Depression risk lower with GLP-1 receptor agonists than DPP-4 inhibitors, target trial finds
Older patients with type 2 diabetes taking glucagon-like peptide-1 (GLP-1) receptor agonists had a modestly decreased risk for incident depression compared with those on dipeptidyl peptidase-4 (DPP-4) inhibitors, but no difference was found compared to sodium-glucose cotransporter-2 inhibitors, according to the target trial emulation study.
Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with a modest decrease in risk for incident depression compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, but not compared to sodium-glucose cotransporter-2 (SGLT-2) inhibitors, according to a target trial emulation study among older adults with type 2 diabetes.
Using Medicare data from 2014 to 2020, researchers matched adults ages 66 years or older with type 2 diabetes by whether they initiated treatment with a GLP-1 receptor agonist, an SGLT-2 inhibitor, or a DPP-4 inhibitor. There were a total of 14,665 matched pairs in the GLP-1 receptor agonist versus SGLT-2 inhibitor cohort (mean age, 72.9 years; 43.8% women) and 13,711 matched pairs in the GLP-1 receptor agonist versus DPP-4 inhibitor cohort (mean age, 73.3 years; 46.6% women). Incident depression was the primary endpoint. None of the included patients had a prior diagnosis of type 1 diabetes, depression, or any other mood disorder, and none had ever used antidepressants. Findings were published Feb. 25 by Annals of Internal Medicine.
A total of 963 depression events occurred among 13,711 GLP-1 receptor agonist users and 1,075 among 13,711 DPP-4 inhibitor users during a median treatment duration of 0.44 year and a median follow-up of 1.65 years. The rate difference in depression was −5.78 (95% CI, −10.49 to −1.07) per 1,000 person-years, with a hazard ratio (HR) of 0.90 (95% CI, 0.82 to 0.98).
A total of 961 GLP-1 receptor agonist users and 902 SGLT-2 inhibitor users were diagnosed with depression during a median treatment duration of 0.42 year and a median follow-up of 1.57 years. The rate difference in depression was 3.48 (95% CI, −0.81 to 7.78) per 1,000 person-years (HR, 1.07; 95% CI, 0.98 to 1.18). Results were consistent across sensitivity and subgroup analyses.
Limitations to the study include unmeasured potential confounders like HbA1c levels and body mass index, in addition to potential misclassifications of outcome. Findings may also not be generalizable to all GLP-1 receptor agonist users, such as younger adults or patients without type 2 diabetes taking the medications for obesity treatment.
The incidence of depression diagnosis in the study population was very low, the authors wrote. “These results, if confirmed in randomized controlled trials, could have important implications for the management of type 2 diabetes, especially in older patients at risk for depression,” they concluded.