newer outcome trials such as SURMOUNT 2, SURMOUNT OSA, SELECT, STEP HFpEF DM, SUMMIT, FLOW, SOUL, ESSENCE, and SYNERGY NASH. The algorithm confirms that lifestyle modification remains the foundation of all therapy, including physical activity, healthy eating patterns, reduction of tobacco and alcohol use, sleep optimization, and attention to mood, diabetes distress, internalized weight bias, and hypoglycemia, all supported by appropriate monitoring with A1c, self-monitored blood glucose, and increasingly continuous glucose monitoring.

The algorithm is closely aligned with the AACE adiposity-based chronic disease (ABCD) framework, recognizing excess adiposity and adipose tissue dysfunction with lipotoxicity as central drivers of insulin resistance and broader cardiometabolic disease. Longitudinal data suggest that 5-15% weight loss is necessary to improve different ABCD components. For prediabetes, the updated algorithm defines impaired fasting glucose, impaired glucose tolerance, and A1c 5.7–6.4% as diagnostic criteria but reframes prediabetes as a cardiometabolic risk state. Weight loss remains the cornerstone of diabetes prevention, with intensive lifestyle interventions aiming for at least 7–10% weight loss. Semaglutide and tirzepatide are recommended as first-line options when appropriate because they consistently produce clinically meaningful weight loss and have demonstrated benefits for diabetes prevention, ASCVD risk, OSA, and MASH in trials such as SURMOUNT 2, SURMOUNT OSA, SELECT, and ESSENCE.