Longitudinal follow-up study of the association between statin use and chronic periodontitis using a nationwide Korean population health screening cohort

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We found the difference in CP between statin user and control with statistical significance. It was evident in men and women over the age of 40. Among long-term statin users, pre-existing periodontitis was low while new-onset periodontitis was high. The relationship between statin use and increased likelihood of developing PC remained significant even after adjusting for confounders, indicating that statin use was independently associated with an increased risk of developing PC.

Large-scale national studies that examine the relationship between statin use and risk of PC based on duration of use are rare. Among 338,762 participants aged ≥40 years, those receiving statins had a 1.32 times greater risk of developing CP (95% CI 1.30-1.33) than matched control participants (incidence: 25 .0% and 22.0% per 100 person-years, respectively). Because the prevalence of periodontitis increases with age27, we adjusted for age in the analysis; the association between statin use and the likelihood of developing new CP (HR 1.32; 95% CI 1.30-1.33) persisted. Although the magnitude of the risk is small, the use of statins may slightly increase the risk of developing CP. Long-term statin users (1 to 3 years, 3 to 5 years, or >5 years) had a higher risk of 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 reducing pre-existing periodontitis, but may increase the risk of developing new periodontitis. The decrease in pre-existing CP over the 5-year period is partly consistent with the results of a prospective, randomized, double-blind study of 83 participants in the United States, which demonstrated that 12 weeks of statin therapy reduced clearly periodontitis.5. The trend of reduction in periodontitis was seen within the first 28 days after starting statins5. An epidemiological study reported that the use of any statin is associated with a 48% decrease in CP-related tooth loss during the first three years, which may suggest that statins possess anti-inflammatory properties. -inflammatory and bone modulation during the first years that can positively influence pre-existing CP28.

Conversely, reports from the literature that support or contradict our conclusions on the increased risk of onset of CP due to statin treatment in long-term users are rare. Most previous studies have focused on the relatively short-term effects of statins on inflammatory parameters of preexisting periodontitis. The accuracy of the current data is supported by the similar clinical characteristics of statin users with respect to obesity, smoking, increased comorbidities, alcohol consumption or dyslipidemia, and hypercholesterolemia, blood pressure blood pressure or fasting blood glucose, as reported in previous studies.1,4,5,16,19. We further found that long-term statin users are more likely to be higher income, urban, obese, non-smokers, and less alcohol users, as well as to have more of comorbidities, than short-term users. This could be due to the pleiotropic effects (whether adverse or beneficial) reported in the use of statins in patients with coronary heart disease, even with average serum cholesterol levels.29.30implying that statins exert a wider range of adverse or beneficial effects independent of their regulation of cholesterol or coronary heart disease4,27,28,29. In a previous study2, it was reported that 15 subsequent cases of periodontitis among 29 hyperlipidemic patients treated with statins were observed during a period of statin intake of 3 to 132 months; although the observed duration varied considerably, one could say that the study looked at the long-term effects of statin use. Notably, a preliminary study identified a high percentage of oral symptoms associated with statin use; these symptoms improved markedly after discontinuation of treatment9raising the possibility of various statin-induced oral adverse effects.

Myopathy, rhabdomyolysis, diabetes and cancers have been reported as adverse effects of statins4,27,28,29. An association between statin-induced adverse events and statin therapy is uncommon4,27,28,29. Clinical trials of pravastatin treatment for hypercholesterolemia with a 15-year follow-up reported a higher incidence of prostate cancer in these patients1, indicating that adverse effects may become evident after a long period of time, such as a decade or more. Similarly, the incidence of CP related to statin use may have been underestimated due to the short periods of previous studies. Our findings may be important regarding the safety of long-term use of statins in the development of periodontitis. Therefore, patients who are prescribed statin therapy should be made aware of the increased risk of diseases, including CP.

The mechanism underlying the association between statin use and an increased risk of PC remains unclear. Statins have cholesterol-independent or pleiotropic effects attributable to several mechanisms vital to cellular functions via post-transcriptional modification of mevalonate intermediates in multiple tissues, including the periodontium1,2,3,4,20,31,32. In fact, systemic administration of statins has potential effects on the periodontium, and their concentration in gingival fluid has been reported to be 10 to 100 times higher than in serum, with an anti-inflammatory effect that influences the IL-1β level in the gum. As statins also possess immunomodulatory and antimicrobial properties33, their long-term effects could include a change in the microbial balance between pathogenic and non-pathogenic species in the oral cavity, which has more than 700 microorganisms; this impairs the periodontal microbiome and causes dysregulation of the host immune response13.32. Interactions between polymicrobial synergistic and dysbiotic action, host response and modifying factors may determine defense against CP or its progression15. Individuals with defective neutrophil recruitment or neutrophil adhesion deficits have an increased susceptibility to periodontitis34.35. The range of drug action seen in statin therapy appears to be greater than expected, and accurate predictions of adverse events are not possible until these events occur.36.

The strengths of this study are its large, nationally representative, population-based data and analyses, which were fully adjusted for socioeconomic status, potential risk factors, and CP-related comorbidities or statin use (eg, fasting blood glucose, total cholesterol, obesity, alcohol, smoking, and blood pressure). To our knowledge, a nationwide follow-up epidemiological study of the association between long-term statin use and CP risk has not yet been attempted. As KNHIS-HS data encompasses information from all hospitals and clinics across the country without exception, a complete medical history could be obtained during the follow-up period.

Our study has certain limitations. First, we did not report what type of statin the patients were using, which precludes us from reporting the association between individual statins and CP. This is particularly important given the conflicting results reported in the literature; some statins may be associated with a higher or lower risk of developing CP. Second, patient compliance could not be confirmed using KNHIS-HSC data. Third, no information regarding the severity of periodontitis, such as probing depth and clinical attachment loss at interproximal sites; type, dosage and frequency of statins; and family history and genetic data of related systemic diseases, were available in the health insurance database. Fourth, as this study is not a randomized controlled study, the results of our study should be interpreted with caution as our results could have the possibility of being biased by unaccounted for covariates. Finally, the possibility of missing data was not taken into account in our analysis.

In summary, we found a positive association between statin use and the development of CP in the adult Korean population. Thus, we suggest the cautious prescription of statins, especially for long-term use, in patients at high risk of developing or in case of CP.

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