Pleiotropic effects of statins in treatment of generalized periodontitis in patients with coronary artery disease: clinical and experimental study (literature review)

O.I. Martovlos (Hodovana); O.V. Skybchyk; T.M.  Solomenchuk

doi:10.26641/2307-0404.2022.2.260061

Authors

O.I. Martovlos (Hodovana) Danylo Halytsky Lviv National Medical University, Pekarska str., 69, Lviv, 79010, Ukraine https://orcid.org/0000-0003-4833-8935
O.V. Skybchyk Danylo Halytsky Lviv National Medical University, Pekarska str., 69, Lviv, 79010, Ukraine https://orcid.org/0000-0002-0279-1323
T.M. Solomenchuk Danylo Halytsky Lviv National Medical University, Pekarska str., 69, Lviv, 79010, Ukraine https://orcid.org/0000-0002-6153-0457

DOI:

https://doi.org/10.26641/2307-0404.2022.2.260061

Keywords:

periodontitis, coronary artery disease, statins, treatment

Abstract

The high prevalence of generalized periodontitis in patients with coronary artery disease (CAD) requires improving the existing ways of periodontal treatment of this category of cardiac patients and finding new ones. Statins are a group of lipid-lowering medications that are widely used for primary and secondary prevention of cardiovascular diseases due to atherosclerotic vascular lesions. In addition to the cholesterol-lowering effect, statins have several pleiotropic effects, including anti-inflammatory, immune-stimulating, antibacterial, antioxidant, osteotropic etc. The analysis of scientific studies of native and foreign authors devoted to studying the influence of pleiotropic effects of statins on the condition of periodontal tissues revealed improvement of periodontal indicators, in particular, gum structure, reduction of the periodontal pockets depth, gum bleeding, and tooth mobility in patients on statin therapy. Experimental in vitro and in vivo studies show a decrease in proinflammatory cytokines (IL-6, IL-8, IL-1β, TNF-a, etc.), which play a key role in the development of generalized periodontitis, as well as the acceleration of reparative processes in alveolar bone tissue when administering topical statins. Despite the prospects of using statins as the main or additional agent in the treatment of periodontal diseases, the question of dosage and method of local delivery of the medication for avoiding the undesirable side effects remains controversial and requires further research.

References

Hodovana OI. [Modern principles of etiology and pathogenesis of generalized dystrophic-inflammatory periodontal diseases with concomitant systemic osteopenia]. Visnyk problem biologiyi i medycyny. 2017;1(137):35-40. Ukrainian.

Hodovana OI, Skybchyk OV, Solomenchuk TM. [Structure of prevalence of the major perio¬dontal diseases in patients with coronary artery disease]. Proceedings of the conference "Modern aspects of diagnosis and treatment of diseases of the internal organs"; 2019 Apr 11; Ivano-Frankivsk, Ukraine; 2019. p. 32-33. Ukrainian.

Goyenko EN, Ryabokon EM, Cherepinska YA, Volkova OS, Bozhko NP, Dontsova DA. [Efficacy of sta-tins in complex treatment of chronic generalized perio-dontitis on the background of post-infarction cardio-sclerosis]. Eksperymentalna i klinichna medycyna. 2015;3(68):144-7. Ukrainian.

Golovach IYu. [Pathogenetic basis of pleiotropic effects of statins and bisphosphonates on effect on bone tissue]. Ratsionalna farmakoterapiya. 2012;2(23):33-37. Ukrainian.

Ievtushenko OM, Nemtsova VD, Tchaikovs-ka VV. [Statins: pharmacoeconomic aspects of the use of HMG-CoA reductase inhibitors]. Klinichna farmatsiya. 2019;1(23):46-55. Ukrainian. doi: https://doi.org/10.24959/cphj.19.1476

Zubachyk V, Riznyk Yu. [Pathogenic significance of endothelial dysfunction of the periodontal microvas-culature in the development and course of generalized periodontitis]. Sovryemennaya stomatologiya. 2013;4:50-53. Ukrainian.

Kazarina LN, Bolsunovsky SM [Effect of statins on the microcirculation of periodontal tissue in patients with metabolic syndrome ]. Medycyna. 2016;2:43-50. Russian.

Mykhailovskaya NS, Shevchenko IO, Zeleni-na OА. [Pathogenetic relationship between coronary heart disease and osteopenic syndrome]. Zaporozhskyi medy-tsynskyi zhurnal. 2015;1(88):105-10. Ukrainian.

Ostrovska SS, Gerasimchuk PG. [Biological as-pects of association between cardiovascular diseases and periodontitis]. Visnyk problem biologiyi i medycyny. 2018;4(147):58-60. Russian. doi: https://doi.org/10.29254/2077-4214-2018-4-2-147-58-61

Solomenchuk TM [The role of statin therapy in general medical practice]. Liky Ukrainy. 2016;3(199):16-24. Ukrainian.

doi: https://doi.org/10.37987/1997-9894.2016.3(199).203549

Andrukhov O, Haririan H, Bertl K, Rausch W.-D., Bantleon H.-P, Moritz A, Rausch-Fan X. Nitric oxide production, systemic inflammation and lipid metabolism in periodontitis patients: possible gender aspect. J Clin Periodontol. 2013 Oct;40(10):916-23. doi: https://doi.org/10.1111/jcpe.12145

Cicek Ari V, Ilarslan YD, Erman B, Sarkarati B, Tezcan I, Karabulut E, et al. Statins and IL-1β, IL-10, and MPO Levels in Gingival Crevicular Fluid: Preliminary Results. Inflammation. 2016;39(4):1547-57. doi: https://doi.org/10.1007/s10753-016-0390-7

Dalcico R, de Menezes AMA, Deocleciano OB, Oriá RB, Vale ML, Ribeiro RA, et al. Protective Mecha-nisms of Simvastatin in Experimental Periodontal Disease. J Periodontol. 2013;84(8):1145-57. doi: https://doi.org/10.1902/jop.2012.120114

Dean IN, Stein SH. Osteoinductive and Osteo-protective Characteristics of Statins. J Int Acad Perio-dontol. 2010;12(3):70-75.

De Monès E, Schlaubitz S, Catros S, Fricain JC. Statins and alveolar bone resorption: A narrative review of preclinical and clinical studies. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119(1):65-73. doi: https://doi.org/10.1016/j.oooo.2014.09.030

Donos N, Calciolari E, Brusselaers N, Goldoni M, Bostanci N, Belibasakis GN. The adjunctive use of host modulators in non‐surgical periodontal therapy. A systematic review of randomized, placebo‐controlled clinical studies. J Clin Periodontol. 2020;47(S22):199-238. doi: https://doi.org/10.1111/jcpe.13232

Gualtero DF, Viafara-Garcia SM, Morantes SJ, Buitrago DM, Gonzalez OA, Lafaurie GI. Rosuvastatin Inhibits Interleukin (IL)-8 and IL-6 Production in Human Coronary Artery Endothelial Cells Stimulated With Aggregatibacter actinomycetemcomitans Serotype b. J Periodontol. 2017;88(2):225-35. doi: https://doi.org/10.1902/jop.2016.160288

Hodovana OI, Solomenchuk TM, Skybchyk OV, Rumynska TM. Evaluation of microbal composition of periodontal pockets in patients with chronic generalized periodontitis and coronary artery disease. Proceedings of the conference “Smartlion 2018, 2nd Symposium Innovation in Medicine”; 2018 Oct 11-13; Lviv, Ukraine; 2018. p. 62-63.

Kheirallah M, Almeshaly H. Simvastatin, dosage and delivery system for supporting bone regeneration, an update review. J Oral Maxillofac Surgery, Med Pathol. 2016;28(3):205-9. doi: https://doi.org/10.1016/j.ajoms.2015.10.005

Lindy O, Suomalainen K, Mäkelä M, Lindy S. Statin use is associated with fewer periodontal lesions: A retrospective study. BMC Oral Health. 2008;8(1):16-23. doi: https://doi.org/10.1186/1472-6831-8-16

Martande SS, Kumari M, Pradeep AR, Singh SP, Suke DK. Comparative evaluation of efficacy of sub-gingivally delivered 1.2% Atorvastatin and 1.2% Sim-vastatin in the treatment of intrabony defects in chronic periodontitis: a randomized controlled trial. J Dent Res Dent Clin Dent Prospects. 2017;11(1):18-25. doi: https://doi.org/10.15171/joddd.2017.004

Masadeh M, Mhaidat N, Alzoubi K, Al-azzam S, Alnasser Z. Antibacterial activity of statins: A comparative study of Atorvastatin, Simvastatin, and Rosuvastatin. Ann Clin Microbiol Antimicrob. 2012;11:1-5. doi: https://doi.org/10.1186/1476-0711-11-13

Mason RP, Walter MF, Day CA, Jacob RF. Inter-molecular differences of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors contribute to distinct pharmacologic and pleiotropic actions. Am J Cardiol. 2005;96(5 SUPPL.):11-23. doi: https://doi.org/10.1016/j.amjcard.2005.06.008

Meisel P, Kroemer HK, Nauck M, Holtfreter B, Kocher T. Tooth Loss. Periodontitis, and Statins in a Population-Based Follow-Up Study. J Periodontol. 2014 Jun;85(6):e160-8. doi: https://doi.org/10.1902/jop.2013.130456

Norata GD, Catapano AL. Statins and periodontal inflammation: A pleiotropic effect of statins or a pleiotropic effect of LDL-cholesterol lowering? Athe-rosclerosis. 2014;234(2):381-2. doi: https://doi.org/10.1016/j.atherosclerosis.2014.03.017

Nyilasi I, Kocsubé S, Pesti M, Lukács G, Papp T, Vágvölgyi C. In vitro interactions between primycin and different statins in their effects against some clinically important fungi. J Med Microbiol. 2010;59(2):200-5. doi: https://doi.org/10.1099/jmm.0.013946-0

Pankaj D, Sahu I, Kurian IG, Pradeep AR. Com-parative evaluation of subgingivally delivered 1.2% rosu-vastatin and 1% metformin gel in treatment of intrabony defects in chronic periodontitis: A randomized controlled clinical trial. J Periodontol. 2018;89(11):1318-25. doi: https://doi.org/10.1002/JPER.17-0434

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2016;37(29):2315-81. doi: https://doi.org/10.1093/eurheartj/ehw106

Pokhrel NK, Kim Y-G, Kim J-Y, Kim H-H, Lee Y. Fluvastatin Inhibits Osteoclast Differentiation and Porphyromonas gingivalis Lipopolysaccharide-Induced Alveolar Bone Erosion in Mice. J Periodontol. 2017;88(4):390-8. doi: https://doi.org/10.1902/jop.2016.160536

Pradeep AR, Karvekar S, Nagpal K, Patnaik K, Raju A, Singh P. Rosuvastatin 1.2 mg In Situ Gel Com-bined With 1:1 Mixture of Autologous Platelet-Rich Fibrin and Porous Hydroxyapatite Bone Graft in Surgical Treat-ment of Mandibular Class II Furcation Defects: A Randomized Clinical Control Trial. J Periodontol. 2016;87(1):5-13. doi: https://doi.org/10.1902/jop.2015.150131

Rad AB, Mokhtari MR, Aghasizadeh E, Far MB, Banihashem A, Rajaei S. Evaluation of statins (Sim-vastatin and lovastatin) in reducing periodontal parameters in patients with chronic periodontitis. Int J Multidiscip Curr Res. 2018;6:1097-103. doi: https://doi.org/10.14741/ijmcr/v.6.5.15

Rosenberg DR, Andrade CX, Chaparro AP, Inos-troza CM, Ramirez V, Violant D, et al. Short-Term Effects of 2% Atorvastatin Dentifrice as an Adjunct to Periodontal Therapy: A Randomized Double-Masked Clinical Trial. J Periodontol. 2015;86(5):623-30. doi: https://doi.org/10.1902/jop.2015.140503

Rosenberg DR, Kernitsky JR, Andrade CX, Ra-mirez V, Violant D, Nart J. Atorvastatin-Medicated Denti-frice Significantly Inhibits CD4+ T Cell Proli¬feration: In vitro Pilot Study. Int J Morphol. 2017;35(2):394-402. doi: https://doi.org/10.4067/S0717-95022017000200002

Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin drcreases IL-6 and IL-8 production in epithelial cells. J Dent Res. 2006;85(6):520-3. doi: https://doi.org/10.1177/154405910608500608

Sangwan A, Tewari S, Singh H, Sharma RK, Narula SC. Effect of hyperlipidemia on response to nonsurgical periodontal therapy: Statin users versus nonusers. Eur J Dent. 2016;10(1):69-76. doi: https://doi.org/10.4103/1305-7456.175685

Saver BG, Hujoel PP, Cunha-Cruz J, Maupomé G. Are statins associated with decreased tooth loss in chronic periodontitis? J Clin Periodontol. 2007;34(3):214-9. doi: https://doi.org/10.1111/j.1600-051X.2006.01046.x

Seidman LM, Aichelmann-Reidy MB, Bashirela-hi N. What every dentist should know about statins. Gen Dent. 2017;65(5):66-69.

Shah SR, Werlang CA, Kasper FK, Mikos AG. Novel applications of statins for bone regeneration. Natl Sci Rev. 2015;2(1):85-99. doi: https://doi.org/10.1093/nsr/nwu028

Sinjab K, Zimmo N, Lin G-H, Chung M-P, Shaikh L, Wang H-L. The Effect of Locally Delivered Statins on Treating Periodontal Intrabony Defects: A Systematic Review and Meta-Analysis. J Periodontol. 2017;88(4):357-67. doi: https://doi.org/10.1902/jop.2016.160384

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(25):2382-91. doi: https://doi.org/10.1016/j.jacc.2013.08.1627