Therapeutic potential of GLP-1RAs in sleep apnea with genetic associations to type 2 diabetes.

BACKGROUND

Some observational studies found that there is an epidemiological association between type 2 diabetes (T2D) and sleep apnea (SA) and glucose-lowering drugs may lower SA risk. However, the causative relationship among them remains unclear.

METHODS

Linkage Disequilibrium Score Regression (LDSC) was utilized to assess the genetic correlation between T2D and SA. Mendelian Randomization (MR) was applied, primarily using the inverse variance weighted (IVW) method, to evaluate the causal relationship between T2D and SA. Additionally, we performed Drug-target MR analysis to evaluate the impact of Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) on SA. We used two kinds of genetic instruments to proxy the exposure of GLP-1RAs, including expression quantitative trait loci of drugs target genes, and genetic variants within drugs target genes associated with glycated hemoglobin A1c(HbA1c) from genome wide association study. Summary-data-based MR (SMR) and IVW were used to calculate the effect estimates. A two-step MR analysis was further employed to explore potential mediating factors in the T2D-SA relationship.

RESULTS

A genetic correlation and bidirectional causal association were found between T2D and SA. GLP-1RAs-mediated reductions in HbA1c levels showed associations with decreased SA risk in two independent datasets: (odds ratio (OR) = 0.48 [95% confidence interval (CI) 0.28-0.83], P = 9.21 × 10; OR = 0.21 [95% CI 0.05-0.92], P = 3.89 × 10); a higher expression of GLP-1R was associated with a decreased risk of SA (OR = 0.98 [95% CI 0.96-1.00], P = 4.55 × 10; OR = 0.95 [95% CI 0.92-0.99], P = 1.71 × 10). Body mass index (BMI) and current tobacco smoking mediated 20.28% and 6.65%, respectively, of the total effect of GLP-1RAs on SA risk.

CONCLUSION

This study suggested a bidirectional causal relationship between T2D and SA, with GLP-1-RAs potentially serving as a therapeutic target for SA. The reduction of SA risk by GLP-1RAs may be partially mediated by decreases in BMI and current tobacco smoking.