Methods
This case-control study, nested into population of Finland, was based on
The Finnish Parkinson’s disease
study (FINPARK), which includes 22,189 community-dwelling persons who
received clinically verified PD diagnosis during 1996–2015. Special
Reimbursement Register maintained by the Social Insurance Institution of
Finland was used to identify persons with PD diagnosis. PD diagnosis was
based on United Kingdom Parkinson’s Disease Society Brain Bank’s
criteria [15]. The FINPARK study and exclusion diagnoses have been
described in detail previously [16].
Identification of persons with diabetes within the FINPARK cohort was
done using Special Reimbursement Register (code 103, since 1972) and
Prescription Register (Anatomical
Therapeutic Chemical classification (ATC) [17]; ATC code A10
excluding guar gum, since 1995). Prescription Register contains
information on all reimbursed prescription drug dispensing for
community-dwelling persons as it does not include drug use during
hospital or public nursing home care. Cases who received diabetes
diagnosis after PD diagnosis (n=927) or less than three years before PD
diagnosis date (index date) (n=639) were excluded (Figure 1). Up to four
controls were matched for every PD case by age (+/- 2 years), sex, same
or adjacent university hospital district, and time from diabetes
diagnosis (+/- 2 years). Controls were persons without PD using the same
exclusion criteria that was applied to PD cases. In addition, controls
who had dementia in Parkinson’s disease (ICD-10 code F02.3) within two
years of index date were excluded. Furthermore, 16 PD cases were
excluded as no controls could be matched to them.
The final study population for our main analysis included 2,017 cases
and 7,934 matched controls. To address healthy user bias and confounding
by indication, we performed a secondary analysis restricted to statin
users only (1,045 cases and 2,817 controls after excluding cases and
controls who were unmatched after the exclusion of nonusers).
The first purchases of statins among PD cases and controls since 1995
were collected from the Prescription Register. Statin use was defined
using ATC codes and included simvastatin, lovastatin, pravastatin,
fluvastatin, atorvastatin, cerivastatin, and rosuvastatin (supplementary
table 1). While pitavastatin is authorized for sale in Finland, no
purchases were present in the study data. A three-year lag time was used
to exclude statin purchases that were made within a three-year period
before PD diagnosis. Statin use was categorized as non-use, statin use
initiated during lag time and use before three-year lag. Cumulative
statin exposure was defined as a continuous variable by defined daily
dose (DDD) [17] which was then divided into tertiles.
Identification of comorbidities (any cardiovascular disease, coronary
artery disease, history of cancer, asthma or
chronic obstructive pulmonary
disease (COPD), stroke, history of traumatic brain injury, and
rheumatoid arthritis and connective tissue diseases) is described in
detail in Supplementary Table 2. Care Register for Health Care
(International Classification of Diseases 8th,
9th, and 10th revision), Special
Reimbursement Register (reimbursement codes) and Cancer Register
(International Association of Cancer Registries Tools coding) were used
to identify these conditions before the three-year lag.
T-test and Mann-Whitney U test were used to compare the distribution of
continuous variables and chi square test to compare the distribution of
categorical variables between cases and controls. Conditional logistic
regression was used to calculate odds ratios (OR) and 95% confidence
intervals (CI) for the risk of PD. Results were adjusted for
comorbidities. Persons with no statin purchases before the three-year
lag were the reference group in the main analysis, and the lowest statin
exposure tertile in the secondary analysis. All analyses were performed
using SAS 9.4 software (SAS Institute, Cary, NC).
Collected data was de-identified thus no ethics committee approval was
required according to Finnish legislation.