Glucagon-like-peptide 1 receptor agonism and attempted suicide: A Mendelian randomisation study to assess a potential causal association

Glucagon-like-peptide 1 receptor agonists (GLP-1RA) have transformed type 2 diabetes (T2D) and obesity management. Multiple regulatory agencies are investigating reported associations between GLP1-RA and increased suicide attempts (SA), but observational data may be prone to confounding. Randomised control trials (RCT) of GLP-1RA were largely undertaken in people at lower risk of SA. Real-world data suggest semaglutide use associates with reduced suicidal ideation and depression but was under-powered to statistically assess risk of SA. Mendelian randomisation (MR) leverages genetic instrument(s) to infer potential causal association between an exposure and an outcome. We undertook MR using missense variants in the gene encoding GLP1R that improve glycemia, lower T2D risk and/or lower BMI, to investigate potential causal association between GLP-1RA and SA. In people of European ancestry, MR did not find evidence genetically proxied GLP1RA increased SA in a general population cohort: (rs10305492, exposure: HbA1c, odds ratio [OR] and 95% confidence interval [CI]: 1.38, 0.41–4.62, p = .60), (rs10305492, exposure: FG, OR 1.27, 0.52–3.13, p = .60) and (rs1042044, exposure BMI, OR 0.30, 0.06–1.48) with concordant results in a multi-ancestry SA case–control cohort. In conclusion, we did not find MR evidence that increased GLP-1RA impacts SA. This awaits confirmation with RCT and real-world data.