Association Between β-Adrenoreceptor Agonists and Antagonists and Parkinson's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: β-agonists and β-antagonists are among the most prescribed drugs worldwide. In 2018, studies suggesting a harmful association between propranolol and Parkinson's disease (PD) prompted a signal procedure by the European Medicines Agency's safety committee, which concluded with no update of product information. Several studies have been published since then. We aimed to systematically review, critically appraise, and meta-analyse all studies on the association between the use of β-antagonists (including propranolol) and β-agonists, and the risk of PD. METHODS: We searched Embase and Medline up to December 2024 for observational and intervention studies that reported relative risk estimates of the association between use of these medicines and PD. Two reviewers screened the records, extracted the data, and assessed the risk of bias. The restricted maximum likelihood method was used to compute pooled effect estimates and 95% confidence intervals (CIs). RESULTS: Twenty-two studies were eligible. Overall, 20 had a high risk of bias in at least one domain. Twelve studies had medium to high risk of outcome misclassification. Of the 14 studies concerning β-antagonists, eleven had an unclear or high risk of protopathic bias, as propranolol is indicated for the treatment of essential tremor. Control for confounding by socio-economic status, area of residence (urban/rural), and smoking (a protective factor against PD) was deficient or lacking in 9/22, 15/22, and 12/22 studies, respectively. Lag times were applied in 9/22 studies. In meta-analysis, the summary relative risk (RR) of PD was 1.41 (95% CI: 1.18-1.68) for the class of β-antagonists (12 studies) and 0.93 (0.84-1.03) for β2-agonists (11 studies). Among specific β-antagonists, the summary RR of PD was 2.36 (1.66-3.36) for propranolol (7 studies), 0.84 (0.80-0.88) for carvedilol (3 studies) and 1.02 (0.87-1.18) for metoprolol (4 studies). For specific β2-agonists, summary RR was 0.88 (0.77-1.01) for salbutamol (7 studies), 0.91 (0.88-0.95) for short-acting β2-agonists (6 studies), and 0.85 (0.76-0.96) for long-acting β2 agonists (5 studies). Restricting to subgroups based on quality criteria resulted in weaker or non-statistically significant associations. CONCLUSION: The quality and quantity of the available evidence do not support a causal association between use of β-adrenoreceptor modulators and PD. Significant associations are most likely explained by protopathic bias and confounding.