Reader response: Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease

This Danish study1 “confirmed (β2-adrenoreceptor [β2AR]) agonist use to be associated with reduced Parkinson disease (PD) risk…,” replicating larger studies in Israel2 and Norway.3 However, the authors' speculations regarding causality, and that smoking may confound the association, conflict with their own study. First, they did not collect smoking data. In Israel,2 the association remained significant after directly adjusting for smoking (which was collected) and smoking-related covariates. Second, even after adjusting for COPD diagnosis, inhaled corticosteroids, and inhaled anticholinergics (their “markers of smoking”), β2AR agonists were significantly associated with reduced PD risk with an OR of 0.64 (0.42–0.98) compared with 0.66 (0.52–0.85) without adjusting (table 4).1 Adjusting for the smoking markers did not attenuate the OR. Once these covariates are statistically controlled, any remaining significant relation between β2AR agonists and reduced PD risk cannot be due to their mediating effects. Whether covariates themselves are related to PD risk is not directly relevant. Third, the beta-blocker propranolol, which increased neuronal SNCA,3 was associated with increased PD risk in Denmark (excluding essential tremor),1 Norway (restricted to cardiovascular indications),3 and Israel (5–8 years lag).2 Finally, β2AR agonists, associated with reduced PD risk after adjusting for smoking-related covariates in Norway,3 Israel,2 and Denmark,1 offered neuroprotection in 3 rodent models.3–5 Thankfully, rodents don't smoke.