Wegovy (Semaglutide) and Risks of Suicidal Ideation and Thyroid Tumors
Wegovy (semaglutide) carries a black box warning for thyroid C-cell tumors based on rodent studies, and there is some disproportionate reporting of suicidal ideation with semaglutide, though no causal relationship has been established.
Thyroid Tumor Risk
Evidence and Risk Assessment
- Semaglutide carries a black box warning regarding the risk of thyroid C-cell tumors observed in rodent studies, though human relevance has not been definitively determined 1, 2
- This warning is similar to that for liraglutide, another GLP-1 receptor agonist 1
- A 2021 study examining liraglutide found no significant elevated risk of thyroid cancer after adjusting for latency, despite initial elevated relative risks in some comparisons 3
- Key findings from this study:
- 85% of thyroid cancers were papillary or follicular variant of papillary
- 46% were microcarcinomas (≤10mm)
- Microcarcinomas were more prevalent in the liraglutide cohort (67% vs 43% in comparators)
- Liraglutide cases had smaller nodules and shorter time-to-diagnosis, suggesting increased surveillance rather than causation 3
Contraindications
- Semaglutide is absolutely contraindicated in:
- Patients with a personal history of medullary thyroid carcinoma (MTC)
- Patients with a family history of MTC
- Patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 2
Suicidal Ideation Risk
Evidence and Risk Assessment
Recent pharmacovigilance studies have examined the potential association between GLP-1 receptor agonists and suicidal ideation:
- A 2024 study found disproportionate reporting of suicidal ideation with semaglutide (Reported Odds Ratio = 2.03) and liraglutide (ROR = 1.64) 4
- Another 2024 study confirmed disproportionate reporting of suicidal ideation and "depression/suicidal" with semaglutide and liraglutide, but found no disproportionate reporting of suicidal behavior, suicide attempts, or completed suicide 5
- Using Bradford Hill criteria and considering confounders, researchers concluded no causal link between GLP-1 RAs and suicidality exists 5
A pooled analysis of clinical trials with liraglutide 3.0 mg found:
- Similar rates of depression (2.1 vs 2.1 events/100 person-years) and anxiety (1.9 vs 1.7 events/100 person-years) between liraglutide and placebo groups
- A small numerical imbalance in suicidal ideation adverse events (0.3% with liraglutide vs 0.1% with placebo)
- No between-treatment imbalances in suicidal ideation/behavior or depression through prospective questionnaire assessments 6
Clinical Implications and Monitoring
For Thyroid Risk
- Screen patients for personal or family history of MTC or MEN2 before initiating therapy
- Do not prescribe semaglutide to patients with these risk factors
- Be aware that increased surveillance may lead to detection of small, clinically insignificant thyroid nodules
For Suicidal Ideation Risk
- While no causal relationship has been established, maintain vigilance for changes in mood or suicidal thoughts
- Consider baseline mental health assessment before initiating therapy
- Exercise caution when prescribing to patients with pre-existing psychiatric disorders
- Inform patients to report any changes in mood or thoughts of self-harm
Other Important Safety Considerations
- Gastrointestinal effects are common (nausea, vomiting, diarrhea, constipation, abdominal pain)
- Risk of pancreatitis requires monitoring and stopping medication if severe abdominal pain occurs
- Caution in patients with history of cholelithiasis or cholecystitis due to increased risk of gallbladder disease 2
- Potential risk of acute kidney injury when initiating or increasing doses 2
Conclusion
While Wegovy carries a black box warning for thyroid C-cell tumors based on animal studies, human evidence suggests this risk may be related to increased surveillance rather than causation. Regarding suicidal ideation, pharmacovigilance data shows disproportionate reporting, but no causal relationship has been established. Appropriate patient selection, monitoring, and education about potential risks are essential when prescribing semaglutide.