Semaglutide, Liraglutide, and Tirzepatide show common and drug-specific adverse reaction signals beyond current SmPCs

The increasing use of GLP-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists for obesity treatment has raised concerns regarding their safety profiles. While these incretin-based therapies are highly effective for weight loss, a comprehensive understanding of their adverse drug reactions (ADRs) is crucial for healthcare professionals and patient safety. Current Summary of Product Characteristics (SmPCs) may not fully capture all potential ADRs, necessitating continuous pharmacovigilance to identify emerging safety signals and ensure informed clinical practice.

Researchers conducted a hierarchical pharmacovigilance analysis using the EudraVigilance (EV) database to evaluate safety data for semaglutide, liraglutide, and tirzepatide. The study integrated System Organ Class (SOC) and Preferred Term (PT) level analyses with SmPC-based evaluation. Both frequentist (ROR, 95% CI) and Bayesian (IC025) disproportionality methods were applied. Analyses were stratified by reporter type (healthcare professionals vs. non-HPs) within each molecule and across all three agents to identify reporting patterns and potential safety signals, including those not yet described in the SmPCs.

The analysis revealed several adverse drug reactions (ADRs) reported for agents whose SmPCs do not currently list them. For instance, optic ischemic neuropathy was reported for tirzepatide (0.28%) and liraglutide (0.17%). Alopecia was noted for liraglutide (0.81%), headache for tirzepatide (2.51%), and intestinal obstruction for tirzepatide (1.55%). Angioedema was reported for liraglutide (0.19%), and hypersensitivity for semaglutide (0.58%) and liraglutide (0.73%). Pancreatitis showed a significant but low-magnitude signal across all three GLP-1 RAs, with higher reporting rates from healthcare professionals compared to non-HPs.

Statistically significant signals (IC025 > 0) were observed in both healthcare professional and full datasets, highlighting drug-specific differences. For semaglutide vs. tirzepatide, signals were identified for optic ischemic neuropathy (0.17; 0.13), gallbladder disorder (0.09; 0.11), and dysesthesia (0.42; 0.43). Conversely, for tirzepatide vs. semaglutide, signals were observed for injection site erythema (0.05; 0.11), injection site pruritus (0.01; 0.11), and injection site reaction (0.02; 0.08).