Semaglutide and Liraglutide for weight loss increase psychiatric, GI, and vision risks in large cohort

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for obesity and overweight management due to their efficacy in weight loss. Despite their widespread use, the long-term safety profile of these agents in real-world clinical practice, particularly for weight management, remains a critical area of uncertainty. Current randomized controlled trials (RCTs) provide valuable data, but large-scale observational studies are essential to identify rarer or delayed adverse events in diverse patient populations, addressing a key gap in understanding GLP-1 RA safety.

This multicentre cohort study utilized electronic health records from 13 South Korean hospitals (2018-2025) to evaluate safety outcomes. Researchers compared adults initiating semaglutide or liraglutide for weight loss with propensity score-matched non-initiators in a new-user design. A total of 2357 semaglutide initiators were matched against 22,602 non-initiators, and 6953 liraglutide initiators against 68,001 non-initiators. Ten specific safety outcomes were assessed using Cox proportional hazards models to estimate site-specific hazard ratios (HRs), which were then combined via meta-analysis.

Initiation of GLP-1 RAs for weight loss was associated with increased risks across several safety outcomes, with notable heterogeneity between agents. For semaglutide, significant increases were observed for psychiatric disorders overall (HR 2.02, 95% CI 1.30-3.14), anxiety disorder (HR 2.39, 95% CI 1.22-4.71), and depressive disorder (HR 3.42, 95% CI 1.51-7.74). Gastrointestinal dysmotility or obstruction risk was also substantially elevated:

Semaglutide initiation was linked to a nearly four-fold increased risk of gastrointestinal dysmotility or obstruction (HR 3.91, 95% CI 1.42-10.82). Vision impairment risk increased by 58% (HR 1.58, 95% CI 1.04-2.41). For liraglutide, risks were elevated for psychiatric disorders overall (HR 1.66, 95% CI 1.36-2.03), anxiety disorder (HR 1.68, 95% CI 1.45-1.96), and depressive disorder (HR 1.51, 95% CI 1.14-2.00). Additionally, liraglutide was associated with increased risks of hepatic impairment (HR 1.46, 95% CI 1.16-1.83), pancreatobiliary disorder (HR 1.33, 95% CI 1.09-1.63), pancreatitis/cholangitis/cholelithiasis (HR 1.40, 95% CI 1.18-1.68), and vision impairment (HR 1.34, 95% CI 1.16-1.55). Sensitivity analyses largely supported these findings, though some specific associations (semaglutide-associated vision impairment, liraglutide-associated hepatic impairment) showed variability.