The STEP-HFpEF Program, comprising the STEP-HFpEF and STEP-HFpEF DM trials, evaluated the effects of once-weekly semaglutide 2.4 mg on obesity-related heart failure with preserved ejection fraction (HFpEF) in patients with and without atrial fibrillation (AF). The study aimed to assess baseline characteristics and clinical features of patients with and without AF, and to determine if the efficacy of semaglutide across key trial outcomes was influenced by AF history. **Methods:** - **Participants:** 1,145 patients with heart failure, left ventricular ejection fraction ≥45%, BMI ≥80 kg/m², and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive semaglutide or placebo for 52 weeks. - **Endpoints:** Dual primary endpoints were change in KCCQ-CSS and body weight. Secondary endpoints included 6-minute walk distance, hierarchical composite endpoint, and C-reactive protein (CRP) changes. Exploratory endpoint was NT-proBNP change. **Results:** - **Participants:** 518 (45%) had a history of AF, with 40% paroxysmal, 24% persistent, and 35% permanent AF. - **Characteristics:** Participants with AF were older, more often male, had higher NT-proBNP levels, and more frequent use of antithrombotic therapies, beta-blockers, and diuretics. - **Efficacy:** - Semaglutide significantly improved KCCQ-CSS and the hierarchical composite endpoint in participants with AF compared to those without AF. - Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status. - Fewer serious adverse events and cardiac disorders were observed in participants treated with semaglutide. **Conclusions:** - AF was observed in nearly half of patients with obesity-related HFpEF, associated with more advanced HF features. - Semaglutide significantly improved HF-related symptoms, physical limitations, and exercise function, as well as reduced weight, CRP, and NT-proBNP in both patients with and without AF. - The magnitude of improvements was more pronounced in those with AF compared to those without AF. The study highlights a favorable benefit-risk balance for semaglutide in patients with obesity-related HFpEF, regardless of AF status, with greater benefits observed in those with AF.The STEP-HFpEF Program, comprising the STEP-HFpEF and STEP-HFpEF DM trials, evaluated the effects of once-weekly semaglutide 2.4 mg on obesity-related heart failure with preserved ejection fraction (HFpEF) in patients with and without atrial fibrillation (AF). The study aimed to assess baseline characteristics and clinical features of patients with and without AF, and to determine if the efficacy of semaglutide across key trial outcomes was influenced by AF history. **Methods:** - **Participants:** 1,145 patients with heart failure, left ventricular ejection fraction ≥45%, BMI ≥80 kg/m², and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive semaglutide or placebo for 52 weeks. - **Endpoints:** Dual primary endpoints were change in KCCQ-CSS and body weight. Secondary endpoints included 6-minute walk distance, hierarchical composite endpoint, and C-reactive protein (CRP) changes. Exploratory endpoint was NT-proBNP change. **Results:** - **Participants:** 518 (45%) had a history of AF, with 40% paroxysmal, 24% persistent, and 35% permanent AF. - **Characteristics:** Participants with AF were older, more often male, had higher NT-proBNP levels, and more frequent use of antithrombotic therapies, beta-blockers, and diuretics. - **Efficacy:** - Semaglutide significantly improved KCCQ-CSS and the hierarchical composite endpoint in participants with AF compared to those without AF. - Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status. - Fewer serious adverse events and cardiac disorders were observed in participants treated with semaglutide. **Conclusions:** - AF was observed in nearly half of patients with obesity-related HFpEF, associated with more advanced HF features. - Semaglutide significantly improved HF-related symptoms, physical limitations, and exercise function, as well as reduced weight, CRP, and NT-proBNP in both patients with and without AF. - The magnitude of improvements was more pronounced in those with AF compared to those without AF. The study highlights a favorable benefit-risk balance for semaglutide in patients with obesity-related HFpEF, regardless of AF status, with greater benefits observed in those with AF.