Semaglutide and Panic Attacks: Active‐Comparator Disproportionality Analysis, Temporal Assessment of Notoriety Bias and Evidence Triangulation in Post‐Marketing Pharmacovigilance

PURPOSE: To evaluate how confounding by indication and notoriety bias shape the apparent semaglutide-panic attack signal in the FDA Adverse Event Reporting System (FAERS) and to interpret this signal using an evidence-triangulation framework integrating randomized and observational studies. METHODS: We conducted an active-comparator restricted disproportionality analysis of FAERS (2018Q1-2024Q4), including individual case safety reports in which semaglutide, dulaglutide or empagliflozin was the primary suspect drug. Panic attack was identified using the MedDRA preferred term. Crude and adjusted reporting odds ratios (RORs, aRORs) with 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for age, sex and indication (Type 2 diabetes, obesity/weight management). Notoriety bias was assessed using prespecified temporal analyses (analyses restricted to reports received before July 1, 2023 and a drug-by-period comparison of 2018-2022 with 2023-2024) and reporting proportions per 10 000 reports. A sensitivity analysis used all other primary-suspect drugs in FAERS as the reference set. In parallel, we conducted a systematic review (MEDLINE, Embase, CENTRAL to November 24, 2025) of randomized trials, cohort and cross-sectional studies, pharmacovigilance analyses and case reports reporting panic attacks or acute anxiety outcomes with semaglutide. RESULTS: Among 33 267 semaglutide, 54 282 dulaglutide and 25 380 empagliflozin reports, panic attacks were recorded in 87 (0.26%), 28 (0.05%) and 13 (0.05%) cases, respectively. Crude RORs were 5.08 (95% CI 3.32-7.78) versus dulaglutide and 5.12 (95% CI 2.86-9.17) versus empagliflozin, attenuating after adjustment to 2.82 (95% CI 1.74-4.56) and 2.75 (95% CI 1.41-5.36). In the pre-warning period crude RORs were 2.24 (95% CI 1.23-4.07) and 2.15 (95% CI 1.00-4.58), attenuating to 1.38 (95% CI 0.69-2.75) and 1.14 (95% CI 0.48-2.68) after adjustment. Panic-attack reports per 10 000 semaglutide reports rose from 6.7 in 2018-2022 to 42.0 in 2023-2024 (drug-by-period interaction p = 0.007). Against all other primary-suspect drugs, the aROR was 1.48 (95% CI 1.18-1.87) overall and 0.76 (95% CI 0.48-1.18) before July 1, 2023. Across 12 studies, randomized trials and active-comparator observational cohorts did not show a consistent increase in panic attacks or anxiety-related outcomes. CONCLUSIONS: Crude FAERS analyses suggested a semaglutide-panic attack signal that attenuated after adjustment was no longer significant before the July 2023 regulatory communication and rose sharply thereafter in a pattern consistent with notoriety bias. Triangulation with randomized trials and active-comparator observational studies does not support a consistent pharmacological association. Disproportionality analyses are hypothesis-generating and cannot estimate incidence or establish causality. This case study illustrates how active-comparator design, temporal assessment of notoriety bias and evidence triangulation can improve the interpretation of post-marketing safety signals.