No Uptick in Suicidal Thinking With GLP-1 Drugs: Medicare Data

Glucagon-like peptide 1 (GLP-1) receptor agonists do not seem to increase the likelihood of suicidal thoughts or actions compared with other diabetes drugs among older adults, suggests a retrospective analysis of Medicare data.

Despite prior worries that the new class of drugs, currently marketed for both diabetes and weight loss, might be leading patients to consider—or follow through on—ideas of suicide or self-harm, the findings are in line with the US Food and Drug Administration’s conclusions published earlier this year that no causal link could be identified.

Senior author Jingchuan Guo, MD, PhD (University of Florida College of Pharmacy, Gainesville), said their new study could not rule out a modestly increased risk of suicidal ideation and/or behavior and doesn’t yet close the door on this critical question.

“For example, the current study did not cover a younger population, such as adolescents,” she wrote in an email to TCTMD. “Also, our findings do not shed light on the potential risk of recurrent suicidal thoughts and behaviors among individuals with a preexisting history.”

For the study, published online Monday in the Annals of Internal Medicine, lead author Huilin Tang, MSc (University of Florida College of Pharmacy), Guo, and colleagues included more than 59,000 Medicare recipients ages 65 and older with diabetes who started treatment with a GLP-1 receptor agonist, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, or a dipeptidyl peptidase-4 (DPP-4) inhibitor between 2016 and 2020.

They used propensity-score matching to analyze the results of 43,614 patients (mean age 73 years; 50.6% women) taking GLP-1 receptor agonists or SGLT2 inhibitors and 42,804 patients (mean age 73.5 years; 54.4% women) taking GLP-1 receptor agonists or DPP-4 inhibitors.

Over median follow-up periods of 1.56 and 1.64 years, respectively, the researchers found no significant differences in the incidence rates of suicidal ideation and behaviors between GLP-1 receptor agonists and either SGLT2 inhibitors (2.40 vs 2.24 per 1,000 person-years; HR 1.07; 95% CI 0.80-1.45) or DPP-4 inhibitors (2.63 vs 2.81 per 1,000 person-years; HR 0.94; 95% CI 0.71-1.24).

The results were maintained in several sensitivity and subgroup analyses.

“Our results provide additional support for the preliminary FDA assessment that there is no evidence of a causal link between use of GLP-1 receptor agonists and suicidal thoughts or actions,” the authors write. “However, the FDA cannot rule out a small increase, and further review of postmarketing data in the Sentinel System is ongoing to monitor the neuropsychiatric safety of GLP-1 receptor agonists.”

Notably, Tang et al say, they could not adjust for body mass index, which has been shown to be tied with depression in the past. “The higher observed risk associated with [semaglutide and liraglutide] may reflect a higher predilection for depression, suicidal ideation, and suicidal behaviors at baseline,” they write. “It will be crucial for future studies to clarify the potential association between these two specific GLP-1 receptor agonists . . . and risk for suicidal ideation and behaviors.”

While the current analysis may go some way to reassuring physicians and patients about the risks of suicidal ideation with semaglutide, that news comes on the background of another worrisome signal. Last week, researchers writing in JAMA Ophthalmology reported that real-world semaglutide use was associated with a more than fourfold increase in the risk of nonarteritic anterior ischemic optic neuropathy compared with non-GLP-1 receptor agonist antidiabetic or weight loss medication use.