|Year : 2019 | Volume
| Issue : 3 | Page : 70-75
Possible Role of Statins on the Inflammatory Biomarkers in Patients With Periodontal Disease: A Cross-Sectional Study
Sahar S Kadhim1, Salah A Al-Windy1, Marwa S Al-Nami2, Hayder M Al-kuraishy1, Ali I Al-Gareeb1
1 Department of Pharmacology, Toxicology, and Medicine, College of Medicine Almustansiriya University, Baghdad, Iraq
2 Department of Pharmacology and Toxicology, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
|Date of Web Publication||28-Nov-2019|
Hayder M Al-kuraishy
Assistant Professor, Department of Pharmacology, Toxicology, and Medicine, College of Medicine Almustansiriya University, Baghdad, 14132
Source of Support: None, Conflict of Interest: None
Introduction: The aim of the present study was to demonstrate the possible role of statins on the inflammatory biomarkers in patients with periodontal disease (PD). Materials and Methods: This cross-sectional study involved 74 patients with PD and/or dyslipidemia divided into Group A: 34 patients with PD (nonstatins users); Group B: 40 patients with PD (statins users); and Group C: 30 healthy controls. Total cholesterol (TC), triglyceride (TG) and high-density lipoprotein, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and malondialdehyde (MDA) were measured . Blood pressure prolife and indices of PD were evaluated in each group. Statistical analysis was conducted by using SPSS version 20.0. Results: Inflammatory and lipid peroxidation biomarkers were higher in patients with PD compared with controls; IL-6, CRP, TNF-α, and MDA sera level were high in PD compared with controls (P = 0.001). Statins therapy led to significant reduction of TC, TG, very low and low-density lipoproteins, blood pressure profile, and cardiac risk indices with elevation in high-density lipoprotein compared with nonstatins users (P < 0.01). Statins therapy led to significant reduction in IL-6, CRP, TNF-α, and MDA sera levels compared with nonstatins users (P < 0.05). Conclusions: Statins therapy reduced PD-induced inflammatory changes in patients with chronic PD through reduction of inflammatory cytokines.
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. Possible Role of Statins on the Inflammatory Biomarkers in Patients With Periodontal Disease: A Cross-Sectional Study. Dent Hypotheses 2019;10:70-5
|How to cite this URL:|
Kadhim SS, Al-Windy SA, Al-Nami MS, Al-kuraishy HM, Al-Gareeb AI. Possible Role of Statins on the Inflammatory Biomarkers in Patients With Periodontal Disease: A Cross-Sectional Study. Dent Hypotheses [serial online] 2019 [cited 2020 Jan 25];10:70-5. Available from: http://www.dentalhypotheses.com/text.asp?2019/10/3/70/271957
| Introduction|| |
Periodontal disease (PD) is a chronic inflammatory disease characterized by destruction of periodontal alveolar bone and ligaments. PD is a common oral disorder of human population and observed as the main cause of tooth loss. Multifaceted and complex interactions between different bacterial species and host immune response have been noted. Therefore, PD is the consequence of persistence bacterial infection and associated chronic inflammation in response to periodontal bacterial pathogens.
The risk factors for PD are smoking, poor oral hygiene, stress, diabetes mellitus, and medications such as nifedipine and phenytoin that lead to induction of abnormal gingival growth.,,,
Statins are inhibitors of hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) involved in de novo cholesterol synthesis. Statins are the first-line therapy for hypercholesterolemia and prevention of coronary heart diseases.
Statins have different pleiotropic effects, such as anti-inflammatory, antioxidant, immune modulation, and antiproliferative, through inhibition of essential isoprenoid intermediates that are important intracellular signals for different cellular processes throughout inflammation and cellular injury.
It has been reported that local or systemic statins therapy is effective in the management of PD through reduction of inflammation and alveolar bone destruction due to inhibition of osteoclast, activation of osteoblast activities, and modulation effect of the morphogenetic proteins at periodontal alveolar bones.
Moreover, chronic inflammations in PD shift lipoproteins to proatherogenic via rising of low-density lipoprotein (LDL-c) and reduction of high-density lipoprotein (HDL-c) through changes in the metabolism of lipoproteins. Consequently, PD-induced chronic inflammation and dyslipidemia may aggravate lipid peroxidation and oxidative stress.
For these reasons, purpose of the present study was to demonstrate the potential role of statins on the inflammatory and lipid peroxidation biomarkers in patients with PD.
| Materials and Methods|| |
This study involved patients with PD with or without dyslipidemia, aged 40 to 69 years recruited from dental and cardiology departments during routine visits, compared with healthy controls matched with age and body weight. Full history and general physical examination as well as dental examination were done by internist physician and dentist. The study procedure divided participants into the following groups:
- Group A: patients with PD (nonstatins users) (n = 34)
- Group B: patients with PD (statins users) (n = 40)
- Group C: healthy controls (n = 30)
Patients being dyslipidemic on statins therapy with periodontitis for more than 6 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.
Measurements of biochemical parameters
A blood sample (8 mL) was gained from patients and enrolled participants that was centrifugated at 3000 rpm and stored till the time of analysis.
Lipid profile: Total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL) were measured by colorimetric ELISA kits method (Abcam, Chicago, USA). Very low-density lipoprotein (VLDL), low-density lipoprotein (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.
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, Business Co. Ltd, China).
Blood pressure profile
Blood pressure was measured at supine position from left arm by digital automated blood pressure monitoring 2 hours apart. Pulse pressure = SBP−DBP and mean arterial pressure (MAP) = (SBP + 2DBP)/3.
Assessment of periodontal status
Oral examination was done with probing depth from at least two sites on different teeth of the quadrants for assessing the degree of PD according to the Diagnostic criteria of PD.
Assessment of the indices of PD
Plaque index: it measures 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.
Gingival index: it measures 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).
Community periodontal index: it measures 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 to 5.5 mm from black area of probe, and 4 = black area of probe that is not visible.
Data analysis was done using SPSS (IBM SPSS Statistics for Windows version 20.0; IBM Corp, Armonk, NY, USA). Unpaired Student t test was used to test the level of significance between the two study groups. Analysis of variance (ANOVA) followed by Benferroni post hoc test was used to compare results of the different groups. The level of significance was regarded when P < 0.05.
| Results|| |
The present study showed that patients with PD had high levels of smoking status and number of teeth compared with controls (P < 0.05). In patients with PD, there was high percentage of dyslipidemia (100%), hypertension (79.72%), and ischemic stroke (6.75%); 54.05% of patients with PD were on statins therapy for at least 6 months (statins on) compared with 45.94% patients not on statins therapy (statins off). Statins on therapy were simvastatin (45.00%) and atorvastatin (55.00%) [Table 1].
Moreover, in patients with PD, there were significant dyslipidemia, high cardiac risk ratio (CRR), and high blood pressure profiles compared with controls (P < 0.01). Inflammatory and lipid peroxidation biomarkers were higher in patients with PD compared with controls; IL-6 serum level was high in patients with PD compared with controls (P = 0.001). CRP serum level was increased in patients with PD compared with the controls (P = 0.001). TNF-α and MDA sera levels were elevated in patients with PD compared with the controls (P = 0.001) [Table 1].
Statins therapy led to significant reduction in TC, TG, VLDL, LDL, blood pressure profile, and cardiac risk indices with elevation in HDL compared with nonstatins user (P < 0.01). In addition, statins therapy reduced both IL-6 and CRP sera levels compared with nonstatins users (P < 0.01). TNF-α and MDA sera level reduced significantly, compared to nonstatins users (P = 0.04, P < 0.01, respectively) [Table 2].
|Table 2: Effects of statins on the inflammatory and lipid peroxidation biomarkers in patients with periodontal disease|
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Prolonged use of statins for more than 6 months led to significant improvement in the periodontal indices compared with nonstatins users. Gingival index, plaque index, and community periodontal index were low in PD patients on statins compared with PD patients not on statins therapy (P < 0.01) [Figure 1].
|Figure 1 Effects of statins on periodontal indices in patients with periodontal disease. CPI, community periodontal index; GI, gingival index; PI, periodontal index.|
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In the present study, atorvastatin led to more significant effect on the inflammatory and lipid peroxidation biomarkers compared with simvastatin. CRP, IL-6, MDA, and TNF-α sera levels were high in simvastatin compared with low level in atorvastatin (P < 0.05) [Figure 2].
|Figure 2 Differential effect of statins on the inflammatory biomarkers in patients with periodontal disease.|
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| Discussion|| |
The present study verified that patients with PD were linked with poor cardiometabolic profile as most of those were hypertensive and dyslipidemic patients. Therefore, PD is regarded as a risk factor for the development of cardio-metabolic disorders.,
Also, the present study showed an association between PD and dyslipidemia as confirmed by a previous study that illustrated an association between PD and risk of dyslipidemia due to induction of atherogenic LDL and activation of cholesterol biosynthesis by periodontal bacteria that causes lipid disorders.
Furthermore, chronic PD induces oxidative stress and systemic inflammation through induction of lipogenesis and lessening of lipid clearance. Similarly, depositions of LDL particles and free fatty acids within white blood cells provoke reactivity and release of inflammatory cytokines of the white blood cells.,
What is more, the present study demonstrated that PD was linked to systemic hypertension that might be due to PD-induced dyslipidemia and systemic inflammations, as confirmed by a recent study.
It has been shown that PD is interrelated with hypertension and other cardiovascular complications due to PD-induced chronic inflammatory changes. These findings are in agreement with our findings as CRR, CVRI, and AI were increased in patients with PD. Also, chronic PD leads to endothelial dysfunction through diminution of endothelial vasodilatation.
Different studies reported that Porphyromonas gingivalis, which is the common bacterial subtype in periodontitis, leads hypertension through activation of endogenous angiotensin ІІ receptors. In addition, P. gingivalis provokes endothelial dysfunction and the binding of LDL to vascular macrophage with potential activation of endothelial inflammatory molecules that eventually cause hypertension.,
In the present study, CRP, TNF-α, IL-6, and MDA sera levels were high in patients with PD compared to healthy controls as PD is linked with elevation of systemic inflammatory cytokines such as IL-1, TNF-α, and IL-6 due to the disproportion of proinflammatory and inflammatory immune responses.,,
Our findings illustrated that patients with PD on statins therapy showed less lipid profile and blood pressure disorders compared with PD patients not on statins therapy as statins is an effective therapy for dyslipidemia and coronary heart diseases.
More to the point, statins therapy in the present study reduced inflammatory biomarkers in patients with PD compared with nonstatins user patients due to anti-inflammatory effect of statins.
In PD, there are noteworthy inflammatory reactions that lead to the destruction of alveolar bone and periodontal tissue. It has been noted that atorvastatin inhibits alveolar bone damage through inhibition of IL-6, metalloproteinases (MMPs), osteoclastogenesis, cyclooxygenase 2, and receptor activator of nucleus factor kappa ligand (RANKL) that are overactivated and overexpressed in PD., Moreover, simvastatin is an effective therapy in the management of PD through inhibition of gingival inflammation that is concerned in the succession of PD-induced bone loss.,
Similarly, simvastatin therapy reduces bone loss and inflammatory reactions in experimental PD via intonation of osteoblast mitophagy. These findings may explain the betterment of periodontal indices with statins. The study by Lindy et al. illustrated that statins therapy in chronic PD lead to significant reduction of periodontal inflammatory injury and reduction of periodontal indices due to potential anti-inflammatory effects.The present study illustrated that statins therapy reduced lipid peroxidation and oxidative stress in patients with PD through reduction of MDA serum levels as both atorvastatin and simvastatin are effective in the prevention of oxidative stress and lipid peroxidation in hyperlipidemic patients. Also, in the present study, atorvastatin was more effective in the reduction of proinflammatory and oxidative stress biomarkers as atorvastatin is more potent and has long duration of action that leads to time-dependent effect.
Finally, both atorvastatin and simvastatin produced comparable effects in the reduction of periodontal indices in patients with PD as different studies demonstrated the similar effect of statins through activation of alveolar bone formations.,
Therefore, simvastatin and atorvastatin are effective in reducing the inflammatory reactions and associated periodontal bone damage in patients with PD as confirmed in the present study.
Limitations of the present study were cross-sectional study with small sample size. Local effect of statins therapy was not estimated to compare with the systemic effect. Nervelessness, this study is regarded as a preliminary step for future large-scale study.
| Conclusion|| |
Statins therapy reduced PD-induced inflammatory changes in patients with chronic PD through reduction of inflammatory cytokines.
Declaration of patient consent
Informed written consent for participation in the study and publication of the data for research and educational purposes had been obtained. All authors verify that they have obtained all suitable patient consent forms. In the form, the patients have given their permission for clinical information and images to be reported in the journal.
Ethical policy and institutional review board statement
This study was approved by the Institutional Review Board / Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines during the conduct of this research project.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Liccardo D, Cannavo A, Spagnuolo G, Ferrara N, Cittadini A, Rengo C, et al. Periodontal disease: A risk factor for diabetes and cardiovascular disease. International journal of molecular sciences 2019;20:1414.
Colombo AP, MagalhŃes CB, Hartenbach FA, do Souto RM, da Silva-Boghossian CM. Periodontal-disease-associated biofilm: a reservoir for pathogens of medical importance. Microb Pathog 2016;94:27-34.
Marcenes W, Kassebaum NJ, Bernabé E, Flaxman A, Naghavi M, Lopez A et al.
Global burden of oral conditions in 1990-2010: a systematic analysis. J Dent Rese 2013;92:592-7.
Stacchi C, Berton F, Perinetti G, Frassetto A, Lombardi T, Khoury A et al.
Risk factors for peri-implantitis: effect of history of periodontal disease and smoking habits. A systematic review and meta-analysis. J Oral Maxillofac Res 2016;7:e3.
Gil L, Mínguez I, Caffesse R, Llambés F. Periodontal disease in pregnancy: the influence of general factors and inflammatory mediators. Oral Health Prev Dent 2019;17:69-73.
Wu YY, Xiao E, Graves DT. Diabetes mellitus related bone metabolism and periodontal disease. Int J Oral Sci 2015;7:63-72.
Samudrala P, Chava VK, Chandana TS, Suresh R. Drug-induced gingival overgrowth: a critical insight into case reports from over two decades. J Indian Soc Periodontol 2016;20:496-502.
] [Full text]
Al-kuraishy H, Al-Gareeb A, Al-Buhadilly A. Rosuvastatin improves vaspin serum levels in obese patients with acute coronary syndrome. Diseases 2018;6:9.
Al-Kuraishy HM, Al-Gareeb AI, Hussien NR, Al-Naimi MS, Rasheed HA. Statins an oft-prescribed drug is implicated in peripheral neuropathy: The time to know more. JPMA. The Journal of the Pakistan Medical Association 2019;69(8):S108-12.
Al-Kuraishy HM, Al-Gareeb AI. Effects of rosuvastatin on metabolic profile: Versatility of dose-dependent effect. Journal of advanced pharmaceutical technology & research 2019;10(1):33.
Griffiths R, Barbour S. Lipoproteins and lipoprotein metabolism in periodontal disease. J Clin Lipidol 2010;5:397-411.
Bastos AS, Graves DT, Loureiro AP, Rossa Júnior C, Abdalla DS, Faulin TD et al.
Lipid peroxidation is associated with the severity of periodontal disease and local inflammatory markers in patients with type 2 diabetes. J Clin Endocrinol Metab 2012;97:E1353-62.
Alkuraishy HM, Al-Gareeb AI, Waheed HJ. Lipoprotein-associated phospholipase A2 is linked with poor cardio-metabolic profile in patients with ischemic stroke: a study of effects of statins. J Neurosci Rural Pract 2018;9:496-503.
] [Full text]
Al-Kuraishy HM, Al-Gareeb AI. Effects of rosuvastatin alone or in combination with omega-3 fatty acid on adiponectin levels and cardiometabolic profile. J Basic Clin Pharm 2016;8:8-14.
Martin-Cabezas R, Seelam N, Petit C, Agossa K, Gaertner S, Tenenbaum H et al.
Association between periodontitis and arterial hypertension: a systematic review and meta-analysis. Am Heart J 2016;180:98-112.
Ayad F, Nathoo SA, Elias A, Stewart B, Panakagos F et al.
Inventors. Improved plaque identification index. United States patent application US 15/106, 281 2016;17:1-5.
Migliorini SE, Pecorari VG, Casati MZ, Santi CG, Neto CF, Dib LL. Oral manifestations, gingival index and dental state of vesiculobullous diseases. IJCN 2018;9:408-22.
Jeong IH, Park MJ. The association between diabetes mellitus and community periodontal index. IJAER 2017;12:2277-81.
Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol 2016;27:941-7.
Lamster IB, Pagan M. Periodontal disease and the metabolic syndrome. Int Dent J 2017;67:67-77.
Schenkein HA, Loos BG. Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases. J Clin Periodontol 2013;40:S51-69.
Al-Kuraishy HM, Al-Gareeb AI, Al-Buhadily AK. Rosuvastatin as forthcoming antibiotic or as adjuvant additive agent: In vitro novel antibacterial study. Journal of laboratory physicians 2018;10(3):271.
Abdo JA, Cirano FR, Casati MZ, Ribeiro FV, Giampaoli V, Casarin RC et al.
Influence of dyslipidemia and diabetes mellitus on chronic periodontal disease. J Periodontol 2013;84:1401-8.
Gordon JH, LaMonte MJ, Genco RJ, Zhao J, Cimato TR, Hovey KM et al.
Association of clinical measures of periodontal disease with blood pressure and hypertension among postmenopausal women. J Periodontol 2018;89:1193-202.
Rebelo MA, de Castro PH, Vieira JM, Robinson PG, Vettore MV. Low social position, periodontal disease, and poor oral health‐related quality of life in adults with systemic arterial hypertension. J Periodontol 2016;87:1379-87.
Bergandi L, Giuggia B, Alovisi M, Comba A, Silvagno F, Maule M et al.
Endothelial dysfunction marker variation in young adults with chronic apical periodontitis before and after endodontic treatment. J Endod 2019;45:500-6.
Czesnikiewicz‐Guzik M, Nosalski R, Mikolajczyk TP, Vidler F, Dohnal T, Dembowska E. Th1‐type immune responses to Porphyromonas gingivalis
antigens exacerbate angiotensin II‐dependent hypertension and vascular dysfunction. Br J Pharmacol 2019;176:1922-31.
Suzuki M, Toyama T, Watanabe K, Sasaki H, Sugiyama S, Yoshino F et al.
Ameliorating effects of Jixueteng in a mouse model of Porphyromonas gingivalis
-induced periodontitis: analysis based on gingival microcirculatory system. Nat Prod Commun 2018;13:1934578×1801301230.
Cardoso EM, Reis C, Manzanares-Céspedes MC. Chronic periodontitis, inflammatory cytokines, and interrelationship with other chronic diseases. J Postgrad Med 2018;130:98-104.
Al-Naimi MS, Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI. Berberine attenuates olanzapine induced-metabolic syndrome. JPMA. The Journal of the Pakistan Medical Association 2019;69(8):S88-92.
Kobayashi T, Ishida K, Yoshie H. Increased expression of interleukin-6 (IL-6) gene transcript in relation to IL-6 promoter hypomethylation in gingival tissue from patients with chronic periodontitis. Arch Oral Biol 2016;69:89-94.
Rasheed HA, Al HM, Al AI. Rosuvastatin Attenuates acute nephrotoxicity through modulation of oxidative stress in Sprague Dawley rats. Animal Research 2019;69(8).
Al-Kuraishy HM, Al-Gareeb AI. Acylation-stimulating protein is a surrogate biomarker for acute myocardial infarction: Role of statins. Journal of laboratory physicians 2017;9(3):163.
Diamantis E, Kyriakos G, Victoria Quiles-Sanchez L, Farmaki P, Troupis T. The anti-inflammatory effects of statins on coronary artery disease: an updated review of the literature. Curr Cardiol Rev 2017;13:209-16.
de Araújo Júnior RF, Souza TO, de Moura LM, Torres KP, de Souza LB, Alves MD et al.
Atorvastatin decreases bone loss, inflammation and oxidative stress in experimental periodontitis. PloS One 2013;8:e75322.
Jin J, Zhang X, Lu Z, Li Y, Lopes‐Virella MF, Yu H et al.
Simvastatin inhibits lipopolysaccharide‐induced osteoclastogenesis and reduces alveolar bone loss in experimental periodontal disease. J Periodontal Res 2014;49:518-26.
Emani S, Gunjiganur GV, Mehta DS. Determination of the antibacterial activity of simvastatin against periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans
: an in vitro study. Contemp Clin Dent 2014;5:377-82.
] [Full text]
Yang CN, Kok SH, Wang HW, Chang JC, Lai EH, Shun CT et al.
Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis. Int Endod J 2019;52:676-88.
Lindy O, Suomalainen K, Mäkelä M, Lindy S. Statin use is associated with fewer periodontal lesions: a retrospective study. BMC Oral Health 2008;8:16.
Marketou ME, Zacharis EA, Nikitovic D, Ganotakis ES, Parthenakis FI, Maliaraki N et al.
Early effects of simvastatin versus atorvastatin on oxidative stress and proinflammatory cytokines in hyperlipidemic subjects. Angiology 2006;57:211-8.
Fang LU, Zhang J, Mou L, Yong LI, Zheng Q. The clinical effects of atorvastatin versus simvastatin on levels of serum lipid, high-sensitivity C-reactive protein and ventricular remodeling in patients with acute coronary syndrome. Chin J Geriat 2017;36:647-9.
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.
Grover HS, Luthra S, Maroo S, Maroo N. The pleotropic role of statins: could it be the imminent host modulation agent in periodontics? Dent Res J 2013;10:143-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2]