Association Between Use of Any of the Drugs Prescribed in Norway and the Subsequent Risk of Parkinson Disease: A Drug-wide Association Study.

BACKGROUND AND OBJECTIVES: The incidence rate of Parkinson disease (PD) has been increasing rapidly during the past years. Yet, no treatments exist to prevent or slow the progression of the disease. Moreover, we are unable to detect early disease stages during which intervention with disease-modifying therapies is most likely to succeed. The objective of this study was to perform an agnostic drug-wide association study estimating the association between the use of any of the drugs prescribed in Norway and the subsequent risk of PD. METHODS: This registry-based cohort study use data from the entire Norwegian population between 2004 and 2019 linked to the Norwegian Prescription Registry, with more than 600 million individual prescriptions. Drug classes were screened according to Anatomical Therapeutic Chemical codes at level 2, corresponding to therapeutic subgroups. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the associations between drug classes and PD risk. All p values were corrected for multiple testing using the false discovery rate. In addition, we conducted sensitivity analyses of exposure definition as well as time-lag and dose-response analyses. RESULTS: The study population comprised 3,223,672 individuals, 15,849 of whom developed PD during the follow-up. We identified 31 drug classes that were statistically significantly associated with PD risk in Norway during the follow-up. Drugs acting on the renin-angiotensin system (HR 0.92, 95% CI 0.89-0.95), corticosteroids for systemic use (0.88, 95% CI 0.84-0.93), and vaccines (0.89, 95% CI 0.82-0.96) were associated with a decreased risk of PD even up to 10 years before PD onset. Drug classes used to treat symptoms related to prodromal signs of PD, such as constipation, urological issues, and depression, were associated with an increased risk of subsequent diagnosis of PD with HRs of 1.6 (95% CI 1.49-1.73), 1.48 (1.42-1.53), and 1.94 (1.87-2.01), respectively. DISCUSSION: This drug-wide study identified 31 drug classes that were associated with the PD risk change. It reveals the links of renin-angiotensin system medications, vaccines, and corticosteroids with PD risk and suggests that monitoring drug usage using pharmacoepidemiology may allow identifying individuals with prodromal PD.

Beta2-adrenoreceptor agonists and long-term risk of Parkinson's disease.

INTRODUCTION: There is limited information on how the association between Parkinson's disease and the use of beta2-adrenoreceptor (ß2AR) agonists varies among groups of short-, long-, and ultra-long-acting ß2AR agonists (SABA, LABA and ultraLABA). METHODS: In this prospective study of the Norwegian population, we estimated the incidence of Parkinson's disease according to exposure to ß2AR agonists as a time-dependent variable by means of Cox regression. We adjusted for educational level, comorbidity and performed a sensitivity analysis excluding individuals with chronic obstructive pulmonary disease (COPD), all factors associated with smoking. Anticholinergics and corticosteroids as drugs with the same indication were analyzed for comparison. RESULTS: In the follow-up period from 2005 to 2019, 15,807 incident Parkinson's cases were identified. After adjustments for sex, education and age as the timescale, SABA (Hazard ratio (HR) = 0.84; 95%CI: 0.79, 0.89; p < 0.001), LABA (HR = 0.85; 95%CI: 0.81, 0.90; p < 0.001) and ultraLABA (HR = 0.6; 95%CI: 0.49, 0.73; p < 0.001) were all associated with a lower risk of Parkinson's disease. After exclusion of COPD patients, corticosteroids and anticholinergics were no longer inversely associated, whereas ß2AR agonists remained associated. CONCLUSION: Of drugs with the same indication of use, only ß2AR agonists remained inversely associated with PD risk after all adjustments, with ultraLABA displaying the overall strongest association. Although the precision of the estimate is limited by the modest number of exposed PD cases without COPD, the association is intriguing and suggest that longer-acting, more lipophilic, and thus likely more brain-penetrant ß2AR agonists could be prioritized for further studies.