A propensity score-matched analysis of electronic health records from 13 South Korean hospitals (2018–2025) covering over 100,000 patients reveals that GLP-1 receptor agonists prescribed for weight loss carry meaningful safety signals beyond their well-known gastrointestinal side effects. Semaglutide initiators (n=2,357) showed a 3.42-fold increased risk of depressive disorder (HR 3.42, 95% CI 1.51–7.74), 2.39-fold elevated anxiety risk, 3.91-fold higher gastrointestinal dysmotility or obstruction risk, and a 1.58-fold increased vision impairment risk. Liraglutide initiators (n=6,953) demonstrated more moderate but still significant elevations across psychiatric outcomes, plus hepatic impairment (HR 1.46) and pancreatobiliary disorders (HR 1.33–1.40).
These findings arrive at a critical moment. GLP-1 agonists have been fast-tracked into mainstream obesity treatment with a narrative emphasizing cardiovascular and metabolic benefits. The psychiatric signal — particularly depression and anxiety — is the most clinically urgent finding here, as it partially contradicts early mechanistic hypotheses that GLP-1 receptor activity in reward circuitry might be protective against mood disorders. The effect sizes are large enough to be clinically meaningful, not merely statistical noise. Limitations are significant: this is an observational Korean cohort with potential residual confounding, the semaglutide group is relatively small, and indication bias (prescribing to higher-risk individuals) cannot be fully eliminated despite matching. Still, the consistency across agents and multiple sensitivity analyses elevates this from preliminary signal to a finding demanding active pharmacovigilance, mandatory psychiatric screening, and cautious patient selection in clinical practice.
