This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I–III (body mass index (BMI) 30.0–34.9 kg m−2, 35.0–39.9 kg m−2 and ≥40 kg m−2) and according to body weight reduction with semaglutide after 52 weeks. The gene discussed is CRP; the disease is obesity due to melanocortin 4 receptor deficiency.