Use of beta 2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease

Objective To verify the previously reported association between long-term use of beta 2-adrenoreceptor (beta 2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively. Methods We obtained odds ratios (ORs) associating time of beta 2AR agonist and antagonist use with PD risk in nationwide Danish health registries. Results We included 2,790 patients with PD and 11,160 controls. Long-term beta 2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40-0.82) in this cohort. Unexpectedly, short-term beta 2AR agonist use was equally associated (OR 0.64, 95% CI 0.42-0.98). Because beta 2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37-0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59-1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25-0.67) were also inversely associated with PD. Increased PD risk was not found for all beta 2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use. Conclusion We confirmed beta 2AR agonist use to be associated with reduced PD risk and beta 2AR antagonist use with increased PD risk. However, our data indicate the association of beta 2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of beta 2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than beta 2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between beta 2AR agonists and antagonists and PD risk.