medwireNews: Use of glucagon-like peptide (GLP)-1 receptor agonists may be linked to a lower risk for depression in older adults with type 2 diabetes when compared with dipeptidyl peptidase (DPP)-4 inhibitors, but not versus sodium–glucose cotransporter (SGLT)2 inhibitors, research shows.
Overall, “the incidence of depression was relatively low” in the study population, say Jingchuan Guo (University of Florida, Gainesville, USA) and colleagues. They therefore believe that “[g]iven the mixed findings,” the protective effect of GLP-1 receptor agonists on depression risk “is uncertain.”
Writing in the Annals of Internal Medicine, the authors explain that there is increasing evidence for a bidirectional relationship between depression and type 2 diabetes, but population-based studies on the potential antidepressant effects of GLP-1 receptor agonists have shown inconsistent results.
To address the limitations of such studies, Guo and team used US National Medicare administrative data from 2014 to 2020 to create a target trial emulation study that compared the risk for depression among adults with type 2 diabetes aged 66 years and older who were initiating treatment with GLP-1 receptor agonists, DDP-4 inhibitors, or SGLT2 inhibitors. The participants had no prior diagnosis of depression or other mood disorders and had not used antidepressants in the previous year.
The first comparison included 13,711 propensity score-matched pairs of individuals (mean age 73.3 years, 46.6% women, 73.9% non-Hispanic White) who were treated with GLP-1 receptor agonists or DPP-4 inhibitors for a median duration of 0.4 years.
During a median 1.7 years of follow-up, the incidence of depression was significantly lower among the 13,711 individuals given a GLP-1 receptor agonist than among their matched peers treated with a DPP-4 inhibitor, at 51.4 versus 57.2 cases per 1000 person–years. The difference between the two treatments corresponded to a significant 10% lower risk for depression among the GLP-1 receptor agonist users.
The second analysis included 14,665 matched pairs of individuals (mean age 72.9 years, 43.8% women, 75.2% non-Hispanic White) who received a GLP-1 receptor agonists or an SGLT2 inhibitor for a median duration of 0.4 years.
In this case, there was no significant difference in the incidence of depression between the two arms during a median 1.6 years of follow-up. The rate was 49.0 cases per 1000 person–years among GLP-1 receptor agonist users and 45.5 cases per 1000 person–years among people using SGLT2 inhibitors.
Although there was no difference in depression risk between people using GLP-1 receptor agonists and those using SGLT2 inhibitors, “this does not negate the possibility that the 2 drugs offer similar benefits for depression risk reduction,” the researchers point out.
In both analyses the results were consistent in multiple subgroup analyses assessing by age, sex, race/ethnicity, insulin use, obesity, and GLP-1 receptor agonist molecular structure.
Of note, however, was the finding that a longer treatment duration with GLP-1 receptor agonists appeared to be associated with a lower risk for depression.
Gou et al say that this could be explained by “previous research [that] showed both anxiogenic and antidepressant effects of GLP- 1 [receptor agonists], with short-term stimulation leading to increased anxiety-like behavior and long-term stimulation reducing depression-like behavior.”
The researchers also comment on the limitations of their study including the possibility of residual confounding by unmeasured variables, such as glycated hemoglobin levels, BMI, and socioeconomic status, as well as the relatively short follow-up period, and the limited generalizability to all GLP-1 receptor agonist users.
The authors conclude: “This study contributes important insights to the ongoing debate about the neuropsychiatric effects of GLP-1 [receptor agonists].”
They add: “Further studies are warranted to confirm our findings and explore their effects in younger populations or those without [type 2 diabetes].
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