Bleeding and Thromboembolic Outcomes Following GLP ‐1 Receptor Agonist Initiation in Patients With Type 2 Diabetes and Atrial Fibrillation Receiving Direct Oral Anticoagulants: A Target Trial Emulation

ABSTRACT Aims Patients with atrial fibrillation (AF) and Type 2 diabetes (T2D) require coordinated stroke prevention and metabolic risk management. Direct oral anticoagulants (DOACs) are standard for stroke prevention, while glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are increasingly used in T2D. In DOAC users, GLP‐1RA initiation may alter body weight and gastrointestinal physiology, potentially increasing DOAC exposure and thereby elevating bleeding risk. We aim to investigate the impact of GLP‐1RA initiation on risks of thromboembolic disease and bleeding in patients with T2D and AF receiving DOACs. Materials and Methods We emulated a target trial comparing GLP‐1RA versus dipeptidyl peptidase‐4 (DPP‐4) inhibitor initiation. We identified Medicare beneficiaries aged ≥ 65 years with T2D and AF receiving DOACs. Randomization was emulated using 1:1 propensity score matching. Primary outcomes include thromboembolic disease and bleeding. Per‐protocol effects were estimated using inverse‐probability‐censoring‐weighted Cox proportional hazards models. Results After matching, 930 patients were included in each group, with mean follow‐up of 1 year. Mean age was 74.7 vs. 74.2 years, and 47.1% vs. 44.2% were women in the GLP‐1RA vs. DPP‐4 inhibitor groups. GLP‐1RA initiation was associated with higher bleeding risk (HR 1.18, 95% CI: 1.03–1.36), lower all‐cause mortality (HR 0.58, 95% CI: 0.36–0.95), and similar thromboembolic risk (HR 1.50, 95% CI: 0.22–10.43). Conclusions Among DOAC‐treated patients with T2D and AF, GLP‐1RA initiation was associated with a less favourable bleeding profile but no evident increase in thromboembolic risk. These findings support careful clinical monitoring and further studies incorporating body weight and renal function to inform individualized treatment.