Editors' note: Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease

Abstract

According to epidemiologic data, use of β2-adrenoreceptor agonists has been associated with a significant, and dose-dependent, lower risk of Parkinson disease (PD). Similarly, β2 antagonists have been associated with a higher risk of developing α-synucleinopathy. In an attempt to corroborate these findings, Drs. Hopfner et al. examined population-based data from the Danish health registries. The investigators observed that β2 antagonist use was strongly associated with PD risk, whereas β2 agonists strongly correlated with a lower PD risk. However, potential confounders to these results are the following novel observations: First, driving the effect of β2 antagonists and later PD is the use of propranolol, which the investigators believe may have been used (perhaps incorrectly) to treat essential tremor (ET). Thus, the authors contend that early PD may have been misdiagnosed as ET in these cases. Second, the most common indication for inhaled β2 agonist use in an older population is chronic obstructive pulmonary disease due to tobacco use. As cigarette use has been associated with a reduced risk of PD, it may be that smoking is the actual factor related to the development of PD and not β2 agonist use. Supporting this claim are the findings that COPD diagnosis and use of inhaled anticholinergics were also inversely and independently related to PD. That said, the use of a β2 agonist remains a significant negative predictor of PD in the fully adjusted model, as was noted by Drs. Scherzer et al. in their comment. Drs. Scherzer et al. also maintain that other large studies (which adjusted for tobacco use) have corroborated the β2 agonist hypothesis. The original authors stand by their conclusions that a relationship cannot be decisively confirmed in the present data set given that biomarkers of long-term smoking significantly interact with their outcomes, and that a dose-response and temporal relationship between β2AR remains ambiguous. According to epidemiologic data, use of β2-adrenoreceptor agonists has been associated with a significant, and dose-dependent, lower risk of Parkinson disease (PD). Similarly, β2 antagonists have been associated with a higher risk of developing α-synucleinopathy. In an attempt to corroborate these findings, Drs. Hopfner et al. examined population-based data from the Danish health registries. The investigators observed that β2 antagonist use was strongly associated with PD risk, whereas β2 agonists strongly correlated with a lower PD risk. However, potential confounders to these results are the following novel observations: First, driving the effect of β2 antagonists and later PD is the use of propranolol, which the investigators believe may have been used (perhaps incorrectly) to treat essential tremor (ET). Thus, the authors contend that early PD may have been misdiagnosed as ET in these cases. Second, the most common indication for inhaled β2 agonist use in an older population is chronic obstructive pulmonary disease due to tobacco use. As cigarette use has been associated with a reduced risk of PD, it may be that smoking is the actual factor related to the development of PD and not β2 agonist use. Supporting this claim are the findings that COPD diagnosis and use of inhaled anticholinergics were also inversely and independently related to PD. That said, the use of a β2 agonist remains a significant negative predictor of PD in the fully adjusted model, as was noted by Drs. Scherzer et al. in their comment. Drs. Scherzer et al. also maintain that other large studies (which adjusted for tobacco use) have corroborated the β2 agonist hypothesis. The original authors stand by their conclusions that a relationship cannot be decisively confirmed in the present data set given that biomarkers of long-term smoking significantly interact with their outcomes, and that a dose-response and temporal relationship between β2AR remains ambiguous.