GLP-1 Agonist Therapy Not Linked to Suicidal Ideation Among Older Adults

There is no clear association between increased risk for suicidal ideation and glucagon-like peptide-1 receptor agonist (GLP-1 RA) use among older adults with type 2 diabetes, according to study findings published in Annals of Internal Medicine.

There has been an emerging concern that GLP-1 RA use increases a person’s risk for suicidal ideation. Previous research findings suggest that GLP-1 RAs dampen the reward felt from eating, which could lead to a higher suicide risk. However, the exact extent of this relationship is not understood very well, especially among older adults with type 2 diabetes.

Researchers conducted 2 retrospective population-based cohort studies to assess the association between suicidal ideation and use of GLP-1 RAs compared with sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptide peptide-4 (DPP-4) inhibitors. Adults 66 years of age and older with type 2 diabetes were randomly sourced from Medicare administrative claims data.

The cohort studies were target trial emulation studies, one of which comprised propensity-score matched participants taking a GLP-1 RA or an SGLT2 inhibitor (n=59,015), whereas the other comprised participants taking a GLP-1 RA or a DPP-4 inhibitor (n=83,275).

The primary outcome was the incidence of suicidal ideation and behaviors such as suicidal ideation, suicide attempt, and self-harm. These incidences were recorded through the corresponding International Classification of Diseases diagnosis codes.

After propensity score matching, the GLP-1 RA vs SGLT2 inhibitor group included 43,614 patients (mean age, 73.0 years), of whom 50.6% were women, 77.3% were non-Hispanic White, and 37.1% had a diagnosis of depression. The GLP-1 RA vs DPP-4 inhibitor group included 42,804 patients (mean age, 73.5 years), of whom 54.4% were women, 76.6% were non-Hispanic White, and 40.9% had a diagnosis of depression.

In the trial comparing GLP-1 RAs and SGLT2 inhibitors, the incidence rates (IRs) of suicidal ideation/behaviors were 2.40 and 2.24 per 1000 person-years, respectively.  Compared with SGLT2 inhibitors, GLP-1 RA medications were not significantly associated with higher risk for suicidal ideation/behaviors (hazard ratio [HR], 1.07; 95% CI, 0.80-1.45).

In the trial comparing GLP-1 RAs and DPP-4 inhibitors, the IRs of suicidal ideation/behaviors were 2.63 and 2.81 per 1000 person-years, respectively. The researchers identified no significantly increased risk for suicidal ideation/behaviors among GLP1-RA vs DPP-4 inhibitor users (HR, 0.94; 95% CI, 0.71-1.24).

A sensitivity analysis demonstrated no association between an increased risk for suicidal ideation/behaviors among patients who used GLP-1 RAs vs SGLT2 inhibitors (HR, 0.84; 95% CI, 0.43-1.22) or DPP-4 inhibitors (HR, 0.84; CI, 0.53-1.33). 

Study limitations include the low rate of suicidal ideation and behaviors, residual confounding from unmeasured covariates such as BMI, potential misclassification due to underdiagnoses of suicidal ideation and behavior from the International Classification of Diseases codes, and a lack of generalizability beyond older adults with type 2 diabetes.

The researchers concluded that “among Medicare beneficiaries with [type 2 diabetes], this study found no clear increased risk for suicidal ideation and behaviors with GLP-1 RAs, although estimates were imprecise and a modest adverse effect could not be ruled out.”

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Endocrinology Advisor