Abstract Body (Do not enter title and authors here): Background:
GLP-1 receptor agonists (GLP-1 RAs) improve cardiovascular outcomes in patients with type 2 diabetes, but their effects in obese adults without diabetes remain unclear. Given rising GLP-1 RA use for weight management, understanding their cardiometabolic and arrhythmic impact in non-diabetic populations is critical. We evaluated cardiovascular, arrhythmia, and safety outcomes among obese, non-diabetic adults using real-world data.

Methods:
We queried the TriNetX Global Collaborative Network to identify adults (≥18 years) with obesity (ICD-10: E66) and no prior diagnosis of diabetes (E10–E13) or atrial fibrillation (AF; I48). Patients prescribed GLP-1 RAs (semaglutide, liraglutide, or dulaglutide) were propensity score–matched 1:1 to non-users based on demographics, comorbidities, and baseline labs. The index event was the first GLP-1 RA prescription, with 12-month follow-up. Outcomes included all-cause mortality, hospitalizations, myocardial infarction (MI), stroke, cardiac arrest, AF, heart failure (HF), cardiomegaly, pancreatitis, and new-onset hypertrophic cardiomyopathy (HCM). Kaplan-Meier survival curves and risk ratios (RR) were calculated.

Results:
After matching, 377,410 patients were included in each group. GLP-1 RA use was associated with a significantly lower risk of all-cause mortality (RR 0.30; HR 0.30; p<0.001), MI (HR 0.71; p<0.001), stroke (HR 0.70; p<0.001), cardiac arrest (HR 0.45; p<0.001), and hospitalization (RR 0.65; HR 0.62; p<0.001). GLP-1 users also showed lower progression to diabetes (RR 0.69; p=0.001). However, GLP-1 use was linked to increased risk of new-onset AF (HR 1.09; p=0.02), cardiomegaly (HR 1.29; p<0.001), and pancreatitis (HR 1.39; p<0.001). No significant difference was observed in incident HCM (HR 0.95; p=0.60).

Conclusion:
In this large, real-world cohort of obese, non-diabetic adults, GLP-1 RA use was associated with significant reductions in all-cause mortality, hospitalizations, and ischemic cardiovascular events. However, a modest increase in atrial fibrillation and pancreatitis was observed. These findings support the broader application of GLP-1 RAs in cardiovascular risk reduction among high-risk, non-diabetic populations. Study limitations include potential residual confounding and limited granularity regarding AF subtype and medication adherence. Prospective studies are needed to validate these observations and assess long-term safety.