‘Reassuring’ findings suggest GLP-1 receptor agonists do not increase suicide risk

Key takeaways:

• Two studies showed no association between GLP-1 receptor agonists and increased risk for suicide or suicidal thoughts.
• However, monitoring mental health remains “essential,” according to experts.

Results from two studies found no association between the use of GLP-1 receptor agonists and increased risk for suicide, suicidal thoughts or depression, findings published in JAMA Internal Medicine showed.

Potential links between suicide or mental health conditions and GLP-1 receptor agonists —particularly semaglutide —have been the focus of several recent analyses and an FDA investigation, which have shown mixed results.

For example, a retrospective cohort study reported that adults receiving semaglutide (Wegovy/Ozempic, Novo Nordisk) as a type 2 diabetes or obesity medication had lower risk for suicidal ideation than those using a drug that is not a GLP-1 receptor agonist.

However, a recent case-control study contrasted those findings, showing that adults — particularly those with anxiety or depressive disorders — receiving semaglutide had an increased risk for suicidal ideation.

The researchers of that study called for “urgent clarification” of drug- and patient-related risk factors, an understanding that has become more important as GLP-1 receptor agonist use continues to rise across the United States, especially for weight management.

GLP-1s not tied to suicide, self-harm

According to Peter Ueda, MD, PhD, an assistant professor at Karolinska Institute in Sweden, and colleagues, the effect of GLP-1 receptor agonists on suicidality is “plausible” becausre the drugs “have been shown to cross the blood-brain barrier.”

However, they also pointed out how some have hypothesized that GLP-1 receptor agonists could protect against mental illness like depression.

In the cohort study, the researchers used 2013 to 2021 nationwide registry data from Sweden and Denmark to assess suicidality, self-harm or depression among new users of either GLP-1 receptor agonists or sodium glucose cotransporter-2 (SGLT2) inhibitors.

Overall, 124,517 adults initiated a GLP-1 receptor agonist and 174,036 initiated an SGLT2 inhibitor. Most of the patients had type 2 diabetes.

Ueda and colleagues found that 77 suicide deaths occurred among GLP-1 receptor agonist users and 71 among SGLT2 inhibitor users during a mean follow-up period of 2.5 years.

The researchers reported HRs of:

• 0.83 (95% CI, 0.7-0.97) for suicide death and nonfatal self-harm; and
• 1.01 (95% CI, 0.97-1.06) for depression and anxiety-related disorders.

The findings indicated that the absolute risk for suicide among broad groups of GLP-1 receptor agonist users “are low and any potential risk increase would be small,” the researchers wrote.

There were several study limitations. Ueda and colleagues noted that some suicide deaths could be misclassified. Meanwhile, risks could still develop with longer term GLP-1 receptor agonist use.

The results, “while reassuring,” could ultimately not rule out smaller absolute risk differences for suicide deaths, “and future studies with more outcome events should be performed as data accumulate,” the researchers wrote.

No association between semaglutide and suicidal thoughts

Semaglutide has been shown to provide weight loss and cardiovascular disease benefits in patients with overweight and obesity, although obesity has been tied to depressive and other psychiatric conditions, Thomas A. Wadden, PhD, a professor of psychology in psychiatry at Perelman School of Medicine at the University of Pennsylvania, and colleagues noted.

Concerns of potential mental health conditions in people with obesity “have accompanied the development of medications for chronic weight management, which... access brain regions that regulate energy intake and may interact with mood influencing pathways,” they wrote.

In the post hoc analysis, the researchers used data of over 3,500 participants from the Semaglutide Treatment Effect in People with obesity (STEP) 1, 2, 3 and 5 trials. The STEP 1, 2 and 3 trials spanned 68 weeks, whereas the STEP 5 trial took place over 104 weeks.

Wadden and colleagues assessed changes in depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9) and suicidal ideation or behaviors using the Columbia Suicide Severity Rating Scale in participants with overweight or obesity using semaglutide 2.4 mg or placebo.

They found that semaglutide users in the STEP 1, 2 and 3 trials were less likely to shift to a more severe category of PHQ-9 depression (OR = 0.63; 95% CI, 0.5-0.79) from baseline to 68 weeks vs. placebo users.

The researchers observed similar results in the STEP 5 trial.

Additionally, 1% or less of participants reported suicidal ideation or behavior during treatment across all four trials — with no differences between semaglutide and placebo users. Meanwhile, just 2.8% of semaglutide users reported any levels of depression that required evaluation by a mental health professional during treatment compared with 4.1% of placebo users.

Monitoring mental health remains ‘essential’

In a related editorial, Timothy S. Anderson, MD, MAS, an assistant professor of medicine at the University of Pittsburgh, and Deborah Grady, MD, MPH, a professor emeritus of medicine and of epidemiology and biostatistics at the University of California, San Francisco, reiterated that the findings are reassuring and support preliminary data from the FDA and European Medicines Agency, but the results do not answer definitely whether or not this drug class poses safety concerns regarding mental health.

“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,” they wrote.

As a result, “continued vigilance in monitoring mental health symptoms is essential,” Anderson and Grady concluded.

References:

• Anderson T, Grady D. JAMA Intern Med. 2024;doi:10.1001/jamainternmed.2024.4320.
• Penn study finds taking semaglutide for weight management does not increase risk of depression or suicidal behavior in people without known major psychopathology. Available at: https://www.pennmedicine.org/news/news-releases/2024/september/semaglutide-and-mental-health. Published Sept. 3, 2024. Accessed Sept. 3, 2024.
• Ueda P, et al. JAMA Intern Med. 2024;doi:10.1001/jamainternmed.2024.4369.
• Wadden T, et al. JAMA Intern Med. 2024;doi:10.1001/jamainternmed.2024.4346.