Popular Weight-Loss Drugs Not Linked to Higher Risks of Suicidality, but Small Caveat: Study

A study published Monday in Annals of Internal Medicine found that glucagon-like peptide-1 receptor agonists (GLP-1RAs), a class of popular weight-loss and Type 2 diabetes drugs, are not linked to higher risks of suicidal ideation and behaviors.
The study involved older patients taking the drug for diabetes.
However, she added that the study did not evaluate patients who took the drug for obesity or follow younger patients. Therefore, her findings could not be applied to these populations.
GLP-1RAs are second-line antidiabetic and weight-loss drugs. They include liraglutide (Saxenda and Victoza) and semaglutide (Wegovy, Ozempic, and Ryebelsus). Other drugs evaluated in the study include dulaglutide (Trulicity), exenatide (Byetta), and lixisenatide (Adlyxin).
The study also evaluated tirzepatide (Mounjaro and Zepbound), which, strictly speaking, is not a GLP-1RA but has GLP-1RA properties.
Compared to two other second-line glucose-lowering drugs, GLP-1 RAs didn’t show significantly higher risks of suicidality on a general level, said Dr. Guo.
Over 43,000 patients prescribed GLP-1RAs were compared to patients who took either sodium-glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is).
SGLT2i reduces blood sugar by removing it from the urine, while DPP4is works similarly to GLP-1RAs drugs. Neither drug has been linked to suicidality in prior reports.
People who took GLP-1RAs had a slightly increased incidence rate of suicidal ideation and behaviors, with 2.4 events, compared to SGLT2i at 2.24 per 1,000 people per year. However, compared to DPP4i users, GLP-1RA users had a slightly lower incidence rate of 2.6, while DPP4i users had an incidence rate of 2.8 per 1,000 people per year.
However, when singled out, semaglutide and liraglutide were linked to a slightly modest increase in suicidality compared to the other two drugs.
Semaglutide had a 70 percent greater risk when compared to the other two drugs, while liraglutide had a less than 20 percent greater risk.
Both agencies announced investigations into the matter.
“However, the FDA cannot rule out a small increase, and further review of postmarketing data … is ongoing to monitor the neuropsychiatric safety of GLP-1 RAs,” Dr. Guo and researchers wrote.
Nevertheless, larger group studies evaluating suicidality have often returned with insignificant links to suicidality and suicidal ideation.
Dr. Roger McIntyre, professor of psychiatry and pharmacology at the University of Toronto, said there is no good evidence of a causal link between GLP-1RAs and suicidality.
He pointed to the Bradford Hill criteria, nine criteria for assessing causality.
One criterion is related to dosage. If GLP-1RAs cause suicidality, the higher the dosage, the greater the risk.
“There’s so little we know about the triggers of suicidality that we are still not able to say, ‘That’s cause and effect,’” he said.
Therefore, even when suicidal behavior coincides with a patient’s drug use, doctors cannot be sure the behavior is causal because other factors may be at play.
Furthermore, people with both obesity and diabetes tend to be at a greater risk of poor mental health. Given that GLP-1RAs are second-line treatment, it is likely that those prescribed medication suffer from treatment-resistant Type 2 diabetes and, therefore, have a worse condition to begin with, Dr. McIntyre reasoned.
While Dr. Guo’s study showed semaglutide and liraglutide use, specifically, was linked to a higher risk of suicidality, Dr. McIntyre said that the popularity of these two drugs may indicate that doctors prescribe the drugs more often because they believe they will more effectively treat patients with worse conditions and who also likely have a worse mental health prognosis.
Nevertheless, he said gathering more data to observe changes is still important.
“The prevailing view in obesity research is that people who are living with obesity … have a problem with the level of reward that they associate with food,” he explained.
At the brain chemistry level, GLP-1RAs do not reduce the pleasure of eating, which would “not be good.”
Instead, “they reduce the exaggerated anticipation of reward,“ Dr. McIntyre said, adding, ”People call that sort of ‘food chatter.’ … It’s almost like being addicted to drugs.”