Pleiotropic effects of statins on the treatment of chronic periodontitis – a systematic review

Abstract

Aim

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss.

Methods

In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected.

Results

Statins have important anti-inflammatory and immune effects, reducing levels of C-reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-α, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts.

Conclusion

Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis.

Introduction

Periodontitis (PD) is a worldwide health problem and affects almost half of the population aged 30 years or older in the United States 1. It is estimated that 5 to 15% of the global population present with the severe forms of PD 2. Its development is related to the formation of a periodontopathogenic biofilm, which induces a periodontal inflammatory response 3,4. Although it is known that microbial challenge is necessary for the development of PD, the host's inflammatory response is ultimately responsible for the appearance of its main clinical features, such as bone loss and periodontal tissue collapse 5,6.

The origin and progression of chronic PD are caused by the interaction of infections caused by periodontopathogenic bacteria and the host's immune response. Systemic, environmental and genetic factors may contribute to its pathogenesis 7. The bacterial byproducts and pro-inflammatory cytokines cause the destruction of periodontal tissue and consequent generation of bone defects that may lead to tooth loss 8. Besides, activated lymphocytes and macrophages infiltrate the inflamed gingival tissue and secrete inflammatory mediators, as interleukin (IL)-1β and prostaglandin E₂ (PGE₂), which can induce bone resorption directly or indirectly, promoting proliferation, activation and differentiation of precursors of osteoclasts and mature osteoclasts 9.

The prerequisites for successful conventional periodontal treatment are patient cooperation, adequate oral hygiene and the mechanical debridement of all dental surfaces 10. This therapy consists of eliminating bacterial deposits existing on the surfaces of teeth, in order to restore the health of the periodontal tissues 11.

Statins, or inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), form an important group of hypolipidaemic drugs that competitively and reversibly inhibit the synthesis of mevalonate, which is the precursor of the synthesis of cholesterol and isoprenoids of great biologic importance, such as geranylgeranyl diphosphate and farnesyl diphosphate 12.

Statins are the most used hypolipidaemic agents due to their effectiveness in reducing the concentration of blood cholesterol and their excellent tolerability, safety and low cost 13. The competitive inhibition of the enzyme HMG-CoA reductase by statins causes compensatory cellular responses, such as higher expression of receptors for low density lipoproteins (LDL) and HMG-CoA reductase. The compensatory increase in HMG-CoA reductase receptors slightly reduces the synthesis of cellular cholesterol, but the elimination of the latter by the LDL receptor mechanism is remarkably potentiated, leading to maintained reductions in serum cholesterol 14.

The general clinical benefits observed in therapy with statins seem to be greater than expected. Statins have an action mechanism similar to the nitrogenous bisphosphonates, inhibiting the mevalonate pathway, being successfully used in the systemic treatment of osteoporosis for acting selectively on the bone tissue and interfering in the action of osteoclasts 15.

In addition to stimulating properties in the bone tissue, statins also have other pleiotropic effects, such as anti-inflammatory and immunomodulatory effects 16. These drugs have been widely studied because they might be beneficial in various dental specialties in which bone formation, reduction of inflammation and immunomodulation are essential for a successful treatment 17,18. The aim of this study is to review the literature in order to evaluate if statins could influence periodontal treatment, improving clinical and radiographic parameters in chronic PD.

Methods

The search for articles was executed in the BIREME and PUBMED databases using the combined key words: statin, periodontal disease, alveolar bone and PD, in English and in Portuguese. Articles published in English and in Portuguese, within the period from 2004 to 2014, were included.

After the complete reading of all texts, the following criteria were considered for inclusion: randomized and controlled clinical trials or cohort clinical studies of chronic PDs in humans, blind studies or double-blind studies, studies which used statins topically or systemically as an adjunct to scaling and root planing or which evaluated the effects of statins in periodontal tissues.

To minimize the possibility of review bias, the screening of articles was carried out independently by two reviewers (IMGE and PBT). Discrepancies regarding inclusion or exclusion of studies were solved by discussions between the reviewers who selected the studies. In cases of doubt, a third examiner (MMSMM) was consulted. There were 73 articles found, 69 in English and two in Portuguese, from the last 10 years. After the application of the inclusion criteria, 11 articles were selected.

Results

From the selected studies, five were controlled and randomized clinical trials 19–23 and six were cohort studies 24–29. Generally, the primary outcome analyzed was the probing depth or the clinical attachment level 19–22,25,27. Two studies 24,29 used tooth loss as the primary outcome, while Saxlin et al. 26 analyzed, primarily, the number of teeth with increased probing depth. Subramanian et al. 23 used ¹⁸F-fluorodeoxyglucose re-uptake as the primary outcome (Table 1).

Table 1.

studies regarding the effects of statins on periodontitis

Reference	Subject distribution	Study design	Main results
Saver et al. [24]	Statin users: 12 631	Cohort	Use of statins was not associated with increase or decrease in tooth loss.
Lindy et al. [25]	Statin users: 21	Cohort	Statin users presented 37% lower number of pathological periodontal pockets and 40% smaller Periodontal Inflammatory Burden Index.
	Non-users: 76
Saxlin et al. [26]	Statins users: 2 032	Cohort	Statin usage was not associated with the number of ≥ 4 mm periodontal pockets among patients with gingival bleeding. Among patients with no gingival bleeding, statins seemed to have increased the number of ≥ 4 mm periodontal pockets.
Pradeep & Thorat [20]	SRP + 1.2% simvastatin gel (local delivery): 30	Randomized controlled double-blind	Patients who received subgingival statin application presented with better improvements in PD, CAL and GI when compared with patients who received the placebo gel.
	SRP + placebo gel (local delivery): 30
Fajardo et al. [19]	SRP + daily 20 mg of atorvastatin (systemic delivery): 19	Randomized controlled double-blind	Individuals who took atorvastatin presented improvements in PD, tooth mobility and radiographic depth of intrabony defects.
	SRP + placebo (systemic delivery): 19
Meisel et al. [27]	Statin users: 219	Cohort	Gingival plaque and loss of CAL were related to increased systemic LDL and CRP concentrations.
	Non-users: 2937		When adjusted to age, gender, smoking, diabetes, education and dental service, statins were identified as effect modifiers, rescinding the relation between CAL and gingival bacterial plaque with the increase of LDL (P < 0.001).
Pradeep et al. [22]	SRP + 1.2% simvastatin gel (local delivery): 17*	Randomized controlled double-blind	Patients treated with simvastatin presented with a higher change in PD, CAL, depth of intrabony defect and percentage of bone defect fill.
	SRP + placebo (local delivery): 18*
Sangwan et al. [28]	Statin users: 50	Cross-sectional single-blind	PD and GI were higher in non-statin users in comparison with statin users and healthy individuals. No differences in periodontal parameters were found between statin users and healthy patients.
	Non-pharmacological treatment: 44
	Healthy controls: 46
Pradeep et al. [21]	SRP + 1.2% atorvastatin gel (locally delivery): not clear	Randomized controlled double-blind	Individuals who received the atorvastatin gel presented with a major reduction in PD, CAL, depth of intrabony defect and percentage of bone defect fill.
	SRP + placebo (local delivery): not clear
	Total of 60 patients.
Subramanian et al. [23]	Daily 80 mg of atorvastatin: 30	Randomized controlled double-blind	Patients receiving daily 80 mg of atorvastatin presented with lower periodontal inflammation (evaluated by 18F-fluorodeoxyglucose positron emission tomography).
	Daily 10 mg of atorvastatin: 29
Meisel et al. [29]	Statin users: 134	Cohort	Patients who used statins throughout the study presented lower prevalence of tooth loss.
	Non-users: 2 555

^*Patients with diabetes. CAL, clinical attachment level; CRP, C-reactive protein; GI, gingival index; LDL, low density lipoproteins; PD, probing depth; SRP, scaling and root planing.

The results of the observational study conducted by Saver et al. 24, which aimed to evaluate, in 12 631 subjects, the relationship between tooth losses caused by chronic PD and the usage of statins over a period of 3 years did not provide any support for the hypothesis that the use of statins could improve the course of chronic PD. The authors evaluated the health plans comprising the using of dental and periodontal treatment, dental extractions and drugs prescriptions. Before the adjustment of the results in respect to possible risk factors, such as diabetes or smoking, the usage of statins was associated with a higher risk of tooth loss. However, after these adjustments were made, there was no suggestion that the use of statins could increase or reduce tooth loss.

Lindy et al. 25 conducted a study which aimed to examine the association of the usage of statins and clinical markers of chronic PD. The probing depth values were collected from the dental registries of 100 patients being treated for chronic PD. The numbers of sites containing moderate periodontal pockets, between 4 and 6 mm of depth, and deep periodontal pockets, deeper than 6 mm, were registered separately. A new index, the periodontal inflammatory burden index, was obtained in this study from the probing depth values. Patients with PD who used statins had a 37% smaller number of pathologic periodontal pockets and presented average values of periodontal inflammatory burden 40% lower than those without that medication. These differences were statistically significant. Subjects who used statins presented milder signs of periodontal inflammatory lesion than those subjects without the statin regimen.

The study conducted by Saxlin et al. 26, to evaluate the periodontal condition of patients with hyperlipidaemia and users of statins, selected 2032 subjects aged between 40 and 69 years. Subjects with diabetes or rheumatic arthritis were excluded because of the complex relation between periodontal infection and these conditions. The periodontal infection was measured in two ways: by taking the number of teeth with periodontal pockets deeper than 4 mm and the number of teeth with periodontal pockets deeper than 6 mm. Among the 134 subjects who used statins, 58 of them used simvastatin, 38 used atorvastatin and the remaining 38 subjects used other kinds of statins. All of the participants underwent periodontal examination which included plaque index, bleeding index, probing depth and clinical attachment level. Researchers found a weak negative association between the usage of statins and periodontal infection in subjects with plaque and gingival bleeding. They also observed that, among subjects without periodontal bleeding, the usage of statins was associated with a higher chance of deep periodontal pockets, suggesting that the medication exerts an effect on the periodontium which depends on its inflammatory condition.

Pradeep & Thorat 20 investigated the efficacy of a 1.2% simvastatin gel as an adjunct to scaling and root planing on chronic PD treatment. The study evaluated 60 patients diagnosed with that condition but systemically healthy. The selected patients were divided into two groups, the group that received the placebo gel and the one that received the gel with 1.2 mg of simvastatin, which was injected into the periodontal pocket after mechanical treatment. The clinical parameters of the sulcus bleeding index, probing depth and clinical attachment level were registered at the beginning of the study and after 1, 2, 4 and 6 months. The radiographic evaluation of the bone defect was made at the beginning of the study and after 6 months. The authors concluded that in the sites with chronic PD treated with scaling and root planing and local application of simvastatin gel there was a greater gain of clinical attachment with significant bone fill.

A double-blind controlled study, conducted by Fajardo et al. 19, included 38 subjects with chronic PD divided into two groups, paired by age, to receive atorvastatin (20 mg) or placebo (20 mg) once a day for 3 months. Mechanical treatment was performed on both groups at the beginning of the study. The clinical and radiographic parameters and the markers of bone remodelling were evaluated at the beginning of the study and after 3 months. Results showed that there was a significant improvement in tooth mobility and reduction of the distance between the alveolar crest and the cementoenamel junction, suggesting that atorvastatin may have beneficial effects on the alveolar bone and on tooth mobility in patients with chronic PD.

A cross-sectional study conducted by Meisel et al. 27, aiming to evaluate the influence of statins on periodontal parameters, included subjects older than 30 years and excluded the toothless. They identified 219 subjects who used statins and 2937 who did not use the drug. Results showed that the levels of C-reactive protein (CRP) were higher in patients with peridontitis, but this relation was not found in patients with periodontal disease who took statins. Gingival plaque and loss of periodontal attachment were associated with increased concentrations of LDL cholesterol (P < 0.001) and CRP. When adjusted for age, gender, smoking, diabetes, education and dental service, statins were identified as effect modifiers, rescinding the relation between loss of attachment and gingival bacterial plaque with the increase of LDL (P < 0.001).

Pradeep et al. 22 developed a study to investigate the efficacy of a 1.2% simvastatin biodegradable gel of controlled release as adjunct to scaling and root planing in 38 patients with diabetes and chronic PD. After the non-surgical periodontal treatment, patients were divided into two groups which received the 1.2% simvastatin gel or placebo. The clinical parameters were measured before root scaling and after 3, 6 and 9 months. Radiographic examinations for the evaluation of intrabony defects were inspected at the beginning of the study and after 6 and 9 months. There was a greater decrease in the bleeding on probing index, the probing depth and the clinical attachment level, and a significant increase in the percentage of bone fill, in the sites treated with 1.2% simvastatin gel applied topically in patients with type 2 diabetes and chronic PD.

In the cross-sectional study carried out by Sangwan et al. 28, 94 patients with hyperlipidaemia were divided into two groups. Fifty subjects used atorvastatin (20 mg day⁻¹, orally) and 44 received non-pharmacological treatment for at least 3 months. The control group was formed with 46 normolipidaemic subjects. The participants underwent periodontal examination which included plaque index, gingival bleeding index, probing depth and clinical attachment level. Hyperlipidaemic patients who were not users of statins, when compared with normolipidaemic subjects and the hyperlipidaemic group which used statins, had a significantly greater gingival bleeding index and probing depth. The study concluded that statins have a positive effect on periodontal health.

In a study developed by Pradeep et al. 21, 60 individuals with PD were treated with scaling and root planing and a single subgingival administration of 1.2% atorvastatin gel or placebo gel. Clinical periodontal evaluation, as well as radiographic assessment of the intrabony defects, were performed 3, 6 and 9 months after the treatment was rendered. The group treated with subgingivally delivered atorvastatin presented a significantly higher change in the periodontal parameters, such as probing depth and clinical attachment level, and in the radiographic parameters, such as depth of intrabony defects and radiographic defect fill.

Subramanian et al. 23 performed a randomized clinical trial in which periodontal patients with risk factors or established atherosclerosis were assigned into groups that received, daily, 80 mg or 10 mg of atorvastatin orally. The periodontal and carotid inflammation were assessed by ¹⁸F-fluorodeoxyglucose positron emission tomography at baseline and at 4 and 12 weeks of treatment. The group that received the higher dose of the medicine presented a significantly lower periodontal inflammation in comparison with those receiving the lower dose. This difference was even more significant in patients with severe bone loss and periodontal inflammation at baseline. Moreover, there was a correlation between the improvements of periodontal and carotid inflammation.

Meisel et al. 29 performed a 5 year cohort study and compared the prevalence of tooth loss in individuals treated and not treated with statins using regression models. When the results were adjusted for age and gender, the use of statins was associated with reduced tooth loss. This association was even higher when adjustments for periodontal risk factors were performed. They also showed that tooth loss had a significant association with LDL concentrations and that the usage of statins was associated with a reduction in tooth loss independently of the LDL concentration.

Discussion

Effects on bone formation (bone morphogenetic protein-2 and osteoprotegerin)

Alveolar bone loss is one of the characteristics of PD, and the suppression of bone resorption is one of the goals in periodontal treatment. Mundy et al. 30 found that the addition of statins to organ cultured neonatal murine calvaria increased new bone formation by two to three-fold. It was shown for the first time that statins, specially simvastatin and atorvastatin, could increase angiogenesis and the expression of messenger RNA (mRNA) of bone morphogenetic protein-2 (BMP-2) in osteoblasts 30.

Since then, many studies have been conducted to verify the effects of statins in bone tissue and their clinical applicability. In vitro studies were carried out, in which different statins were able to stimulate osteogenic differentiation and inhibit adipogenic differentiation simultaneously in mesenchymal cells from the bone marrow 31–33. Studies in animals confirmed the anabolic 34–37 and the antiresorptive 18,38 effect of statins in oral and maxillofacial bone tissue, as well as bone tissue from other locations such as tibia 39,40 and calvaria 17,41,42. Recent studies in humans also showed that the usage of statins has a positive effect on the reduction of alveolar bone defects 20–23, this being reflected in the periodontal health 28,29. Furthermore, their use might be related to a smaller depth of periodontal pockets and to less inflammatory signs in the periodontal disease 21,23,26.

Studies indicate that the topical application of this drug in the bone microenvironment stimulates bone formation 20–22. Positive results were reported during the regeneration of bone defects after the application of simvastatin with different carriers, such as calcium sulfate 41, methylcellulose gel 20–22,43,44, bovine bone matrix 42, collagen sponge 45 and the bisphosphonate alendronate 34.

It is suggested that low concentrations of topically applied statins bear positive effects over the proliferation of osteoblasts and the differentiation of human periodontal ligament cells 43,46. A lower dose of a statin may reduce inflammation in soft tissues without implications for the effect on bone formation 35,43. Other studies showed that the effect of statins on bone repair presents a positive dose-dependent relationship 32,47. It is important to consider that, in the study of Subramarian et al. 23, there was no evidence of dose dependence, because the group receiving daily 10 mg of atorvastatin did not show any beneficial effects. The lack of action of the medicine observed in that group might be due to the fact that some patients had taken statins before being enrolled in the research 23,48.

The main advantage of the local administration of statins is a greater local bioavailability 40. Results of studies in which statins were topically applied to the location where bone repair was desired showed that there was significant bone formation, even though a low concentration of the drug was administrated (Table 1) 20–22. The study which administrated the drug systemically, in turn, used a much higher dose, though without analyzing the dose–response effect 19. The hepato-selectivity of statins also hinders their action on bone tissue, when administrated systemically 49.

The significant reduction in the depth of periodontal pockets may suggest a gain in bone height 19–23. This finding was observed radiographically or tomographically in various studies from the significant reduction in the distance between the cementoenamel junction and the alveolar crest 19–23. The bone formation may be due to the role that statins have in the increase of BMP-2 expression, increase of angiogenesis and reduction of inflammation during wound healing 30. A study 44 showed that the increase in the levels of BMP-2 related to the use of simvastatin may be dependent on the levels of cyclooxygenase-2 (COX-2).

The antiresorptive effect of the statins seems to be a result of the increased production of mRNA of osteoprotegerin (OPG) by osteoblasts. In these cells, atorvastatin increased up to three times the production of mRNA of OPG 50. It was also verified that, in inflammatory conditions, the production of OPG by human gingival fibroblasts can be increased up to 10 times 51.

The effect of the statins upon bone formation is, in part, due to their role as an immunomodulator agents, by their ability to block the synthesis of important isoprenoid intermediates 16,52. Thus, the interference in isoprenoid production leads to the formation of osteoclasts with wrinkled margins. Consequently, osteoblasts are inactivated and bone resorption is inhibited 15,53.

It has been shown that statins are able to reduce the incidence of steroid-induced osteonecrosis 54–56. The better, yet not completely, understood mechanism by which statins affect osteonecrosis might help to explain its effects on PD. In vitro, Li et al. 31 showed that lovastatin was able to enhance osteoblastic differentiation, up-regulate osteblastic genic expression and increase osteocalcin activity in multipotential cell lines. Jiang et al. 56 found that pravastatin up-regulated the Wnt signalling pathway, leading to enhanced osteoblastic differentiation and protection of steroid-induced osteonecrosis in rats. These mechanisms might help to explain the increased radiographic bone fill observed in some studies following statins administration in periodontal patients 20–23.

Although many studies have found a positive effect of statins on bone formation and repair, some others do not confirm this finding 24,49,57–60. Therefore, more studies regarding the usage of statins are encouraged in order to clarify its effects on alveolar bone metabolism.

Anti-inflammatory and immunomodulator effects

Apparently, the beneficial effects of statins might be partially mediated by the pleiotropic anti-inflammatory effect that this drug has on the periodontal tissue. Protection from periodontal disease was observed in the results of Lindy et al. 25, which showed a clear effect that subjects who used statins presented with less clinical signs of inflammatory s when compared with subjects without the statins regimen. The study showed that the increasing periodontal destruction which goes along with ageing was not apparent in statins users.

The findings of Saxlin et al. 26 partially concur with the results of Lindy et al. 25. Saxlin et al. 26 suggest that statins provoke beneficial effects when a primary aetiologic factor, dental biofilm or any sign of periodontal infection or gingival bleeding, occurs in the host. Thus, subjects who use statins and do not present with a dental biofilm or gingival bleeding have a higher chance of having deep periodontal pockets. The results of Pradeep & Thorat 20, Fajardo et al. 19, Pradeep et al. 22, Sangwan et al. 28 and Subramanian et al. 23 are similar to the results obtained by Lindy et al. 25 regarding the anti-inflammatory effects of the statins.

The significant decrease in tooth mobility found in patients who received atorvastatin might be explained by the anti-inflammatory effect of this drug 19. The improvement in the periodontal clinical parameters observed in all groups of the study may be an outcome of the non-surgical periodontal treatment and of the oral hygiene instructions provided at the beginning of the treatment for all participants with chronic PD. Identical results were obtained by Pradeep et al. 22 and Pradeep et al. 21, who observed the reduction of bleeding on probing from the beginning of the study until after 6 months of simvastatin or atorvastatin usage. Therefore, it is suggested that the observed anti-inflammatory effect is caused by the drug, since both groups improved plaque control.

High levels of CRP were observed in patients with PD, when compared with periodontally healthy patients 27. Elevated concentrations of CRP have been associated with tooth loss in patients with high LDL 29. However, this increase was not found in periodontally affected patients who used statins 27. These findings concur with the ones from another study 61 in which it was observed that statins were able to decrease levels of CRP after only 6 weeks of treatment.

Statins may also be able to influence the level of tissue destruction in periodontal disease due to their interaction with the immune response from the host, inhibiting adhesion and extravasation of leukocytes in inflammation sites, resulting in diminished co-stimulation of T cells and the decrease of inflammatory cytokines, such as IL-1β, IL-6 and tumour necrosis factor-α (TNF-α) 52,62. A clear immunomodulator action can be observed by the decrease in production of IL-1β, IL-6 and TNF-α by cells from the periodontal ligament induced by simvastatin 63. These mechanisms might partially explain the benefits of statins upon diseases in which inflammation is a component of pathogenesis 21,22,28.

Few studies have evaluated the effects of statins on the levels of inflammatory cytokines in gingival crevicular fluid (GCF). Fentogul et al. 64 showed that the levels of TNF-α in the GCF of patients with PD reduced after 3 months of systemic administration of statins. Periodontal treatment, associated with statin usage, also reduced the crevicular levels of IL-6 64. It has been shown that GCF concentrations of IL-6, in individuals with PD and taking statins, was positively correlated with the bleed on probing, as the GCF concentrations of TNF-α were associated with increased probing pocket depth and clinical attachment level 65. Another study 66 showed that patients with PD and using statins chronically presented with lower levels of IL-1β in the GCF in comparison with periodontal patients who were not taking statins.

Matrix metalloproteinases (MMP) are considered one of the main proteinases involved in the destruction of the periodontium 67. It was verified in vitro that statins decreased the secretion of MMP-1, MMP-2, MMP-3 and MMP-9 and significantly inhibited the expression of mRNA of MMP-8 and MMP-9 67,68. It is suggested that the inhibition of MMP-1 by simvastatin was the result of the suppression of the expression of mRNA of MMP, which may be related to the reduction of isoprenoid intermediates 53.

Conclusion

Although there are few studies of the applicability of statins in chronic PD in the literature, results indicate that statins hold beneficial effects, stimulating bone formation and decreasing inflammation and immunomodulation. This implies that this group of drugs might have a great potential to improve the therapeutic effect in the treatment of PD, since they are safe and not costly, but not as a substitute for the standard of periodontal treatment, which consists in removing microorganisms, considered to be the primary aetiologic factor of the disease. New studies are needed to evaluate the clinical applicability of the statins in the treatment of chronic PD.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.