The use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) have increased significantly in recent years due to its marked efficacy in body weight reduction in clinical trials and most recently, due to claims by celebrities and social media personalities that they have lost weight after using Ozempic (Semaglutide). While there were earlier concerns on supply shortage due to high demand of on-label and off-label use, there has been reports of a new adverse event signal that has drawn scrutiny from health authorities in the United States (US), European union (EU) and in Asia about its possible link to suicidal episodes.
EU, FDA And HSA Releases Alerts On Suicidal Thoughts
Health Science Authority (HSA) Singapore had just release a safety alert regarding the risk of suicidal thoughts and self-harm associated with the use of GLP-1 RA, such as Liraglutide (Saxenda) and Semaglutide (Wegovy, Ozempic)[1]. This is based on reports from the European Medicine Agency (EMA) on reports of suicidal thoughts and self-injury in people using Liraglutide and Semaglutide [2]. The Icelandic medicines agency currently has150 reports of possible cases, however the authorities still cannot be sure if these cases are directly caused by the use of GLP-1 RA. Liraglutide and Semaglutide are currently indicated for weight management, in addition to diet and exercise for people who are obese or overweight in the presence of at least 1 weight-related health problem. Aside from the EU, the US Food Drug Administration (FDA) has also received 265 reports of suicidal ideation in patients taking GLP-1 RA since 2010, with 36 of these cases resulting in death by suicide or suspected suicide [3]. Some patients reported suicidal thoughts appearing after initiation of the drug or increase in dose.
What Do The Trial Data Say?
The clinical trials of these GLP-1 RA have proved them to be relatively safe, with most patients experiencing gastrointestinal side effects. The most common cause of trial drug withdrawal was serious gastrointestinal side effects. Semaglutide trials did list psychiatric disorders, thought not specified, as one of the common adverse events in the Semaglutide group but the incidence was not more than the placebo group [4].
In the Liraglutide trial [5], it was reported that there were no clinically relevant differences in any mental health assessments for either group. However, there were 4 participants treated with Liraglutide and none in the placebo group that reported suicidal ideation during the trial duration, 2 of which recovered despite continuing on Liraglutide treatment.
In the Tirzepatide trial [6], there were total of 5 cases of major depressive disorder or suicidal ideation in the Tirzepatide treatment groups and none in the placebo group. However, there was no details provided on the patients who experienced these side effects. There was no mention of mood disorder or suicidal ideation in the Dulaglutide trials [7].
Local Information (Singapore)
The Singapore product leaflet [8] for Liraglutide has included suicidal behavior and ideation as one of the possible adverse events, citing that 0.2% (6) of 3384 Liraglutide treated participants reported suicidal ideation and advised prescribers to monitor for any unusual changes in mood of behavior. There was also a caution to avoid Liraglutide in patients with prior suicidal attempts or active suicidal ideation. The local PI for other GLP-1 RA such as Semaglutide, Dulaglutide and Tirzepatide does not have any warning for suicidal ideation
Although current investigations are ongoing, the association of suicidal ideation and use of GLP-1 RAs is something worth monitoring closely until the FDA or EU has released any updated statements. If there are any suspected cases, prescribers should promptly report them to their respective health authorities.
References:
- HSA is assessing the potential risk of suicidal thoughts and self-harm with glucagon-like peptide-1 receptor agonists (GLP-1 RA) [Internet]. [cited 2023 Oct 15]. Available from: https://www.hsa.gov.sg/announcements/safety-alert/hsa-is-assessing-the-potential-risk-of-suicidal-thoughts-and-self-harm-with-glucagon-like-peptide-1-receptor-agonists-(glp-1-ra)
- O’Riordan M. EMA investigating suicidal thinking with GLP-1 drugs for weight loss [Internet]. TCTMD.com; 2023 [cited 2023 Oct 15]. Available from: https://www.tctmd.com/news/ema-investigating-suicidal-thinking-glp-1-drugs-weight-loss
- Respaut R, Terhune C. Wegovy, other weight-loss drugs scrutinized over reports of suicidal thoughts [Internet]. Thomson Reuters; 2023 [cited 2023 Oct 15]. Available from: https://www.reuters.com/business/healthcare-pharmaceuticals/wegovy-other-weight-loss-drugs-scrutinized-over-reports-suicidal-thoughts-2023-09-28/
- Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387(3):205–16. doi:10.1056/nejmoa2206038
- Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine. 2015;373(1):11–22. doi:10.1056/nejmoa1411892
- Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2021;384(11):989–1002. doi:10.1056/nejmoa2032183
- Frias JP, Bonora E, Nevarez Ruiz L, Li YG, Yu Z, Milicevic Z, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (award-11). Diabetes Care. 2021;44(3):765–73. doi:10.2337/dc20-1473
- Saxenda Injection PI; November 2022. [cited 2023 Oct 15]. Available from Health Sciences Authority Therapeutic Products Infosearch.
