GLP-1 receptor agonists not linked to suicidal thoughts, PRAC concludes

15th April 2024

Available evidence does not support a causal association between glucagon-like peptide-1 (GLP-1) receptor agonists and suicidal and self-injurious thoughts and actions, according to the European Medicine Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC).

This conclusion follows a review into GLP-1 receptor agonists starting in July 2023 after receiving case reports from the Icelandic medicines agency of suicidal thoughts and thoughts of self-injury from people using liraglutide and semaglutide.

At the time, the EMA said it was ‘not yet clear whether the reported cases are linked to the medicines themselves or to the patients’ underlying conditions or other factors‘.

The PRAC review has since included the results of a recent real-world cohort study looking at the association of semaglutide with risk of suicidal ideation.

Based on a large database of electronic health records, it investigated the incidence of suicidal thoughts in patients with overweight and type 2 diabetes mellitus treated with semaglutide or other non-GLP-1 receptor agonist medicines for diabetes or overweight.

The study found no causal association between the use of semaglutide and suicidal thoughts.

The EMA conducted a separate study based on electronic health records. This examined the risk of suicide-related and self-injury-related events in people with type 2 diabetes mellitus and found no causal association between the use of GLP-1 receptor agonists and this risk.

The PRAC also considered additional data from the marketing authorisation holders for semaglutide (brand names Ozempic, Rybelsus and Wegovy), liraglutide (brand names Victoza and Saxenda), degludec/liraglutide (brand name Xultophy), exenatide (brand names Byetta and Bydureon), lixisenatide (brand name Lyxumia), glargine/lixisenatide (brand name Suliqua), and dulaglutide (brand name Trulicity).

After reviewing the available evidence from non-clinical studies, clinical trials, post-marketing surveillance data and the available studies the PRAC announced that no update to the product information is warranted.

It added that close monitoring by the marketing authorisation holders is required and any new evidence on the issue must be reported.

This mirrors a similar conclusion from the US FDA in January 2024, in which it stated: ‘Our preliminary evaluation has not found evidence that use of these medicines causes suicidal thoughts or actions.‘

Fluoroquinolone use not linked to higher ED visits or hospital admission for suicidality

24th October 2022

Fluoroquinolone use is not associated with a higher risk of ED visits or hospital admissions for suicidality following short-term use

Short-term fluoroquinolone use does not result in a higher risk of either emergency department (ED) visits or hospital admission for suicidality when treating either pneumonia or a urinary tract infection (UTI) compared to other antibiotics. This was the main finding of an analysis using a national commercial US health insurance claims database by US researchers from Boston.

The safety of fluoroquinolones has been under the spotlight for many years. In 2016, the US food and Drug Administration (FDA) issued a safety announcement in which it was reported that as a class, the medicines were associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient. Serious potential central nervous system adverse effects listed by the FDA include anxiety, depression, hallucination, confusion and suicidal thoughts. Similarly in Europe, the Pharmacovigilance Risk Assessment Committee has also suggested that healthcare professionals should advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of a side effect involving muscles, tendons or bones or the nervous system, including suicidal thoughts.

But how common is suicidal ideation among the general population of patients prescribed fluoroquinolones, particularly in the short-term, was the question posed by the US team in the present study. Equally important, was whether this risk of suicidality was sufficient to warrant either an ED visit or hospital admission and, if the risk was any higher than any clinically appropriate comparator drugs. The researchers focused on pneumonia and a UTI since fluoroquinolones are often used in the management of both indications. Several fluoroquinolones were analysed including ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin and ofloxacin. The researchers chose azithromycin and trimethoprim-sulfamethoxazole as comparator drugs for the pneumonia and UTI cohorts since these are commonly used alternatives for the two conditions. Participants were then matched 1:1 within each cohort. The study outcome of interest was suicidality which they defined as any hospital admission or emergency department visit and participants were followed-up for a maximum of 60 days after starting treatment.

Fluoroquinolone use and suicidality

A total of 825,420 patients with pneumonia and 3,463500 with a UTI were included in the analysis. The mean age of pneumonia participants was 51.4 years (48.6% male) although the UTI cohort were slightly younger (mean age 43.6 years, 8.4% male).

Overall, 0.03% of both fluoroquinolone and azithromycin users were either admitted to hospital or an ED for suicidality during follow-up. Among the UTI cohort, an identical proportion (0.04%) of both fluoroquinolone and trimethoprim-sulfamethoxazole users experienced suicidality resulting in an admission or ED visit. There was no significant difference among the pneumonia (Hazard ratio, HR = 1.01, 95% CI 0.76 – 1.36) and UTI (HR = 1.03, 95% CI 0.91 – 1.17) cohorts. These findings were consistent across the different subgroups based on sex, age or with a history of mental illness.

The authors concluded that the use of fluoroquinolones was not associated with a higher risk of suicidality leading to an ED visit or hospital admission compared to either azithromycin or trimethoprim-sulfamethoxazole. However, they added the caveat that it was not possible to exclude a small increased risk or on suicidal thoughts that did not lead to either an ED visit or hospital admission.

Citation
Wang J et al. Association between initiation of fluoroquinolones and hospital admission or emergency department visit for suicidality: population based cohort study BMJ 2022