Using a nationwide and large-scale cohort data, this longitudinal follow-up study demonstrated that both men and women aged over 40 years who use statins have an increased likelihood of newly occurring CP compared with matched controls. Among long-term statin users, pre-existing periodontitis was low while newly occurring periodontitis was high. The relation between statin use and increased likelihood of CP occurrence remained significant even after adjustment for confounders, indicating that statin use was independently involved in an increased tendency to develop CP.
Large-scale nationwide studies are scarce on the relationship between statin use and CP risk based on duration of use. Among the 338,762 participants aged ≥40 years, those receiving statin exhibited a 1.32-fold higher chance for developing CP (95% CI 1.30–1.33) than matched control participants (incidence: 25.0% and 22.0% per 100 person-years, respectively). Although the magnitude of risk is low, statin use may slightly increase the risk of developing CP. Long-term statin users (1–3 years, 3–5 years, or >5 years) had a higher risk for CP than short-term users (≤1 year). Pre-existing periodontitis decreased in long-term statin users compared to short-term users, implying that statins may likely be effective in decreasing pre-existing periodontitis but adversely effects newly occurring periodontitis. Decrease in pre-existing CP during the 5-year period is partly in line with results from a prospective double-blind, randomized study among 83 participants conducted in USA, which demonstrated that 12 week-therapy of statin markedly reduced periodontitis5. The trend of reduction in periodontitis was perceived in first 28 days after initiation of statin intake5. An epidemiologic study reported that the use of any statin is associated with a 48% decrease in CP-related tooth loss in the initial three years, which may suggest that statins possess anti-inflammatory and bone modulating features during the first several years that may positively influence pre-existing CP17.
Conversely, literature is still scarce to support our findings on increased risk of CP occurrence due to statin therapy among long-term users. The accuracy of the present data is supported by the similar clinical characteristics of statin users with respect to obesity, smoking, increased comorbidities, alcohol drinking, or dyslipidemia, and high total cholesterol, blood pressure, or fasting glucose level, as reported in previous studies1,4,5,16,20. This may be because most of the previous studies focused on the relatively short-term effects of statins on the inflammatory parameters of pre-existing periodontitis. In a previous study2, it was mentioned that subsequent 15 periodontitis among 29 patients with hyperlipidemia treated with statins were observed during a statin intake period of 3 to 132 months; though the observed duration ranged widely, compared to other studies relatively long-term use of statins was studied. Notably, a preliminary study identified that a high percentage of oral symptoms are associated with statin use, and these symptoms markedly improved after suspension of the treatment9, raising the possibility of diverse statin-induced oral adverse effects.
Myopathy, rhabdomyolysis, diabetes, and cancers have been reported as adverse effects of statins4,27−29. An association between statin-induced adverse events and statin therapy is infrequent4,27−29. Clinical trials of pravastatin therapy for hypercholesterolemia with a 15-year follow-up reported a greater incidence of prostate cancer in these patients1, which indicates that adverse effects may become evident after a long time such as a decade or more. Likewise, incidence of CP related to statin use might have been underestimated because of the short periods of previous studies. Our findings may be of importance with respect to the safety of the long-term use of statins in the development of periodontitis. Therefore, patients who are prescribed statin therapy needs to be informed of the increased risk of diseases, including CP.
The mechanism underlying the association between statin use and increased risk of CP remains unclear. Statins have cholesterol-independent or pleiotropic effects attributable to several mechanisms vital to cellular functions via the post-transcriptional modiଁcation of mevalonate intermediates in multiple tissues, including the periodontium1–4, 20,21,30. In fact, the systemic administration of statins have potential effects in the periodontium, and it has been reported that their concentration in gingival crevicular fluid is 10- to 100-fold higher than in the serum, with an anti-inflammatory effect that influences the level of IL-1β in the gingiva. As statins also possess immunomodulatory and antimicrobial properties31, their long-terms effects might include a shift in the microbial balance between pathogenic and nonpathogenic species in oral cavity which has over 700 microoranisms; this deteriorates periodontal homeostasis and immune response of the host13,32. Interactions between the polymicrobial synergistic and dysbiotic action, host response, and modifying factors may determine the defense against CP or its progression13. Individuals with defective neutrophil recruitment or neutrophil adhesion deficiencies reportedly have increased susceptibility to periodontitis33,34. The range of drug action observed in statin therapy seems to be greater than expected and the precise predictions of adverse events are not possible until those events occur32.
The strengths of this study are its large, representative, nationwide population-based data and analysis that was fully adjusted for socioeconomic status, potential risk factors, and comorbidities related to CP or statin use (e.g., fasting blood glucose, total cholesterol, obesity, alcohol, smoking, and blood pressure). To the best of our knowledge, a nationwide follow-up epidemiologic study on the association between long-term statin intake and CP risk has not previously attempted. As the KNHIS-HS data encompass information from every hospital and clinic across the entire nation without exception, full medical histories could be obtained during the follow-up period.
There are limitations to our study. Statin users had been treated with different statins. No information pertaining to the severity of periodontitis, measurements such as probing depth and clinical attachment loss at interproximal sites that could help diagnose CP, type, dosage, and frequency of statins, family history and genetic data of related systemic diseases were available in the health insurance database; however, the possibility of missing data was not taken into consideration.
In summary, our nationwide cohort study indicates that both men and women aged over 40 years taking statins may have a slightly increased likelihood of subsequent CP onset, especially if used long term, which warrants potential cautions regarding the onset of CP as a possible adverse effect of long-term statin use.
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