Two new studies investigate the risk of suicidality with GLP-1 receptor agonists

Two new studies have investigated the risk of suicidality with glucagon-like peptide-1 (GLP-1) receptor agonists. Study oneThe first study examined the psychiatric safety of subcutaneous semaglutide 2.4 mg once weekly in people without known major psychopathology. This study was a post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicentre STEP 1, 2 and 3 trials (3,377 participants, 68 weeks) and STEP 5 trial (304 participants, 104 weeks), which included adults with overweight or obesity and some also had type 2 diabetes. Depressive symptoms and suicidal ideation/behaviour were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia–Suicide Severity Rating Scale. Psychiatric and nervous system disorder adverse events were also investigated.Results showed that in the STEP 1, 2 and 3 trials, mean baseline PHQ-9 scores for the semaglutide and placebo groups were 2.0 and 1.8, respectively, indicating no/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 and 2.4, respectively; the estimated treatment difference (95%CI) between groups was −0.56 (−0.81 to −0.32) (p < 0.001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95%CI, 0.50–0.79; p < 0.001). Based on the Columbia–Suicide Severity Rating Scale, 1% or fewer participants reported suicidal ideation/behaviour during treatment, with no differences between semaglutide and placebo. Psychiatric disorder adverse events were generally balanced between groups. Similar results were observed in STEP 5.The authors conclude that treatment with semaglutide 2.4 mg weekly did not increase the risk of developing symptoms of depression or suicidal ideation/behaviour vs placebo.1 Study twoThe second study assessed the association between use of GLP-1 receptor agonists and the risk of suicide death in routine clinical practice. The cohort study used nationwide register data from Sweden and Denmark. It included adults (18–84 years of age) who started treatment with a GLP-1 receptor agonist (new users; n=124,517) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor (comparator group, n=174,036). Most of the patients had type 2 diabetes.The primary outcome was suicide death. Secondary outcomes were the composite of suicide death and nonfatal self-harm and the composite of incident depression and anxiety-related disorders. Using propensity score weighting, hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated separately in the two countries and pooled in a meta-analysis.During a mean follow-up of 2.5 years, 77 suicide deaths occurred among users of GLP-1 receptor agonists and 71 suicide deaths occurred among users of SGLT2 inhibitors: weighted incidences were 0.23 vs 0.18 events per 1000 person-years (HR, 1.25; 95%CI, 0.83–1.88), with an absolute difference of 0.05 (95%CI, −0.03 to 0.16) events per 1000 person-years. The HR was 0.83 (95%CI, 0.70–0.97) for suicide death and nonfatal self-harm, and the HR was 1.01 (95%CI, 0.97–1.06) for incident depression and anxiety-related disorders.The authors conclude that in this cohort study, which included mostly patients with type 2 diabetes, no association was seen between use of GLP-1 receptor agonists and an increased risk of suicide death, self-harm, or incident depression and anxiety-related disorders. Suicide death among GLP-1 receptor agonist users was rare. The upper limit of the confidence interval was compatible with an absolute risk increase of no more than 0.16 events per 1000 person-years.2CommentaryAuthors of an accompanying editorial point out that the results of these two studies 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, these studies do not answer all psychiatry safety questions posed by this drug class. Neither study clearly answers the question of whether GLP-1 receptor agonists worsen symptoms among patients with preexisting mental health problems, such as moderate or severe depression, as these patients were excluded from Study #1 and these symptoms were not captured by Study #2. In addition, these studies examined only two GLP-1 receptor agonists (semaglutide and liraglutide); neither study examined tirzepatide, a gastric inhibitory polypeptide/GLP-1 receptor agonist.3 The editorial points out that due to the increased interest in using GLP-1 receptor agonists for nonapproved uses (e.g., treatment of substance use disorders), continued vigilance in monitoring mental health symptoms in patients taking GLP-1 receptor agonists is essential.3References:Wadden TA, Brown GK, Egebjerg C, et al. Psychiatric safety of semaglutide for weight management in people without known major psychopathology. Post hoc analysis of the STEP 1, 2, 3, and 5 trials. JAMA Intern Med 2024; published online September 3, 2024. (accessed September 3, 2024).Ueda P, Söderling J, Wintzell V, et al. GLP-1 receptor agonist use and risk of suicide death. JAMA Intern Med 2024; published online September 3, 2024. (accessed September 3, 2024).Anderson TS, Grady D. Glucagon-like peptide-1 receptor agonists and suicidality—two important pieces of data but an incomplete puzzle (editorial). JAMA Intern Med 2024; published online September 3, 2024. (accessed September 3, 2024).

Two new studies investigate the risk of suicidality with GLP-1 receptor agonists

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