Disproportionality Analysis of Tirzepatide vs. Semaglutide and Liraglutide: System Organ Class-Level Post-Marketing Reporting Patterns in EudraVigilance.
This pharmacovigilance study compared post-marketing adverse event reporting patterns for tirzepatide (a dual GIP/GLP-1 receptor agonist) against semaglutide and liraglutide (GLP-1 receptor agonists) using aggregated Individual Case Safety Reports (ICSRs) from the EudraVigilance database. Researchers applied pairwise disproportionality analyses using reporting odds ratios (RORs) at the System Organ Class (SOC) level, with false discovery rate correction and sensitivity analyses limited to serious and healthcare professional-reported cases. The study found that, compared with semaglutide, tirzepatide was associated with higher relative reporting for immune system disorders (ROR 1.97) and hepatobiliary disorders (ROR 1.71). Compared with liraglutide, tirzepatide showed higher reporting for musculoskeletal (ROR 2.02) and psychiatric disorders (ROR 2.14), but lower reporting for neoplasms (ROR 0.28). Eight SOCs remained significant across all analytical conditions. The authors emphasize that these findings are hypothesis-generating only, as disproportionality analyses cannot establish causality, do not adjust for exposure levels, and are subject to reporting biases inherent in spontaneous pharmacovigilance databases. Confirmation in exposure-adjusted studies is recommended.
Why this grade: While the study uses real-world human safety data, it relies on a spontaneous reporting database subject to reporting bias, lacks exposure adjustment, and cannot establish causality, limiting its evidentiary strength.
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, introduces a mechanistically distinct approach within incretin-based therapies. While its efficacy is established, real-world data comparing post-marketing safety with established GLP-1 receptor agonists remain limited. This study assessed System Organ Class (SOC)-level reporting patterns for tirzepatide versus semaglutide and liraglutide using EudraVigilance data. Aggregated individual case safety reports (ICSRs) were analyzed using pairwise disproportionality analyses based on a case/non-case approach. Reporting odds ratios (RORs) with 95% confidence intervals were calculated. False discovery rate (FDR) correction using the Benjamini-Hochberg procedure and sensitivity analyses restricted to serious and healthcare professional-reported cases were performed to assess robustness. After FDR adjustment, 20 SOCs were significant in tirzepatide-semaglutide and 23 in tirzepatide-liraglutide comparisons; eight SOCs remained significant across all analytical conditions. Compared with semaglutide, tirzepatide showed higher reporting for immune (ROR 1.97, 95% CI 1.75-2.21) and hepatobiliary disorders (ROR 1.71, 95% CI 1.61-1.82). Versus liraglutide, higher odds occurred for musculoskeletal (ROR 2.02, 95% CI 1.85-2.21) and psychiatric disorders (ROR 2.14, 95% CI 1.99-2.30), and lower odds for neoplasms (ROR 0.28, 95% CI 0.26-0.31). Tirzepatide shows heterogeneous reporting patterns compared with GLP-1 receptor agonists, with consistent excess reporting for hepatobiliary, immune, and musculoskeletal disorders. These findings are hypothesis-generating and warrant confirmation in exposure-adjusted studies.
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