GLP-1s ‘modestly lower’ the risk for depression in adults with diabetes

Key takeaways:

• GLP-1s reduced depression risk vs. DPP-4 inhibitors but not SGLT2 inhibitors.
• However, both GLP-1s and SGLT2 inhibitors may offer similar antidepressant benefits, researchers noted.

The use of GLP-1 receptor agonists corresponded with a lower risk for depression among older adults with type 2 diabetes compared with dipeptidyl peptidase 4 inhibitors, results of a target trial emulation study suggested.

GLP-1s did not reduce the risk for depression compared with sodium-glucose cotransporter 2 (SGLT2) inhibitors, another frequently prescribed diabetes treatment, according to study investigators.

The findings are consistent with those of a previous study suggesting that GLP-1s, particularly tirzepatide (Zepbound, Eli Lilly), lower the risk for anxiety and depression.

However, conflicting results and several limitations of past analyses examining the antidepressant effects of diabetes medications “underscore the need for further investigation, particularly in high-risk populations, such as older adults with type 2 diabetes,” Huilin Tang, PhD, a postdoctoral researcher at the University of Pennsylvania Perelman School of Medicine, and colleagues wrote in the Annals of Internal Medicine.

Tang and colleagues used U.S. national Medicare claims data from 2014 to 2020 to emulate a target trial evaluating depression risk in adults aged 66 years or older with type 2 diabetes initiating treatment with SGLT2 inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors or GLP-1s.

The researchers matched participants given GLP-1s in a 1:1 ratio with those assigned to one of the other treatments, while they followed all those included in the study cohort until either death, the onset of depression, loss to follow-up, up to 2 years of follow-up or to the end of the study.

The analysis included 14,665 pairs in the GLP-1s vs. SGLT2 inhibitors group and 13,711 pairs in the GLP-1s vs. DPP-4 inhibitors group.

The researchers reported a rate difference of depression between GLP-1 and SGLT2 inhibitor users of 3.48 (95% CI, –0.81 to 7.78) per 1,000 person-years, with no difference in risk reduction between the two medications.

In contrast, GLP-1s lowered the risk for depression vs. DPP-4 inhibitors (HR = 0.9; 95% CI, 0.82-0.98), with a rate difference of depression between the treatments of –5.78 (95% CI, –10.49 to –1.07) per 1,000 person-years.

In subgroup and sensitivity analyses, Tang and colleagues found an inverse association between GLP-1 treatment duration and incident depression compared with SGLT2 (P = .005) and DPP-4 (P = .001) inhibitors.

They observed that this result could be explained by findings from prior research, which showed that short-term stimulation from GLP-1s led to increased anxiety-like behavior while long-term stimulation reduced depression-like behavior.

“Our study found that GLP-1RAs are associated with a modestly decreased risk for depression in older adults with type 2 diabetes when compared with DPP4is, but no difference between GLP-1RAs and SGLT2is, suggesting that GLP-1RA use may offer antidepressant effects,” the researchers wrote.

Although the researchers observed no difference in risk between GLP-1s and SGLT2 inhibitors, “this does not negate the possibility that the two drugs offer similar benefits for depression risk reduction,” Tang and colleagues added. “Both GLP-1[s] and SGLT2 [inhibitors] offer improved glycemic control, weight reduction and cardiorenal benefits, which could contribute to improved overall well-being and reduced depressive symptoms.”

The researchers identified some study limitations, such as unmeasured confounders like diabetes severity, HbA1c, BMI and socioeconomic status.

Tang and colleagues added that the study’s older population may limit the findings’ general applicability to younger adults.

More studies, particularly randomized controlled trials with longer follow-up periods, are needed “to confirm our findings and explore their effects in younger populations or those without type 2 diabetes,” according to researchers.