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

OBJECTIVES: The European Medicines Agency (EMA) has recently raised concerns about the potential risk of suicide associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, the evidence remains limited. Therefore, we conducted this network meta-analysis of randomized outcome trial data to assess the effect of newer glucose-lowering drugs (GLDs), i.e., GLP-1RAs, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT2) inhibitors, on the risk of suicide.

METHODS: We conducted a systematical search of Pubmed, Embase, and CENTRAL up to November 2023 to identify published randomized placebo-controlled outcome trials focusing on GLP-1RAs, DPP-4 inhibitors, and SGLT2 inhibitors. Suicide outcomes including suicidal ideation, suicide attempts, and completed suicide, were extracted from clinicaltrials.gov. We estimated pooled odds ratios (OR) and 95% confidence interval (CI) using a frequentist network meta-analysis with a random-effects model.

RESULTS: We included 26 trials involving 198,177 adult participants with or without type 2 diabetes. Over a median follow-up of 2.2 years, 104 suicide cases were reported. Network meta-analysis of the 26 included trials revealed that GLP-1RAs (OR, 1.10; 95%CI, 0.57-2.14), DPP-4 inhibitors (OR, 0.54; 95%CI, 0.23-1.29), and SGLT2 inhibitors (OR, 0.83; 95%CI, 0.45-1.52) were not significantly associated with an increased risk of suicide compared to placebo. There was no significant difference between DPP-4 inhibitors and GLP-1RAs (OR, 0.49; 95%CI, 0.16-1.46), between SGLT2 inhibitors and GLP-1RAs (OR, 0.75; 95%CI, 0.31-1.85), or between SGLT2 inhibitors and DPP-4 inhibitors (OR, 1.54; 95%CI, 0.53-4.45). No association with suicide outcomes was found in the comparison of each drug to placebo either.

CONCLUSIONS: This network meta-analysis found no association between newer GLDs and risk of suicide. Real-world data studies are warranted to confirm our findings.