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 Table of Contents  
ORIGINAL RESEARCH
Year : 2020  |  Volume : 12  |  Issue : 1  |  Page : 66-73

Statins improve periodontal disease–induced inflammatory changes and associated lipid peroxidation in patients with dyslipidemia: Two birds by one stone


1 Department of Oral Radiology, College of Dentistry, Asoul Al-Dean, Baghdad University, Baghdad, Iraq
2 Department of microbiology, College of Science, Baghdad university, Baghdad, Iraq
3 Department of Pharmacology and Toxicology, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq

Date of Submission26-Jul-2019
Date of Decision20-Sep-2019
Date of Acceptance04-Oct-2019
Date of Web Publication25-Feb-2020

Correspondence Address:
Prof. Hayder M Al Kuraishy
Department of Pharmacology, Toxicology, and Medicine, College of Medicine, Al-Mustansiriya University, P.O. Box 14132, Baghdad.
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jioh.jioh_194_19

Rights and Permissions
  Abstract 

Aim: To show the potential role of statins on the inflammatory and lipid peroxidation biomarkers in patients with periodontal disease (PD). Materials and Methods: This case-controlled cross-sectional study involved 74 patients with PD and/or dyslipidemia divided into: Group (A): 34 patients with PD not on statin therapy (non-statin users), Group (B): 40 patients with PD on statin therapy (statin users), and Group (C): 30 healthy controls. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and malondialdehyde (MDA) were measured. Also blood pressure profile and the indices of PD were evaluated in each group. Statistical analysis was conducted by using the Statistical Package for the Social Sciences (SPSS). Results: Patients with PD showed high cardiometabolic disturbances compared with control subjects. Inflammatory and lipid peroxidation biomarkers were higher in patients with PD compared with control subjects; IL-6, CRP, TNF-α, and MDA sera level were high in patients with PD compared with control subjects (P = 0.001). Statin therapy, either simvastatin or atorvastatin, led to significant reduction in TC, TG, VLDL, LDL, blood pressure profile, and cardiac risk indices with elevation in HDL compared with non-statin user (P < 0.01). Also, statin therapy in patients with PD led to significant reduction in IL-6, CRP, TNF-α, and MDA sera levels compared with non-statin user (P < 0.05). Simvastatin and atorvastatin produced improved periodontal indices compared with non-statin user (P < 0.05). Conclusion: Both simvastatin and atorvastatin are effective therapies in patients with PD through amelioration of PD-induced inflammatory disorders and periodontal indices.

Keywords: Lipid Peroxidation, Periodontal Disease, Periodontal Indices, Statins


How to cite this article:
Kadhim SS, Al-Windy SA, Al-Nami MS, Al Kuraishy HM, Al Gareeb AI. Statins improve periodontal disease–induced inflammatory changes and associated lipid peroxidation in patients with dyslipidemia: Two birds by one stone. J Int Oral Health 2020;12:66-73

How to cite this URL:
Kadhim SS, Al-Windy SA, Al-Nami MS, Al Kuraishy HM, Al Gareeb AI. Statins improve periodontal disease–induced inflammatory changes and associated lipid peroxidation in patients with dyslipidemia: Two birds by one stone. J Int Oral Health [serial online] 2020 [cited 2020 Apr 3];12:66-73. Available from: http://www.jioh.org/text.asp?2020/12/1/66/279218




  Introduction Top


The periodontal diseases (PD) are a group of chronic inflammatory diseases, involving the soft tissue and bone surrounding the teeth in the jaws, or known as periodontium. Periodontal diseases including gingivitis and periodontitis are among the most common dental diseases after tooth decay in humans. Periodontal diseases are characterized by inflammation of tooth-supporting tissues caused by bacterial infection.[1] In PD, there are complex interactions between different bacterial species and host immune response, which result in chronic inflammatory reactions.[2] It has been reported that PD is the result of persistence bacterial infection and associated chronic inflammation in response to periodontal bacterial pathogens. The most common forms of PD are periodontitis and gingivitis. Gingivitis is a reversible inflammation of gingiva without destruction of alveolar bone. Periodontitis is the inflammation and the loss of alveolar bone of periodontium.[3]

The risk factors for PD are categorized into modifiable risk factors and non-modifiable factors. The smokers are three times more liable for PD than nonsmokers.[4] Hormonal changes during ovulation and pregnancy predispose for the development of PD due to progesterone-induced gingival changes.[5] Diabetes mellitus induces inflammatory reactions, which damage the periodontal ligaments and cause subsequent tooth loss.[6],[7]

Statins are among the most widely used medications in the management of dyslipidemia since being approved in the 1980s. Statins are inhibitors of hydroxy-methyl-glutaryl coenzyme A, which are involved in de novo cholesterol synthesis. Statins are the first-line therapy for hypercholesterolemia and dyslipidemia in the prevention of primary and secondary coronary heart diseases (CHDs).[8]

Statins have potential pleiotropic effects, through the inhibition of essential isoprenoid intermediates, which are important intracellular signals for different cellular processes during inflammation and cellular injury.[9]

Recently, it was found that statins have potential role in the management of PD because statin therapy, leads to reduction of inflammation and prevents alveolar bone destruction in PD. These effects are due to inhibition of osteoclast and activation of osteoblast activities through modulation the effect of different protein signals like morphogenetic proteins.[10]

Griffiths and Barbour[11] showed that chronic inflammations in PD shift lipoproteins to be pro-atherogenic through the elevation of low-density lipoprotein (LDL-c) and the reduction of high-density lipoprotein (HDL-c) via alteration in the metabolism of lipoproteins. Thus, PD-induced chronic inflammation and dyslipidemia may aggravate lipid peroxidation and oxidative stress as revealed in a study by Bastos et al.[12]

Therefore, the objective of this study was to show the potential role of statins on the inflammatory and lipid peroxidation biomarkers in patients with PD.


  Materials and Methods Top


This case-controlled cross-sectional study involved 74 patients with PD and/or dyslipidemia, age range: 40–69 (52.87 ± 7.63) years, who were randomly recruited from dental and cardiology departments during routine visits compared with 30 healthy controls matched with age and body weight. This study was approved by the ethics committee of the Research Deputy of Al-Mustansiriya University according to the reference approval 98HMK in January 6, 2019, which was coincided with the Declaration of Helsinki. Full history and general physical examination as well as dental examination were carried out by internist physician and dentist. The study procedure divided participants into the following:

Group (A): 34 patients with PD not on statin therapy (non-statin users)

Group (B): 40 patients with PD on statin therapy (statin users)

Group (C): 30 healthy controls

Patients with dyslipidemia with periodontitis for more than six months were included in the study.

Any patients with endocrine disorders, metabolic disorders, diabetes mellitus, pregnancy, lactation, psychiatric and mental disorders, fibrate medications, hepatic dysfunction, end-stage kidney disease, active infection, and sepsis were excluded from the study.

Biochemical measurements

Lipid profile and cardiac indices: A blood sample (8 mL) was obtained from patients and enrolled subjects, which was centrifuged at 3000rpm and stored till the time of analysis.

Lipid profile: Total cholesterol (TC), triglyceride (TG), and HDL were measured by colorimetric enzyme-linked immunosorbent assay (ELISA) kits method (abcam, ab65390, chigo, USA). Very low-density lipoprotein (VLDL), LDL, atherogenic index (AI = log (TG/HDL), cardiac risk ratio (CRR = TC/HDL), non-HDL-c = TC-HDL-c, and cardiovascular risk index (CVRI = TG/HDL) were measured according to a study by Alkuraishy et al.[13]

Inflammatory and lipid peroxidation biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and malondialdehyde (MDA) were measured by ELISA kit methods (Cat. no. ABIN11154322; Wuhan USCN, Shanghai, China).

Measurement of blood pressure: Blood pressure was measured at supine position from left arm by digital automated blood pressure monitoring, 2h apart. Pulse pressure = systolic blood pressure (SBP) – diastolic blood pressure (DBP) and mean arterial pressure (MAP),

[INLINE 1].[14]

Estimation and evaluation of periodontal status: Full mouth clinical examination was carried out with probing depth from at least one of the quadrants for the assessment of the degree of PD. Diagnostic criteria of PD include at least two sites on different teeth with clinical attachment level (CAL) > 6mm with probing pocket depth (PPD) >6mm, at least five sites with CAL > 6mm, PPD > 6mm, or CAL > 5mm.[15]

Assessment of the indices of PD: Plaque index (PI) is used to measure the rate of plaque formation on tooth surfaces; 0 = No plaque, 1 = invisible thin film of plaque adjacent to the area of tooth, 2 = visible film on tooth margin, and 3 = abundant plaque on the tooth surface.[16]

Gingival index (GI) measured the severity of gingivitis; 0 = healthy gingival, 1 = mild inflammation (red edematous gingival), 2 = moderate inflammation (bleeding on probing), and 3 = severe inflammation (spontaneous bleeding and ulceration).[17]

Community periodontal index (CPI) measured the severity of periodontitis and gingivitis; 0 = healthy gingival, 1 = bleeding after gentle probing, 2 = calculus felt during probing, 3 = gingival margin on 3.5–5.5mm from black area of probe, and 4 = black area of probe is not visible.[18]

Statistical analysis: Data analysis was carried out by using the Statistical Package for the Social Sciences (SPSS) (IBM SPSS Statistics for Windows, version 20.0, 2014, IBM, Armonk, New York). Unpaired Student’s t-test was used to test the level of significance between two study groups. Analysis of variance (ANOVA) followed by Bonferroni post hoc test was used to compare the results of different groups. The level of significance was regarded when P < 0.05.


  Results Top


Results of this study showed that 74 patients with PD compared with 30 healthy control subjects significantly differed regarding smoking status and number of teeth (P < 0.05). Patients with PD were characterized by high incidence of dyslipidemia (100%) and hypertension (79.72%) with a previous history of myocardial infarction (9.45%) and ischemic stroke (6.75%). Approximately 54.05% of patients with PD were on statin therapy (statins on) compared with 45.94% patients who were not on statin therapy (statins off). Of the patients with statins on therapy, 45% were on simvastatin and 55% on atorvastatin therapy; other characteristics are shown in [Table 1].
Table 1: Characteristics of the study

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Effects of PD on cardiometabolic and inflammatory biomarkers: Patients with PD showed high cardiometabolic disturbances compared with control subjects. Significant dyslipidemia, high CRR, and high blood pressure profile were observed compared with control subjects (P < 0.01). Also, inflammatory and lipid peroxidation biomarkers were higher in patients with PD compared with those in control subjects; IL-6 serum level was high in PD (4.62 ± 1.38 pg/mL) compared with that in control subjects (0.95 ± 0.04 pg/mL) (P = 0.001). CRP serum level was increased in PD (4.82 ± 2.62mg/L) compared with that in the control (1.96 ± 1.02mg/L) (P = 0.001). TNF-α and MDA sera levels also elevated in patients with PD (8.21 ± 3.58 pg/mL and 6.38±2.74mmol/L, respectively) compared with those in control subjects (P = 0.001) [Table 1].

Effects of statin therapy on cardiometabolic and inflammatory biomarkers in patients with PD: Statin therapy either simvastatin or atorvastatin led to significant reduction in TC, TG, VLDL, LDL, blood pressure profile, and cardiac risk indices with elevation in HDL compared with non-statin user (P < 0.01). Also, statin therapy in patients with PD led to significant reduction in both IL-6 and CRP sera levels compared with non-statin user (P < 0.01). TNF-α serum level was reduced from 8.21 ± 3.58 pg/mL to 6.18 ± 4.79 pg/mL (P = 0.04), whereas MDA serum reduced more significantly from 6.38 ± 2.74 mmol/L in patients with PD (statins off) to 3.49 ± 2.62 mmol/L in patients with PD (statins on) (P < 0.01) [Table 2].
Table 2: Effects of statins on cardiometabolic profile, inflammatory, and lipid peroxidation biomarkers in patients with periodontal disease compared with control

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Effects of statin therapy on periodontal indices in patients with PD: Prolonged uses of statins (statins on) showed a significant improvement in the periodontal indices compared with non-statin user patients. GI, PI, and CPI were low in patients with PD on statin therapy compared with patients with PD not on statin therapy (P < 0.01) [Figure 1].
Figure 1: Effects of statins on periodontal indices in patients with periodontal disease. (GI = gingival index, PI = plaque index, CPI = community periodontal index)

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Correlation of periodontal indices inflammatory biomarkers in patients with PD: Periodontal indices were significantly correlated with IL-6 (r = 0.87, P < 0.000001), CRP (r = 0.86, P < 0.000001), TNF-α (r = 0.64, P = 0.00004), and MDA (r = 0.57, P = 0.0004) in patients with PD not on statin therapy. Also, PD on statin therapy showed less correlation with other inflammatory biomarkers [Table 3].
Table 3: Correlation of periodontal indices with inflammatory and lipid peroxidation biomarkers in patients with periodontal disease

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Differential effect of statins on inflammatory and lipid peroxidation biomarkers in patients with PD: In patients with PD on statin therapy, atorvastatin revealed more significant effect on the inflammatory and lipid peroxidation biomarkers compared with simvastatin. CRP serum level was 2.97 ± 1.33mg/L in simvastatin group compared with low level in atorvastatin group (2.11 ± 1.21mg/L, P = 0.03, and –28.9% change). IL-6 serum level was high (2.83 ± 1.29 pg/mL) in simvastatin group compared with low level in atorvastatin group (2.02 ± 1.23mg/L, P = 0.04, with −28.62% change). MDA serum level was high (3.59 ± 2.04 mmol/L) in simvastatin group compared with that in atorvastatin group (2.28 ± 1.56 mmol/L, P = 0.02, with −43.18% change). Also, TNF-α serum level was high in simvastatin group (6.18 ± 2.79 pg/mL) compared with that in atorvastatin group (4.39 ± 1.92 pg/mL, P = 0.02, with −28.96% change) [Figure 2].
Figure 2: Differential effect of statins and simvastatin on the inflammatory and lipid peroxidation biomarkers in patients with periodontal disease

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Differential effect of statins on periodontal indices in patients with PD: Simvastatin and atorvastatin produced insignificant differences on the periodontal indices regarding GI, PI, and CPI in patients with PD on statin therapy (P > 0.05) [Figure 3].
Figure 3: Differential effect of statins on periodontal indices in patients with periodontal disease. (GI = gingival index, PI = periodontal index, CPI = community periodontal index)

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  Discussion Top


Chronic PD through local inflammatory reactions, bone damage, and tooth loss can have a major systemic effect and impact on the body beyond the oral cavity.[19]

This study showed that patients with PD were associated with poor cardiometabolic profile as most of those patients were hypertensive and dyslipidemic with a history of smoking and alcohol drinking. Therefore, PD is regarded as a potential risk factor for the development of hypertension and other metabolic disorders as revealed by Lamster and Pagan.[20]

Our findings well divulged an association between PD and dyslipidemia compared to the healthy controls as confirmed by Schenkein and Loos,[21] which exemplified a potential link between PD and risk of dyslipidemia due to induction of pro-atherogenic and atherogenic LDL, oxidative stress, augmentation of cholesterol biosynthesis by periodontal bacteria, bacterial lipopolysaccharide, and provoking of thrombotic complications, causing lipid disorders.

Moreover, there is a bidirectional nexus between PD and dyslipidemia as chronic PD induces systemic inflammation and oxidative stress with subsequent dyslipidemia through induction of lipolysis, lipogenesis, and reduction of lipid clearance. Likewise, depositions of LDL particles and free fatty acids within white blood cells (WBC) provoke WBC’s reactivity and release of inflammatory cytokines.[22] But Abdo et al.[23] found insignificant effect of chronic dyslipidemia on the incidence of PD.

Moreover, this study showed that PD led to systemic hypertension and high blood pressure profile compared with healthy controls, which might be due to PD-induced dyslipidemia and systemic inflammations as confirmed by Gordon et al.[24]

Myriad of studies authenticated a possible link between PD and hypertension due to PD-induced chronic inflammatory changes.[25] These findings are consistent with our findings as CRR, CVRI, and AI increased in our patients with PD. It has been reported that were chronic PD leads to endothelial dysfunction due to systemic inflammatory changes and induction of oxidative stress; thus, periodontal therapy reduces the risk of hypertension and endothelial dysfunction.[26]

Furthermore, Porphyromonas gingivalis, which is the common bacterial subtype in periodontitis, leads to hypertension through escalating the sensitivity of vascular endothelium to the endogenous angiotensin ІІ (Ang ІІ). Also, it provokes the binding of LDL to vascular macrophage and the induction of endothelial dysfunction and subsequent hypertension with potential activation of endothelial inflammatory molecules.[27],[28]

Interestingly, this study confirmed significant elevation of CRP, TNF-α, IL-6, and MDA in patients with PD compared to healthy controls as disclosed by Cardoso et al.,[29] which showed that PD is linked with the elevation of systemic inflammatory cytokines such as IL-1, TNF-α, and IL-6 owing to imbalance of pro-inflammatory and inflammatory immune responses.

TNF-α is a pro-atherogenic cytokine released from inflamed periodontal tissues and plays a role in the stimulation of IL-6 production. IL-6 activates the production of CRP from liver, and it causes noteworthy systemic effects such as dyslipidemia, hypertension, and obesity.[30] These cytokines are correlated with the severity of PD and periodontal indices, which may predict the prognosis of PD severity[31] as shown in our study.

On the contrary, patients with PD on statin therapy showed less disorders in lipid profile and blood pressure changes as well as cardiovascular indices compared with patients with PD not on statin therapy, as statin was an effective therapy for dyslipidemia and CHDs.[32]

Besides, statin therapy (simvastatin or atorvastatin) in this study reduced inflammatory biomarkers in patients with PD significantly compared with non-statin user patients due to anti-inflammatory effect of statins as revealed in a study by Li et al.[33]

It has been shown that statins are effective in the reduction of systemic inflammatory biomarkers (TNF-α, IL-6, IL-1, and CRP) and other pro-inflammatory cytokines in chronic inflammatory disorders.[34] In PD, there are localized and systemic inflammatory reactions that lead to periodontal tissue damage and alveolar bone destruction. Atorvastatin inhibits bone damage through inhibition of IL-6, which is the biomarker of bone resorption. In addition, atorvastatin blocks the action of metalloproteinase, osteoclastogenesis, cyclooxygenase 2 (COX 2), and receptor activator of nucleus factor kappa ligand (RANKL), which are over-activated and over-expressed in PD.[35] Besides, Jin et al.[36] showed that simvastatin is effective in the management of PD through inhibition of gingival inflammation and osteoclastogenesis that are involved in the progression of PD-induced bone loss. In addition, simvastatin has potent antibacterial activity against P. gingivalis and Actinobacillus actinomycetemcomitans, which are implicated in the pathogenesis of PD.[37]

Recently, Yang et al.[38] confirmed that localized simvastatin therapy is effectual in the reduction of bone loss and inflammatory reactions in the experimental PD through modulation of osteoblast mitophagy. These findings may explain the better periodontal indices in patients with statin therapy compared with patients with PD on statins off.

In addition, this study showed that statin therapy reduced lipid peroxidation and oxidative stress in patients with PD through reduction of MDA serum levels as confirmed in a study by Marketou et al.,[39] which reported that both atorvastatin and simvastatin are effective in the prevention of oxidative stress and lipid peroxidation in patients with hyperlipidemia. But in this study, atorvastatin was more effective in the reduction of pro-inflammatory and oxidative stress biomarkers as atorvastatin was more potent and had long duration of action that led to time-dependent effect.[40]

In spite of these differences between atorvastatin and simvastatin, both produced comparable effects in the reduction of periodontal indices in patients with PD. Many studies showed similar effect of statins regardless of class-specific effect as all statins produced equal effect in the activation of the synthesis and release of bone morphogenetic protein, osteoprotegerin, and RANKL from gingival tissue, which are important for alveolar bone formations.[41],[42]

Therefore, simvastatin and atorvastatin are effective in reducing the inflammatory reactions and associated periodontal bone damage in patients with PD.

Study limitations: Limitations of this study were that this was a cross-sectional study, which limited follow-up of patients’ status and small sample size; matrix metalloproteinases (MMP-1), MMP-9, and RANKL were not evaluated. Despite these limitations, this study was regarded as a prelude study for future large-scale study to find the potential dose-dependent effect of statins on patients with PD in relation to osteoblast and osteoclast bioactivity.

This study has shown that PD is associated with dyslipidemia and hypertension due to augmentation of pro-inflammatory, oxidative stress and lipid peroxidation biomarkers. Both simvastatin and atorvastatin are effective therapies in patients with PD through amelioration of PD-induced inflammatory disorders and periodontal indices.

Ethical policy and institutional review board statement

This cross-sectional study was approved by the ethics committee of the Research Deputy of Al-Mustansiriya University according to the reference approval 98HMK in January 6, 2019, which was coincided with the Declaration of Helsinki.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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