Objective: To examine the relation of past exposure to statins with Parkinson’s disease (PD) incidence.

Background: Drug repurposing has recently emerged as a promising approach to identify potential PD treatments. Among candidates, a few studies showed an inverse association of statins with PD [1-3], but no cohort studies with a long follow-up and repeated statin use assessment are available. The prodromal PD period raises the issue of reverse causation which has been little addressed in previous observational studies.

Method: E3N is an ongoing French cohort study of 98,995 women recruited in 1990 and surveyed every 24-36 months through self-administered questionnaires on lifestyle and medical history (including PD) and drug claims databases (since 2004) [4]. Incident users who initiated statins after mid-2004 were identified through linked drug claims databases. Incident PD cases were ascertained through a multistep process, and their medical records were examined by an expert panel in order to validate diagnoses; in case of insufficient data, we used a validated PD algorithm [5]. The association of statins with PD incidence until 31/12/2018 was quantified using Cox proportional hazards regression models with age as the time scale, in which the mean daily dose of statins over 5-year periods was included as a time-dependent Weighted Cumulative Exposure index, thus allowing to examine potential susceptibility windows [6]. Exposures were lagged by 5-years to address reverse causation; thus, we examined PD according to past exposures from the 6^th year before end of follow-up going backwards to 2004 (baseline). All analyses were adjusted for rural residence, smoking, physical activity, and co-morbidities (including hypercholesterolemia).

Results: Of 74,143 women aged ≥53 years free of PD at the baseline (mean follow-up=14.5 years), 573 developed PD. For each 0.1 Defined Daily Dose increment, incident exposure to statins 6 to 10 years before PD onset was associated with a non-significant increased risk (Hazard ratio [HR]=1.06, 95% confidence interval [CI]=0.99-1.12), while incident users exposed over the previous 11-15 years had a significantly decreased risk (HR=0.55 [0.43-0.70]). Risk reduction was persistent in a 10-year lagged analysis. We observed similar results for lipophilic and hydrophilic statin subgroups.

Conclusion: Past exposure to statins, but not exposure closer to disease onset, is associated with reduced PD risk.

References: 1. Undela K, Gudala K, Malla S, Bansal D. Statin use and risk of Parkinson’s disease: a meta-analysis of observational studies. J Neurol. 2013;260(1):158-65. 2. Sheng Z, Jia X, Kang M. Statin use and risk of Parkinson’s disease: A meta-analysis. Behav Brain Res. 2016;309:29-34. 3. Yan J, Qiao L, Tian J, Liu A, Wu J, Huang J, et al. Effect of statins on Parkinson’s disease: A systematic review and meta-analysis. Medicine (Baltimore). 2019;98(12):e14852. 4. Clavel-Chapelon F. Cohort Profile: The French E3N Cohort Study. International journal of epidemiology. 2015;44(3):801-9. 5. Moisan F, Gourlet V, Mazurie JL, Dupupet JL, Houssinot J, Goldberg M, et al. Prediction model of Parkinson’s disease based on antiparkinsonian drug claims. American journal of epidemiology. 2011;174(3):354-63. 6. Dankner R, Agay N, Olmer L, Murad H, Keinan Boker L, Balicer RD, et al. Metformin Treatment and Cancer Risk: Cox Regression Analysis, With Time-Dependent Covariates, of 320,000 Persons With Incident Diabetes Mellitus. American journal of epidemiology. 2019;188(10):1794-800.

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