A comprehensive study comparing patients with diabetes who use glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to those using other antidiabetic drugs has found no increased risk of suicidality once confounders were accounted for. The findings, published in the BMJ, provide reassurance for clinicians and patients alike, as concerns about the mental health impacts of these drugs have been a topic of debate in recent years.

For patients managing diabetes, GLP-1 receptor agonists (GLP-1 RAs) do not appear to elevate the risk of suicidal thoughts or actions compared to dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors, according to a large cohort study from the United Kingdom. The study, which included data from primary care practices and national health databases, sought to address earlier concerns raised by both the European Medicines Agency and the Food and Drug Administration (FDA) regarding potential links between GLP-1 RAs and suicidal ideation.

The study’s lead investigator, Samantha B. Shapiro, noted that previous research had mixed results, with some studies even suggesting that GLP-1 RAs might be protective against suicidal thoughts. “All of these studies had their own strengths, but also their own shortcomings,” Shapiro said. To address these issues, the researchers applied a more rigorous design that aimed to avoid various biases, including immortal time bias and confounding factors.

The study found that when baseline characteristics like body mass index, socioeconomic status, history of mental health issues, age, and other comorbidities were taken into account, the initial doubling of risk seen in crude analyses disappeared. “We went from a doubling of risk to no effect on the risk,” Shapiro stated, emphasizing the importance of considering these confounding factors.

Shapiro and her team analyzed data from two cohorts of patients with diabetes. The first cohort included approximately 36,000 GLP-1 RA users and 234,000 DPP-4 inhibitor users. Crude analyses initially showed a higher risk of suicidality with GLP-1 RAs, but after adjusting for confounders, this association vanished. The second cohort, which included around 32,000 GLP-1 RA users and 96,000 SGLT2 inhibitor users, showed similar results.

The study also examined specific endpoints such as suicidal ideation, self-harm, and suicide, finding no significant differences. Additionally, the researchers found no signals of harm when analyzing data by individual drug, age, sex, body mass index, history of suicidal ideation, history of depression, or socioeconomic status.

From a biological standpoint, the researchers suggested several potential mechanisms through which GLP-1 RAs could theoretically lead to suicidality, including hyperactivity of the hypothalamic-pituitary-adrenal axis, sudden weight loss leading to elevated suicide risk, and underexpression of brain-derived neurotrophic factor linking low body weight and increased anxiety.

In an accompanying editorial, Peter Ueda and Björn Pasternak from the Karolinska Institutet highlighted the study’s strengths, including the use of appropriate comparator drugs and an active comparator new user design. They also noted limitations, such as the low event rates and the inclusion of GLP-1 drug types that are not commonly used in current practice.

Ueda and Pasternak concluded that future studies should specifically assess the safety of semaglutide and tirzepatide, which have become popular due to their significant effects on weight reduction and glucose control. They also suggested that a similar study among patients taking GLP-1 RAs for obesity is warranted, as this group represents a different subset of people.

Shapiro emphasized that while clinicians should continue to monitor the mental and emotional well-being of their patients, they can be relatively assured that these drugs are psychiatrically safe. “At least in the populations who are using GLP-1 RAs for diabetes, I think clinicians can be relatively assured that these drugs are psychiatrically safe,” Shapiro confirmed. She also highlighted the numerous beneficial effects of these medications, including diabetes control, cardiovascular effects, and renal effects.

For U.S. readers, these findings are particularly relevant given the widespread use of GLP-1 RAs in the management of diabetes and obesity. The study’s results provide valuable insights for healthcare providers and patients, reassuring them that these medications do not pose an increased risk of suicidality when used appropriately.

In conclusion, the study offers a robust analysis of the safety of GLP-1 RAs, addressing long-standing concerns and providing clear evidence that these drugs do not increase the risk of suicidal ideation, self-harm, or suicide. As the use of GLP-1 RAs continues to grow, particularly with the rise of obesity and diabetes in the U.S., these findings are crucial for informing clinical practice and patient care.