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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 7  |  Issue : 1  |  Page : 8-14

Are statins worthy for treatment of periodontitis? A systematic review and meta-analysis


1 Department of Periodontology, K. M. Shah Dental College and Hospital, Sumandeep Vidyapeeth, Vadodara, Gujarat, India
2 Department of Pediatrics, SBKS Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, Gujarat, India
3 Department of Medicine, SBKS Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, Gujarat, India

Date of Web Publication6-Feb-2017

Correspondence Address:
Monali Shah
Department of Periodontology, K. M. Shah Dental College and Hospital, Sumandeep Vidyapeeth, Pipria, Waghodia, Vadodara, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2321-8568.199531

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  Abstract 

Background: Statins are drugs used for locking the synthesis of cholesterol as it inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. Besides action on cholesterol, statins also possess multiple pleiotropic actions such as anti-inflammatory, immunomodulatory, antioxidant, antithrombotic, angiogenesis promotion and increase in bone formation; other new pleiotropic effects of statins are continuously being described, but their clinical relevance has not been established. Objective: This systematic review and meta-analysis was planned to assess the effect of systemic or local statin therapy on clinical as well as radiographic periodontal parameters in patients with chronic periodontitis. Methodology: A search was performed in the electronic databases of MEDLINE/PubMed, EBSCO and Cochrane databases for randomised controlled trial on humans, and hand search was also carried out. The included articles were screened for their risk of bias and data extracted in predefined format. The meta-analysis was performed using comprehensive meta-analysis. Software: Random effects model was used for pooled analysis. Results: Six studies were included in systematic review having moderate to low risk of bias. Four studies were included in meta-analysis. Results of meta-analysis for clinical parameters such as clinical attachment level (1.95 mm), probing depth (2.28 mm) and marginal sulcular bleeding index (1.10) as well as for radiographic parameters such as intrabony defect (1.90 mm) were statistically significant for locally applied statins. Conclusion: As statins are effective and safe in short-term use and locally delivered and user-friendly, they can be more widely used in periodontal treatment.

Keywords: Local drug delivery, meta-analysis, periodontitis, pleiotropic effect, statins, bone regeneration


How to cite this article:
Shah M, Muley P, Muley A. Are statins worthy for treatment of periodontitis? A systematic review and meta-analysis. Adv Hum Biol 2017;7:8-14

How to cite this URL:
Shah M, Muley P, Muley A. Are statins worthy for treatment of periodontitis? A systematic review and meta-analysis. Adv Hum Biol [serial online] 2017 [cited 2020 Jul 13];7:8-14. Available from: http://www.aihbonline.com/text.asp?2017/7/1/8/199531


  Introduction Top


Statins are drugs used for locking the synthesis of cholesterol as it inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. Besides action on cholesterol, statins also possess multiple pleiotropic actions such as anti-inflammatory, antioxidant, antithrombotic, angiogenesis promotion, immunomodulatory and increase in bone formation. Other than these, many other new pleiotropic effects of statins are continuously being described and evaluated for various indications, but their clinical relevance has not been established.[1] Simvastatin has been reported to promote bone deposition by action on specific bone morphogenetic protein (BMP) which can induce osteoblast differentiation and inhibit osteoclastic activity.[2] Simvastatin increases the release of osteocalcin, type I collagen and bone sialoprotein as well as enhances mineralisation and decreases the production of interleukin-6 and 8 with effect on alkaline phosphatase activity.[3] They also stimulate vascular endothelial growth factor release in dose-dependent manner and may promote osteoblast differentiation.[4] This gave rise to the encouraging hypothesis that use of statins can improve periodontal inflammation and diminish bone loss and thus result in improved tooth preservation.[5]

Periodontitis is a global health problem affecting almost 50% of the population aged more than 30 years. It is estimated that 5%–15% of the world population suffer from severe periodontitis. The interaction of periodontal pathogenic bacteria and the host immune response plays the most important role in origin and progression of periodontitis. Therapies targeting host immunoresponse to periodontal pathogens give promising results.

An increasing number of observational studies reported benefits of statins on tooth preservation or periodontal health benefits.[6],[7] Systemic administration of statin is observed to be associated with fewer signs of periodontal inflammation, beneficial effects on alveolar bone, decreased tooth mobility and reduced risk of tooth loss in patients with periodontal disease when compared with scaling and root planing alone.[8],[9],[10] Evidence from various studies indicates many statin-induced side effects such as rhabdomyolysis, hepatotoxicity, myopathies, diabetes, peripheral neuropathy and others. Although in all evidence the benefits are potential and risk of side effects are less,[11] short-term use and local application of statins still lower the risks of side effects.

Statins when applied locally seem to modulate bone formation and have an anti-inflammatory effect by decreasing the production of interleukin-6.[3],[4] Local drug delivery appears promising as can reduce or omit the side effects of systemic administration of the drug, so the concept of treating localised problem with localised drug is becoming more and more popular. With the objective to improve the periodontal health and achieve periodontal regeneration, various locally delivered drugs have been studied. Local delivery of agents using controlled release systems should be considered as an adjunct to mechanical debridement that is scaling and root planing for the treatment of localised forms of periodontal destruction.[12] Local application of simvastatin has proven to be efficient to stimulate bone formation in vitro for human periodontal ligament cells.[13] Currently, studies using locally delivered statins with different delivery system in periodontal defects have reported positive results.[14],[15]

Many evidence concerning the role of topical simvastatin on bone regeneration comes from animal studies (mainly rats) focusing on extraoral bone defects.[16] To the best of our knowledge, there is no systematic review and meta-analysis published to assess clinical benefit of statins, administered, either systemically or locally on periodontal parameters. This systematic review and meta-analysis was planned to assess the effect of systemic or local statin therapy on clinical as well as radiographic periodontal parameters in patients with chronic periodontitis.


  Methodology Top


Searching

This systematic review and meta-analysis of randomised control trials (RCTs) was carried out to investigate the role of statins in the management of periodontitis. Electronic databases of MEDLINE/PubMed, EBSCO and Cochrane databases were searched for relevant studies. Medical subject headings (MeSH or MH) as search terms when available or keywords such as statin OR simvastatin OR rosavastatin OR atorvastatin AND periodontitis were used, and studies till month of searching, that is, April 2016 were included. We limited the electronic searches to 'human', 'English language' and controlled clinical trials, RCT and clinical trials. The reference lists of identified studies were hand searched for additional studies. Last 1-year issues of Journal of Periodontology, Journal of Clinical Periodontology and articles ahead of print were also searched.

Study eligibility criteria

All RCTs where statin is given in diagnosed cases of periodontitis were included in the study. All non-RCTs, observational studies and studies that did not report the clinical periodontal outcomes were excluded from the study.

Data extraction

All titles and abstracts of retrieved articles were screened by three reviewers independently as per the inclusion and exclusion criteria. The full text was obtained and examined in the absence of sufficient information in title or abstract. A joint decision was achieved after discussion in case of disagreement. The full text of all the included studies was obtained. Relevant data were extracted in predefined format from the included studies. The demographic data, intervention, comparator, follow-up, sample size and outcome monitored were recorded.

Assessment of quality of trial

The risk of bias is assessed based on criteria such as randomisation, allocation concealment, blinding of the examiner, completeness of follow-up, similarity of groups at start of the study using Cochrane collaborations' tool for assessment of bias. When all criteria were met, the risk of bias was estimated as low, more than one criterion was partially fulfilled, moderate risk of bias was assigned and when two or more criteria were not met, a high risk was assigned.

Primary outcome variable

The primary outcome variables were the changes in clinical attachment level (CAL) and changes in the depth of intrabony defect (IBD) measured at baseline and 6-month follow-up.

Secondary outcome variable

Other clinical variable considered were changes in probing depth (PD) and gingival index as measured by marginal sulcular bleeding index (mSBI) at the baseline and 6-month follow-up.

Statistical analysis

The data of study characteristics, drugs and doses used, sample size and outcome were collected. The outcome was difference in means in all studies presented as mean and standard deviation. Studies with follow-up of 6 months were included in the meta-analysis. For data analysis, Comprehensive Meta-analysis software was used. I2 was obtained by applying test for heterogeneity. Random effects model was used and pooled analysis was presented as difference in means and confidence interval (CI).


  Results Top


Studies retrieved

After the extensive and systematic search of the literature, six relevant studies were retrieved,[10],[14],[15],[17],[18],[19] of which four relevant articles were from electronic database [10],[14],[15],[19] and two relevant articles were from hand search [Figure 1].[17],[18]
Figure 1: Searching.

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Risk of bias in included trials

Randomisation and blinding were reported adequately in all studies. Allocation concealment was not reported in three studies [14],[15],[19] while two [17],[18] had unclear information for the same. None of the trial has an issue related to loss of follow-up. The participants who were lost to follow-up were not included in the analysis. In all studies, baseline characteristics were similar. Three studies showed moderate risk of bias and other three showed low risk of bias [Table 1].
Table 1: Risk of bias in included studies

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Study characteristics [Table 2]
Table 2: Study characteristics of included studies

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The number of patients in studies ranged from 38 to 90. The age of the patients included ranged from 25 to 80 years. In most of the studies, an initial periodontal therapy included full-mouth scaling and oral hygiene instructions. Of six studies, four were conducted in India,[14],[15],[17],[18] one in the USA [19] and one in Mexico.[10] Only two studies used systemic atorvastatin and compared low and high dose in one [19] and placebo in other.[10] In other four studies, 1.2% atorvastatin, rosuvastatin or simvastatin gel was compared with placebo gel as local drug delivery system.

Outcome

Changes in clinical attachment level

All studies reported gain in CAL. Gain in CAL reported in statin group ranged from 2.33 ± 0.48[17] to 4.36 ± 1.92 mm [14] and in placebo group it was 1.37 ± 0.49[17] to 2.36 ± 0.51 mm [Table 3].[15] CAL gain was significant in statin group compared to that of placebo using random effects model (standard mean difference [SMD]: 1.94 mm; 95% CI: 1.07–2.80) [Figure 2].
Table 3: Baseline, follow-up and difference in clinical attachment level for studies included in meta-analysis

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Figure 2: Meta-analysis forest plot for CAL.

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Changes in intrabony defect

A significant difference in IBD was observed in statin group as compared to placebo. Reduction in IBD when treated with subgingival application of statins was reported between 2.83 ± 0.53[17] and 1.41 ± 0.74 mm [Table 4].[14] In statin group, significant reduction in IBD was found compared to control group (SMD: 1.90 mm; 95% CI: 1.46–2.35) with significant heterogeneity (I2 = 98.43%, P < 0.00) [Figure 3].
Table 4: Baseline, follow-up and difference in intrabony defect for studies included in meta-analysis

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Figure 3: Meta-analysis forest plot for IBD.

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Changes in probing depth

All studies in meta-analysis had reported significant reduction in PD (P < 0.05). Reduction in PD reported in local statins group ranged from 2.33 ± 0.48[17] to 4.26 ± 1.59 mm,[14] and the same in placebo group was 1.20 ± 1.24 to 1.56 ± 0.53 mm [Table 5].[15] Reduction in PD was significant in local statin group compared to control group (SMD: 2.28; 95% CI: 1.61–2.94) with significant heterogeneity (I2 = 88%, P = 0.001) [Figure 4].
Table 5: Baseline, follow-up and difference in probing depth for studies included in meta-analysis

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Figure 4: Meta-analysis forest plot for PD.

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Changes sulcular bleeding index

Difference in SBI was reported in all included studies and found statistically significant results in both groups. Difference observed in statins group ranges from 1.84 ± 0.31[15] to 3.71 ± 0.24[18] [Table 6]. Change in mSBI was significant test group treated with statins compared to placebo group in random effect model (SMD: 1.10; 95% CI: 1.92–0.29) in all included studies with significant heterogeneity (I2 = 99%, P < 0.00) [Figure 5].
Table 6: Baseline, follow-up and difference in marginal sulcular bleeding index for studies included in meta-analysis

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Figure 5: Meta-analysis forest plot for SBI.

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Results of studies administered systemic statins

Fajardo et al.[10] in their RCT gave atorvastatin (20 mg) or placebo daily for 3 months and observed improvement in both groups. After comparing, significant improvements were observed in IBD - 0.75 ± 0.7 versus 0.09 ± 0.4 mm, P = 0.0006 in the atorvastatin group.

Subramanian et al.[19] in RCT conducted on 83 patients compared 80 mg atorvastatin with 10 mg atorvastatin observed that high-dose atorvastatin is associated with a reduction in periodontal inflammation at 12-week follow-up. None of these two studies had reported any side effect or adverse effect of statins during the study period and observed that the oral drug is well tolerated.


  Discussion Top


The primary goal of periodontal therapy is regeneration of lost periodontal support. Untreated periodontal diseases may result in destruction of tooth supporting structures. Various cost-effective material/molecules are being evaluated for safety and efficiency to promote periodontal regeneration in recent years. Apart from lipid lowering action, statins have pleiotropic effects such as anti-inflammatory, antioxidant and anabolic effects on bone.[20]

To assess the therapeutic benefits of statins in periodontitis, only RCTs were included in the present systematic review and meta-analysis. The present meta-analysis was aimed at assessing effect of systemic or local statin on clinical as well as radiographic periodontal parameters in patients with chronic periodontitis.

In a multicentric double-blind trial, high-dose atorvastatin is associated with a reduction in periodontal inflammation. The impact of statins was greatest in active periodontitis patients and was evident after a 4-week treatment period.[9] A well-conducted RCT included in this systematic review concluded that systemic administration on 20 mg atorvastatins is an effective therapeutic device in the management of periodontal disease, due to its beneficial effect on alveolar bone metabolism compared to placebo.[10] Only these two evidence has evaluated systemic administration of atorvaststin and one [19] of these has not evaluated any clinical periodontal parameter while other [10] has just evaluated distance from cementoenamel junction to alveolar crest. These studies were excluded from meta-analysis.

Local stimulation of BMP-2 can lead to new bone formation. Mundy et al. identified that four different statins (i.e., lovastatin, simvastatin, mevastatin and fluvastatin) has increased gene expression for BMP-2 in osteoblasts.[13]

A systematically performed literature review by Sophia [21] also has observed that statins have a broad therapeutic effects and promising in regenerative therapies. The results of the present meta-analysis also suggested that statins have beneficial effects on the periodontitis if given systemically for short-term as well as delivered locally.

Estanislau et al.[22] in a systematic review support the same with the observation that indicate statins have beneficial effects by stimulating bone formation, decreasing inflammation and immunomodulation.

Summary of main results

Reduction in IBD and gain in CAL are the primary outcomes to determine success of regenerative periodontal therapy. All the included RCTs performed the statistical analysis and compared the IBD and CAL. They observed statistically significant difference for both. The meta-analysis showed SMD for reduction in IBD1.90 mm (1.46–2.35) and gain in CAL was found to be 1.94 mm (1.07, 2.81).

Statins show beneficial effect systemically as well as locally but cannot substitute for the standard periodontal treatment, which consists of mechanical debridement as local deposits are considered to be the primary aetiologic factor of the disease.

Limitations of the present systematic review and meta-analysis

One of the primary limitations of this analysis is that reviewers were not able to procure any unpublished data or data from any ongoing trials. The majority of the included trials were conducted in single institute which can affect its generalisability to global population.


  Conclusion Top


There are very few studies on applicability of statins in chronic periodontitis in the literature, but results of this meta-analysis indicate that statins hold beneficial effects. This suggests that this group of drugs might have a great potential to improve the outcomes in the treatment of periodontitis since they are safe and not costly. However, they cannot substitute the standard periodontal treatment, which consists of removing microorganisms, considered to be the primary aetiologic factor of the disease. This systematic review and meta-analysis of current evidence of has confirmed the benefits of using statins compared to placebo. This showed a standardised mean difference of 1.94 mm in CAL (1.07, 2.81) and 1.91 mm for IBD (1.46, 2.35) after treatment of IBDs with statins.

Clinical implications

This analysis showed statistically as well as clinically significant improvements in the clinical and radiographic periodontal parameters such as CAL, IBD, reduction in PD and SBI were treated with statins. As statins are effective and safe in short-term use and locally delivered and user-friendly, they can be more widely used in periodontal treatment.

Implications for future research

Local as well as systemic statins can be a cost-effective treatment alternative for periodontitis where its efficacy can be evaluated in large multicentred trials and various other indications in periodontology as well as implant dentistry. Local statin therapy with various controlled release system can be evaluated for maximum benefits. Long-term benefits and safety of the same also need to be evaluated.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
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2.
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Takenaka M, Hirade K, Tanabe K, Akamatsu S, Dohi S, Matsuno H, et al. Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells. Biochem Biophys Res Commun 2003;301:198-203.  Back to cited text no. 4
    
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Fajardo ME, Rocha ML, Sánchez-Marin FJ, Espinosa-Chávez EJ. Effect of atorvastatin on chronic periodontitis: A randomized pilot study. J Clin Periodontol 2010;37:1016-22.  Back to cited text no. 10
    
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Pradeep AR, Thorat MS. Clinical effect of subgingivally delivered simvastatin in the treatment of patients with chronic periodontitis: A randomized clinical trial. J Periodontol 2010;81:214-22.  Back to cited text no. 14
    
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Pradeep AR, Kumari M, Rao NS, Martande SS, Naik SB. Clinical efficacy of subgingivally delivered 1.2% atorvastatin in chronic periodontitis: A randomized controlled clinical trial. J Periodontol 2013;84:871-9.  Back to cited text no. 15
    
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17.
Pradeep AR, Garg V, Kanoriya D, Singhal S. 1.2% rosuvastatin versus 1.2% atorvastatin gel local drug delivery and redelivery in treatment of intrabony defects in chronic periodontitis: A randomized placebo-controlled clinical trial. J Periodontol 2016;87:756-62.  Back to cited text no. 17
    
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Subramanian S, Emami H, Vucic E, Singh P, Vijayakumar J, Fifer KM, et al. High-dose atorvastatin reduces periodontal inflammation: A novel pleiotropic effect of statins. J Am Coll Cardiol 2013;62:2382-91.  Back to cited text no. 19
    
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Suresh SS, Jayakumar. Statins in periodontal regeneration – The current scenario. Indian J Dent Adv 2012;4:808-13.  Back to cited text no. 21
    
22.
Estanislau IM, Terceiro IR, Lisboa MR, Teles Pde B, Carvalho Rde S, Martins RS, et al. Pleiotropic effects of statins on the treatment of chronic periodontitis – A systematic review. Br J Clin Pharmacol 2015;79:877-85.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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