Long-Term Statin Use and the Risk of Parkinson's Disease

This historical cohort study demonstrates that long-term statin use is associated with a significant decrease in the incidence of Parkinson's disease.
Published Online: August 12, 2013
Bitya Friedman, MD; Amnon Lahad, MD, MPH; Yizchak Dresner, MD, MS; and Shlomo Vinker, MD
Background: Recent studies have suggested a relation between statin use and the risk of Parkinson’s disease (PD). However, the conclusions are inconsistent. Some studies found an increased incidence of PD among statin users; others found a decreased incidence. Others showed that PD incidence was related to baseline cholesterol levels.

Objectives: To examine the association between baseline levels of low-density lipoprotein cholesterol (LDL-C), long-term statin use, and the incidence of PD.

Methods: The study group consisted of a historical cohort of 94,308 men and women in Israel aged 45 years or more without PD or statin use at baseline, between 2000 and 2007. PD incidence among long-term statin users was compared with that among nonusers. The cohort was divided into 4 groups according to baseline LDL-C levels, and their relative risks of developing PD were  calculated with adjustment for potential confounders (sex, age, socioeconomic status, history of ischemic heart disease, hypertension, stroke, and smoking). The association between different variables was analyzed with a Cox proportional hazards model.

Results: During the study period, 1035 incident cases of PD were identified. Statin use was associated with a significant decrease in the incidence of PD (odds ratio, 0.73, 95% confidence interval, 0.60-0.88; P = .001). No association was found between baseline LDL-C levels and PD risk.

Conclusions: Our results provide additional evidence regarding the lower incidence of PD among statin users. These findings warrant further research regarding the possible neuroprotective role of statins in PD and other neurodegenerative diseases.

Am J Manag Care. 2013;19(8):626-632
Statins are widely used in the prevention of cardiovascular morbidity. In this study, statin use was associated with a significant decrease in the incidence of Parkinson’s disease (PD).
  • This finding adds to our knowledge about the beneficial effects of statins and strengthens the benefit-risk ratio of these medications.

  • The findings warrant further research regarding the possible neuroprotective role of statins in PD and other neurodegenerative diseases.

  • These results also raise the possibility of statin use for prevention of PD progression, especially as statins are known to be safe, inexpensive, and widely available.
Parkinson’s disease (PD) is the second-most common neurodegenerative disorder after Alzheimer's disease, and it causes much disability and suffering for patients and their families. It is a progressive disease with no known cure and becomes more  common as people get older; thus, it will become an even greater and more frequent burden as the worldwide population ages.1 It is imperative that every effort should be made to identify possible preventable causes and risk factors for this disease.

Recent studies have suggested that cardiovascular factors—hypertension, diabetes, hypercholesterolemia, and smoking—play a role in the etiology of PD. A few researchers examined the association between diabetes,2,3 body mass index,4,5 hypertension,6 and PD, and some found a positive correlation. By contrast, however, there is evidence that smoking is a protective factor for PD.7,8

Some studies have also shown an inverse correlation between lowdensity lipoprotein cholesterol (LDL-C) levels and PD incidence, with lower PD incidence rates in people with higher LDL-C levels.9-11 These findings have prompted further investigations on the influence of cholesterol and cholesterol-lowering medications on PD risk.12-16

CHOLESTEROL, STATINS, AND PARKINSON’S DISEASE

Statins (ie, HMG-CoA reductase inhibitors) have been widely used as cholesterol-lowering drugs for more than 15 years. They have been proved to be both effective and safe for preventive treatment of cardiovascular morbidity and mortality. The most common adverse effects associated with statin use are elevation of liver function tests and myopathy.17,18

Investigating the possible influence of statins on PD risk is of great importance not only for improving our understanding of PD etiology, but also for identifying additional potential effects of this widely used medication.

A number of the hypothesized mechanisms in the pathogenesis of PD may be influenced by blood cholesterol levels or by use of statins. Over the past few years, the biologic actions of statins have been a subject of extensive research. A recent review by Roy and Pahan19 summarizes some of the proposed mechanisms by which statins may affect the pathogenesis and progression of PD. Statins have an anti-inflammatory effect and have been shown to attenuate glial activation, inhibit oxidative stress, and protect dopaminergic neurons in animal models of PD.20 They also suppress the aggregation of α-synuclein protein, an important component in PD, as demonstrated in in vitro models.21

It has also been suggested that statins could affect PD via inhibition of HMG-CoA reductase.22 This pathway is shared by coenzyme Q10, known as ubiquinone, which is an important antioxidant and may play a role in PD. An unintended consequence of statins is lowering of coenzyme Q10 levels, thus potentially increasing the risk and worsening the course of PD.23 Another possible link between statins and cholesterol and PD is the apolipoprotein E e2 allele, which is associated with increased incidence of cases of sporadic PD24 and also related to lower levels of LDL-C in the serum.25

According to these various biologic theories, statins may either have a protective or a deleterious effect regarding PD. Empirical evidence is needed to determine their actual effect. Recently, a number of epidemiologic studies have examined the association between cholesterol levels, statin use, and PD incidence.9-16,26 However, these studies have revealed conflicting results with no clear conclusion.

While some studies found a decrease in PD incidence related to statin use,9,12,13,15 others have shown that differences in PD incidence were related to baseline cholesterol levels (ie, cholesterol metabolism playing a role in PD pathogenesis). 9,10,11,26 Most of the latter found an inverse association between serum cholesterol levels and PD incidence; however, one study showed opposite results.26

The conclusions regarding statins varied, with some studies suggesting they have a protective role in PD,9,10,12,13,15 and others not finding any significant association between statin use and PD.11,14,16 These inconsistent results are perhaps due to the diverse methods used and the different populations studied. Many of the studies mentioned the need for a large epidemiologic study to verify their results.

As statins are known to be very safe, cheap, and widely available, we believe that it is important to determine their effect on PD, because this might have practical implications for prevention of this debilitating disease. We set out to study the association between baseline LDL-C level, long-term statin use, and the incidence of PD using our large patient database.

METHODS

This population-based historical cohort study was based on the computerized clinical database of Clalit Health Services, the largest health service in Israel. The database includes laboratory results, a central register of medical diagnoses (smoking, diabetes, hypertension, ischemic heart disease, cerebrovascular accidents [CVAs]), information on medication purchase, and sociodemographic details.27

The study population included all eligible people over the age of 45 years living in 1 administrative region in central Israel, between the years of 2000 and 2007. According to Israeli guidelines, LDL-C measurements are taken routinely as a standard screening for all males over the age of 35 years and all females over the age of 45 years.28

The date of entry into the study was defined as the date of the first measurement of LDL-C as documented in the patient’s file, between January 1, 2001, and December 31, 2005. This date was personal for each participant. Exclusion criteria were (1) existing PD as indicated by use of anti-parkinsonian medication prior to the study period (Table 1); (2) statin use before the commencement of the study; (3) neuroleptic drug use, a frequent cause of secondary parkinsonism (Table 2); (4) change of health insurance during the study; and (5) subjects with no recorded LDL-C value during the study period.

We applied these exclusion criteria to the study population during the year prior to study commencement (ie, January 1, 2000, to December 31, 2000) to ensure that participants had not been exposed to statins or diagnosed with PD before the study period.

Exposure was defined as statin purchase as recorded in the computerized database between the years of 2001 and 2005. Statins purchased were simvastatin (93%), pravastatin, atorvastatin, and rosuvastatin. The level of exposure was calculated as the number of months of statin use before the diagnosis of PD. Statin use was considered chronic if at least 6 monthly prescriptions were dispensed over a period of 9 consecutive months. Purchase of fewer than 6 monthly prescriptions was not considered as exposure.

Outcome was defined as incident of PD as indicated by a record of at least 2 monthly prescriptions for anti-parkinsonian drugs. These drugs are used specifically for parkinsonian symptoms, primary or secondary, while the medical diagnoses in computerized patient files are not always as reliable as the central register.

In order to validate the diagnosis, we reviewed manually 500 medical files of patients identified from the computerized database as having newly diagnosed PD according to the criteria mentioned above. Diagnosis of PD was validated if a clinical diagnosis of PD was recorded in the file at the time that anti-parkinsonian medication was instituted. The diagnosis was validated in more than 90% of the files.

A number of independent confounding variables were included in the statistical analysis, based on previous studies linking them to PD: (1) patient sex; (2) low socioeconomic status (defined as exempted by social security from copayments); (3) history of diabetes, ischemic heart disease, hypertension, or previous CVA; and (4) smoking status as regularly recorded in the electronic files. Due to a high rate of missing data, body mass index was not included in the statistical analysis.

The analysis was conducted in 2 stages. In the first stage, we used the Adult Treatment Panel III classification of cholesterol levels to divide the whole cohort into 4 groups according to baseline LDL-C levels.29 We determined the incidence of PD in the different groups and compared relative risks, adjusting for the potential confounders. In the second stage, we compared the PD incidence among statin users with that among nonusers, adjusting for confounders and for baseline LDL-C levels. The association between the different variables was analyzed by using Cox proportional hazards models.30

RESULTS

The cohort consisted of 94,308 subjects over the age of 45 years, of whom 52.8% were female and 22.3% were defined as having low socioeconomic status (Table 3). The mean age at the end of the study period was 66.90 years (standard deviation, 10.85 years).

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