Semaglutide 2.4 mg Cardiometabolic Long-Term Effects in Patients With Obesity or Overweight in a Real-World Setting: A Retrospective Cohort Study in the United States (SMILE).

AIMS: To evaluate the real-world associations between semaglutide 2.4 mg and cardiometabolic comorbidities, biomarkers and cardiovascular risk among adults with overweight or obesity. METHODS: This retrospective cohort study used US claims data and laboratory measurements from the Komodo Research Database (2016-2024). Adults with obesity or with overweight and ≥ 1 obesity-related comorbidity were included. Patients on semaglutide 2.4 mg for ≥ 12 months were compared with non-users (including users of other obesity medications) using propensity score weighting with residual imbalances adjusted in regression model. Outcomes included time to onset of cardiometabolic comorbidities, change in cardiometabolic biomarkers and changes in 10-year ASCVD risk score at 12 months. RESULTS: 25 783 semaglutide 2.4 mg users and 8 948 913 non-users were identified. Semaglutide 2.4 mg was associated with significantly lower risks for incident prediabetes or type 2 diabetes, type 2 diabetes only, hypertension, ASCVD, heart failure and CVD (HRs 0.45-0.75; all p < 0.05), as well as greater improvements in BMI (-4.1 kg/m), SBP (-6.2 mmHg), HbA1c (-0.4%), LDL cholesterol (-7.7 mg/dL), triglycerides (-28.6 mg/dL) and HDL cholesterol (+1.9 mg/dL; all p < 0.001). At 12 months, semaglutide 2.4 mg users (N = 161) demonstrated a greater reduction in ASCVD risk score (-0.7% vs. +0.3%; between-group difference -1.0%, p < 0.001), with a decrease in the proportion at intermediate-high ASCVD risk (14.9%-9.3% vs. 17.7%-18.7%; OR 0.3 [95% CI: 0.1, 0.6], p < 0.001). CONCLUSIONS: Semaglutide 2.4 mg was associated with lower risk of multiple cardiometabolic comorbidities, favourable changes in biomarkers, and lower estimated ASCVD risk in this population.