Zhao, Zhenxiang

ABSTRACT 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 2 ), 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.

Introduction: Semaglutide 2.4 mg has been shown to reduce the risk and severity of cardiometabolic comorbidities (CMCs) and to improve cardiometabolic biomarkers in patients with overweight or obesity in clinical trials. However, real-world evidence in these areas is limited. Research Question: This study compared the incidence rates of CMCs and 12-month changes in biomarkers between adults with overweight/obesity with and without once-weekly subcutaneous semaglutide 2.4 mg use. Methods: A retrospective cohort study using a large U.S. claims database linked with clinical data evaluated patients with semaglutide 2.4 mg use for ≥12 months (June 2021–June 2023) and those without. For each CMC, including hypertension, T2D, dyslipidemia, HF, prediabetes, ASCVD, and CVD, patients were excluded from analysis of each individual CMC if they had claims indicating the corresponding CMC during the 12-month baseline. For each biomarker, patients were required to have the corresponding biomarker measurements at both baseline and 12-month follow-up. For each CMC and biomarker, propensity score weighting was used to balance patient characteristics between semaglutide 2.4 mg users and non-users. Time to CMCs were compared using weighted Cox proportional hazards models and biomarker changes were compared using weighted linear regression. Results: Sample sizes ranged from 14,067 to 25,490 in semaglutide 2.4 mg users and 4,271,926 to 8,578,948 in non-users across CMCs. After balancing, baseline characteristics were similar between users and non-users. Mean age ranged from 44.4 to 47.2 years among users and 44.4 to 47.4 years among non-users; 77%–83% of users and 75%–82% of non-users were women. Compared to non-users, semaglutide 2.4 mg users had significantly lower risk of incident hypertension (Hazard ratio [HR]: 0.62, 95% confidence intervals [CI]: 0.57; 0.68), T2D (HR: 0.45, 95% CI: 0.39; 0.51), HF (HR: 0.48, 95% CI: 0.38; 0.61), prediabetes (HR: 0.75, 95% CI: 0.70; 0.80), ASCVD (HR: 0.65, 95% CI: 0.58; 0.72), and CVD (HR: 0.69, 95% CI: 0.64; 0.75) (all p<0.001). The risk of dyslipidemia was similar between users and non-users (HR: 1.05, 95% CI: 1.00; 1.11, p=0.05). Semaglutide 2.4 mg use was also associated with significant improvements in cardiometabolic biomarkers specified in Table 1 and slower decline in eGFR. Conclusion: In adults with overweight/obesity, semaglutide 2.4 mg was associated with lower risk of specified CMCs and greater improvements in cardiometabolic biomarkers.