Discussion
Taken together, the findings of our nationwide case-control study of
persons with diabetes do not support the suggestion of lower risk of PD
among statin users based on earlier studies on the general population
[5,6] or persons with diabetes [8-10]. On the contrary, higher
risk of PD in those with highest cumulative statin exposure was
observed, regardless of whether nonusers or those with lowest cumulative
exposure were used as the reference group. No association was observed
when medium or low cumulative exposure tertile was compared to statin
no-use, nor when medium tertile was compared to low cumulative exposure
tertile. Considering the high DDDs of highest cumulative statin exposure
tertiles (mean 2500+ DDDs) in both analyses, statin exposure within
these groups can be considered long-term.
Our findings are not in line with previous studies reporting lower risk
of PD among statin users with diabetes [8-10]. However,
methodological differences may partly explain the differences. In our
case-control study, we matched cases and controls according to diabetes
duration, whereas only one of the earlier cohort studies propensity
score-matched for diabetes duration [10]. In addition, all persons
in our study had used diabetes medications during the exposure
assessment time, and those 44 (<0.5% of the study population)
who had not yet initiated their diabetes medications during the exposure
assessment time did so during the lag time [18]. In contrast, two of
the prior studies apparently also included those with who managed with
lifestyle modifications [8,10]. Furthermore, one study was
restricted to metformin users, leaving out persons with diabetes who
were treated with other diabetes medications [9]. Further, to
account for reverse causality, i.e., impact of prodromal PD symptoms on
contact with prescribers increasing the likelihood of changes in drug
exposure among cases, we did not consider exposure during the three-year
lag before the outcome, while all prior studies considered all statin
exposure until the diagnosis of PD. In addition, the exposure levels in
our study differ from the earlier studies: The highest cumulative statin
exposure tertiles started from 616 [8] and 675 [10] DDDs, which
would correspond to less than two years of statin treatment
(atorvastatin 20 mg) [17] which is less than the length of lag time
used in our study. It should also be noted that two of these earlier
studies were based on the same data source, National Health Insurance
reimbursement database of Taiwan, although with different population
sample, follow-up period and definition of statin use [8,10].
Of the two previous nested case-control studies that were not restricted
to persons with diabetes, one found no association between users and
nonusers [19] whereas the other reported that statin use of 12
months or more was associated with increased risk of PD compared to
statin use of less than six months [20]. These nested case–control
studies differed from ours as they included people without diabetes, did
not assess cumulative statin exposure, nor did they utilize lag time.
Interestingly, a case-control study by Liu et al. reported a higher risk
of PD among users of lipophilic statins compared to nonusers, although
the study was limited to persons aged less than 65 years which may limit
the generalizability of results [21].
We applied a three-year lag period to decrease the effect of possible
protopathic bias [22]. The lag duration was based on an earlier
FINPARK study that showed an increase in muscle relaxant use already
three years before PD diagnosis indicating prodromal motor symptoms
[23]. The lag time might be important also due to the observation
that cholesterol levels have been reported to begin declining already 4
years before diagnosis [24]. On the other hand, reverse causality
may partially explain the inverse association in earlier studies with
shorter follow-up time, because initiation of statin therapy or
increasing intensity may be less likely during the prodromal phase of PD
if there is a decline in cholesterol levels [24].
Prescription register accurately represents statin use in Finnish
population as this register includes all reimbursed medication purchases
to which all Finnish citizens are eligible. However, data on drugs used
in hospitals or public nursing homes was not available. Registry-based
study approach effectively controls for selection bias and recall bias.
A common limitation of register-based studies is the accuracy of PD
diagnosis. In our study, we applied data from multiple sources to
ascertain PD cases. Due to reimbursement criteria and additional
exclusions performed by us described earlier [16], it is likely that
these persons had clinically verified PD. In addition, the proportion of
excluded cases in the FINPARK study (25.9%) is in line with the
estimated proportion of false diagnoses [15,25,26]. Weaknesses of
our study include the possibility of residual confounding explaining our
findings.
Duration of diabetes was controlled by matching, but severity of
diabetes was unknown. However, if diabetes severity is an intermediate
variable between statin use and PD, adjusting for it would not be
feasible as it would introduce overadjustment bias [27]. We could
not adjust for low-density lipoprotein cholesterol levels as they are
not recorded in the registers. However, as higher low-density
lipoprotein cholesterol levels have been suggested to be a significant
confounder for the association between statin use and lower risk of PD
in earlier studies [7], and we observed a slightly higher risk of PD
among those with higher statin exposure and no association in the
use-nonuse analyses, it seems unlikely that adjustment for low-density
lipoprotein cholesterol levels would have led towards an inverse among
statin users.
To decrease the influence of confounding by indication we restricted our
study to persons with diabetes, a population at increased risk of PD
[13,14]. Due to the resulting limitation in sample size, we were
unable to assess whether the association of increased risk of PD with
high cumulative statin exposure was driven by specific statins, statin
therapy intensity or the length of exposure, or any combination thereof.
In addition, our study included persons who had used multiple statins
and therefore we did not perform more detailed statin -specific
analyses. It has been suggested that the association between statins and
PD is different for lipophilic and hydrophilic statins [21].
However, all statins regardless of their lipophilicity can cross the
blood-brain barrier, although lipophilic statin may impair brain
cholesterol synthesis slightly more [28]. In our study the number of
hydrophilic statin users was small due to major overlap with lipophilic
statin use. Therefore, we did not perform dose-response analyses based
on different categories. It has been suggested that initiation of statin
therapy may rapidly “unmask” PD in those with preclinical symptoms
[11,29]. We did not explore the unmasking theory as any association
near PD diagnosis would be indistinguishable from protopathic bias;
Incidence of preclinical PD symptoms may increase healthcare contacts
which can increase the likelihood of initiation of statin therapy.
However, since the prevalence of statin users only during the lag time
was indifferent between PD cases and controls, our results do not
support this theory.
Our nationwide study that controlled for diabetes duration and reverse
causality does not provide support for the hypothesis that statin use
decreases the risk of PD.