In the STEP-HFpEF Program, semaglutide 2.4 mg once weekly significantly improved heart failure-related symptoms, physical limitations, and exercise function, and reduced body weight in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), regardless of atrial fibrillation (AF) status. Among 1,145 participants, 45% had a history of AF, with 40% having paroxysmal AF, 24% persistent AF, and 35% permanent AF. Patients with AF were older, more often male, had higher NT-proBNP levels, and more frequently had NYHA functional class III symptoms. Semaglutide led to larger improvements in KCCQ-CSS (11.5 vs 4.3 points) and the hierarchical composite endpoint (win ratio 2.25 vs 1.30) in patients with AF compared to those without AF. The proportion of patients experiencing ≥5, ≥10, ≥15, and ≥20-point improvements in KCCQ-CSS was higher in those with AF. Semaglutide consistently reduced CRP, NT-proBNP, and body weight across all AF subtypes. There were fewer serious adverse events and cardiac disorders in patients treated with semaglutide compared to placebo, regardless of AF status. The study found that semaglutide had a more pronounced effect on HF-related symptoms and physical limitations in patients with AF compared to those without AF. The results suggest that semaglutide is well tolerated and offers significant benefits in patients with obesity-related HFpEF, regardless of AF status. The findings highlight the importance of considering AF in the management of obesity-related HFpEF and support the use of semaglutide as a treatment option for this population.In the STEP-HFpEF Program, semaglutide 2.4 mg once weekly significantly improved heart failure-related symptoms, physical limitations, and exercise function, and reduced body weight in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), regardless of atrial fibrillation (AF) status. Among 1,145 participants, 45% had a history of AF, with 40% having paroxysmal AF, 24% persistent AF, and 35% permanent AF. Patients with AF were older, more often male, had higher NT-proBNP levels, and more frequently had NYHA functional class III symptoms. Semaglutide led to larger improvements in KCCQ-CSS (11.5 vs 4.3 points) and the hierarchical composite endpoint (win ratio 2.25 vs 1.30) in patients with AF compared to those without AF. The proportion of patients experiencing ≥5, ≥10, ≥15, and ≥20-point improvements in KCCQ-CSS was higher in those with AF. Semaglutide consistently reduced CRP, NT-proBNP, and body weight across all AF subtypes. There were fewer serious adverse events and cardiac disorders in patients treated with semaglutide compared to placebo, regardless of AF status. The study found that semaglutide had a more pronounced effect on HF-related symptoms and physical limitations in patients with AF compared to those without AF. The results suggest that semaglutide is well tolerated and offers significant benefits in patients with obesity-related HFpEF, regardless of AF status. The findings highlight the importance of considering AF in the management of obesity-related HFpEF and support the use of semaglutide as a treatment option for this population.