Spotlight on GLP-1 receptor agonists and suicidality

Several recent studies assessed whether there is an association between use of glucagon-like peptide-1 (GLP-1) receptor agonists and suicidality.

A cohort study comparing new users of GLP-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors was published by JAMA Internal Medicine on Sept. 3 and found no significant difference in suicide. It included 124,517 patients who started a GLP-1 receptor agonist and 174,036 who initiated an SGLT-2 inhibitor, all in Sweden and Denmark. During mean follow-up of 2.5 years, the groups had 77 and 71 suicide deaths, respectively, for weighted incidences of 0.23 versus 0.18 events per 1,000 person-years (absolute difference, 0.05 [95% CI, −0.03 to 0.16] event per 1,000 person-years). “The findings indicate that the absolute risks of suicide death in broad groups of patients using GLP-1 receptor agonists are low and any potential risk increase would be small,” said the study authors.

Similarly, a manufacturer-funded post hoc analysis of multiple placebo-controlled trials of semaglutide, published the same day by JAMA Internal Medicine, also found no association between the drug class and suicidal ideation (SI). The trials included 3,681 patients (more than two-thirds women) who completed the Patient Health Questionnaire (PHQ-9) at baseline and week 68. The results showed no increase in clinically significant symptoms of depression; participants treated with semaglutide were less likely to shift to a more severe category of PHQ-9 depression during the study (odds ratio, 0.63 [95% CI, 0.50 to 0.79]; P<0.001). Using the Columbia–Suicide Severity Rating Scale, 1% or fewer of participants reported SI or suicidal behavior during treatment, with no differences between groups. “A small number of patients taking semaglutide, 2.4 mg, may experience depression or SI, which may be related to psychosocial complications of obesity or other factors, including life stressors,” said the study authors, who encouraged clinicians to monitor mental health in all patients with overweight or obesity.

An editorial accompanying both studies said they “are reassuring and support the preliminary conclusions of the US Food and Drug Administration and the European Medicines Agency that there is inadequate evidence to link GLP-1 receptor agonists with suicidality; however, they do not answer all psychiatry safety questions posed by this drug class.” Remaining questions include whether GLP-1 receptor agonists could worsen symptoms in patients with pre-existing mental health problems such as moderate or severe depression, and whether suicide risk might be elevated with other related drugs, such as the gastric inhibitory polypeptide/GLP-1 receptor agonist tirzepatide.

Two other recent studies analyzed data from the World Health Organization (WHO) on the question. One, published by Diabetes, Obesity and Metabolism on Aug. 19, reviewed more than 130 million adverse drug reaction reports to the WHO from 1967 to 2023. It found that although there were 332 reports of suicidality associated with GLP-1 receptor agonists from 2005 to 2023, there was no evidence of an association between the drug class and suicidality, whether the drugs were used for diabetes or obesity treatment. However, diabetes and obesity drugs other than GLP-1 receptor agonists were associated with higher risk of suicidality, according to the analysis. Like the authors of the other research, they speculated that suicidality trends could be influenced by other factors in the treated patients' lives. “Nevertheless, the increasing reports of suicidality among GLP-1 [receptor agonist] users cannot be entirely disregarded,” the authors said.

In contrast, the other analysis of the WHO database, published by JAMA Network Open on Aug. 20, found a signal of semaglutide-associated suicidal ideation. It was a disproportionality analysis that used a case-control design to look at risks of suicidality with semaglutide and liraglutide. The study found a total of 107 cases of suicidal and/or self-injurious adverse drug events reported between November 2000 and August 2023 with semaglutide and 162 with liraglutide. Significant disproportionality was detected only for semaglutide-associated suicidal ideation, and it remained significant when compared with dapagliflozin, metformin, and orlistat. “When repeating the analysis after excluding cases in which antidepressants were coreported, we did not detect a disproportionality signal. … This is consistent with an interaction between baseline psychopathology and semaglutide effects and warrants further investigation,” the study authors said. They noted that patients with affective disorders were excluded from premarket trials of the drug.

An accompanying commentary noted that the data on this question are conflicting and said that this study was well conducted and adds an important piece to the knowledge on this potential safety issue. “Waiting for more precise data, [GLP-1] receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” the commentary said.