Association of GLP1RAs with risk of chronic obstructive pulmonary disease: evidence from drug target Mendelian randomization.

BACKGROUND

Glucose-lowering glucagon-like peptide-1 receptor agonists (GLP1RAs) are widely used to treat type 2 diabetes (T2D) and obesity. However, their potential benefits in pulmonary diseases remain unclear. To address this, we used Mendelian randomization (MR) analysis to assess the causal effects of genetically proxied GLP1RAs on chronic obstructive pulmonary disease (COPD) and related conditions, including bronchitis and asthma.

METHODS

We selected cis-expression quantitative trait loci (cis-eQTLs) as instrumental variables to genetically proxy GLP1RAs. Summary-level data were obtained from the eQTLGen and FinnGen consortia. MR analyses were used to identify the association between genetically proxied GLP1RAs and COPD, as well as COPD-related diseases. T2D, HbA1c levels, and BMI were used as positive controls.

RESULTS

After Benjamini-Hochberg correction for multiple testing, MR analyses indicated that genetically predicted GLP1RAs were significantly associated with lower risks of COPD (OR [95% CI] = 0.838 [0.74-0.948], P = 0.013), early-onset COPD (< 65 years) (OR [95% CI] = 0.751[0.622-0.906], P = 0.01), COPD-related respiratory insufficiency (OR [95% CI] = 0.720[0.55-0.944], P = 0.024), acute bronchitis (OR [95% CI] = 0.787 [0.693-0.893], P = 0.002), asthma (OR [95% CI] = 0.872 [0.782-0.973], P = 0.023), and other symptoms and signs involving the circulatory and respiratory systems (OR [95% CI] = 0.426 [0.217-0.834], P = 0.023). No significant association was observed for later-onset COPD (≥ 65 years) (OR [95% CI] = 0.921 [0.783-1.082], P = 0.315) or chronic bronchitis risk (OR [95% CI] = 0.950 [0.889-1.016], P = 0.146).

CONCLUSIONS

Genetically predicted GLP1RAs are associated with a lower risk of early-onset COPD, COPD-related respiratory insufficiency, acute bronchitis, and asthma. These findings highlight potential benefits of GLP1RAs in T2D patients with coexisting pulmonary diseases and support the need for further investigation in COPD management.