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Peer-reviewedCC BY 4.0Pharmacoepidemiology and Drug Safety

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

  • Ben Melamed1
  • Mahak Parsi‐Zahabi1
  • Mohammad Ali Omrani1
  • Bala Swetha Baskaran1
  • Lujain Ez Eddin1
  • Nazgol Kermanshahi1
  • Niaz Chalabianloo1
  • Flory Tsobo Muanda1,2,3,4
4 affiliations
  1. 1Department of Physiology and Pharmacology Western University London Ontario Canada
  2. 2ICES Western, Kidney, Dialysis & Transplantation Research Program London Ontario Canada
  3. 3Department of Epidemiology and Biostatistics Western University London Ontario Canada
  4. 4London Health Sciences Centre, Lawson Health Research Institute London Ontario Canada
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{melamed2026semaglutide,
  title = {{Semaglutide and Panic Attacks: Active‐Comparator Disproportionality Analysis, Temporal Assessment of Notoriety Bias and Evidence Triangulation in Post‐Marketing Pharmacovigilance}},
  author = {Ben Melamed and Mahak Parsi‐Zahabi and Mohammad Ali Omrani and Bala Swetha Baskaran and Lujain Ez Eddin and Nazgol Kermanshahi and Niaz Chalabianloo and Flory Tsobo Muanda},
  journal = {Pharmacoepidemiology and Drug Safety},
  year = {2026},
  month = oct,
  doi = {10.1002/pds.70517},
  url = {https://doi.org/10.1002/pds.70517},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Semaglutide and Panic Attacks: Active‐Comparator Disproportionality Analysis, Temporal Assessment of Notoriety Bias and Evidence Triangulation in Post‐Marketing Pharmacovigilance
AU  - Ben Melamed
AU  - Mahak Parsi‐Zahabi
AU  - Mohammad Ali Omrani
AU  - Bala Swetha Baskaran
AU  - Lujain Ez Eddin
AU  - Nazgol Kermanshahi
AU  - Niaz Chalabianloo
AU  - Flory Tsobo Muanda
PY  - 2026
DA  - 2026/10/27
JO  - Pharmacoepidemiology and Drug Safety
DO  - 10.1002/pds.70517
UR  - https://doi.org/10.1002/pds.70517
AB  - 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.
SN  - 1053-8569
SN  - 1099-1557
ER  -