Newer Glucose-Lowering Drugs and Risk of Depression: A Meta-Analysis of Randomized Outcome Trials

OBJECTIVES: Preclinical studies have indicated that newer glucose-lowering drugs (GLDs), i.e., dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter-2 (SGLT2) inhibitors, may have antidepressant effects. However, data from population studies remains limited. Therefore, we aimed to evaluate the effect of these newer GLDs on the risk of depression through a meta-analysis of randomized outcome trial data.

METHODS: We systematically searched PubMed, Embase, and CENTRAL until November 2023 to include randomized placebo-controlled outcome trials that reported the depression outcomes associated with DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors. The depression outcomes were extracted from clinicaltrials.gov. We estimated pooled odds ratios (OR) and 95% confidence interval (CI) using Peto’s method.

RESULTS: Twelve SGLT2 inhibitor trials were included in the meta-analysis that reported the depression outcome. The depression incidence rate for SGLT2 inhibitors and placebo were 26/23,815 and 18/23,899, respectively, yielding a lower risk of depression among those taking SGLT2 inhibitors than those receiving placebo (OR, 0.51; 95%CI, 0.31-0.85). The meta-analysis did not show a significant decrease in the risk of depression for either GLP-1RAs (8 trials; OR, 0.77, 95%CI, 0.50-1.11) or DPP-4 inhibitors (5 trials; OR, 0.69; 95%CI, 0.38-1.25).

CONCLUSIONS: SGLT2 inhibitors may be associated with a lower risk of depression, whereas no significant decrease in the risk was observed for GLP-1RAs and DPP-4 inhibitors. Comparative effectiveness studies using real-world data are warranted to confirm our findings.