Abstract
BACKGROUND AND AIM: Glucagon-like peptide-1 receptor (GLP-1R) agonists are well-established therapies for obesity and type 2 diabetes mellitus (T2DM). Emerging evidence also suggests their potential role in managing obstructive sleep apnea (OSA). This study aimed to investigate the association between GLP-1R agonists and OSA using genetic evidence. METHODS: Cis-expression quantitative trait loci (cis-eQTLs) associated with the GLP1R gene were identified and used as genetic proxies for GLP-1R agonist exposure. To validate the selected genetic instruments, positive control analyses were conducted for T2DM and body mass index (BMI). Mendelian randomization was employed to evaluate the effect of genetically proxied GLP-1R agonists on OSA. OSA data were obtained from FinnGen Release 11 (R11), comprising 50,200 cases and 401,484 controls of European ancestry. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by heterogeneity tests and sensitivity analyses. RESULTS: IVW analysis showed that genetically predicted GLP-1R agonist exposure was associated with a reduction in BMI (β = -0.063, 95% confidence interval [CI]: -0.10 to -0.03, p = 8.43 × 10(-4)) and a decreased risk of T2DM (odds ratio [OR] = 0.80, 95% CI: 0.65 to 0.98, p = 0.032), supporting the validity of the genetic instruments. Notably, GLP-1R agonists were also associated with a significantly lower risk of OSA (OR = 0.83, 95% CI: 0.76 to 0.91, p = 6.15 × 10(-5)). No evidence of heterogeneity or horizontal pleiotropy was detected, and leave-one-out analysis confirmed the robustness of the findings. CONCLUSION: This study provides genetic evidence supporting the protective role of GLP-1R agonists against OSA, highlighting their potential as a therapeutic strategy for OSA management.