The FDA has been investigating reports of suicidal ideation and actions communicated through the FDA Adverse Event Reporting System in patients who are taking GLP-1 RAs. In January, the FDA reported in their safety communication that their “preliminary evaluation has not found evidence that use of these medicines causes suicidal thoughts or actions.” The FDA further noted, however, that because there were a small number of reports of ideation and behaviors seen in the GLP-1 RA–treated group compared with controls, they are not ruling out this small potential risk entirely and indicated that further studies are needed.

To further explore and define this risk, Björn Pasternak, lead author and principal researcher at the Department of Medicine, Solna, Karolinska Institute, and colleagues conducted an active-comparator new-user cohort study that included subjects from Sweden and Denmark from 2013 to 2021. Inclusion criteria were adults aged 18 to 84 years who initiated treatment with GLP-1 receptor agonists or were prescribed sodium-glucose cotransporter-2 (SGLT2) inhibitors (as the comparator). The researchers used propensity score weighting and hazard ratios (HRs) with 95% confidence intervals.

Of the 124,517 adults for whom a GLP-1 RA was initiated and the 174,036 for whom a SGLT2 inhibitor was initiated, 77 suicide deaths occurred among users of GLP-1 RAs and 71 suicide deaths occurred among users of SGLT2 inhibitors. The weighted incidences were 0.23 versus 0.18 events per 1,000 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 1,000 person-years. The HR was 0.83 (95% CI, 0.70-0.97) for death by suicide and nonfatal self-harm. For secondary outcomes, the HR was 1.01 (95% CI, 0.97-1.06) for incident depression and anxiety-related disorders.

The researchers’ primary outcome was death by suicide and self-inflicted deaths due to an undetermined intent, as recorded in the cause of death registers. Secondary outcomes included a composite of death by suicide and nonfatal self-harm as diagnosed by a physician; self-harm as a separate secondary outcome; and a composite of incident depression and anxiety-related disorders.

Commenting on the relevance of the study, Dr. Pasternak stated, “We found no clear link between the use of the drugs and an increased risk of suicide death, self-harm or depression and anxiety-related disorders. This is reassuring,” he said.

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