Association of the severity and progression rate of periodontitis with systemic medication intake   Daniela Batista-Cárdenas1, Agatha Araya-Castillo2, María P. Arias-Campos2, Ana P. Solís-Rivera2, Jeniffer Jiménez-Matarrita2, Lucía Piedra-Hernández2, Luis Madriz-Montero2, Karol Ramírez2*   1School of Statistics, Faculty of Economic Sciences, University of Costa Rica, Costa Rica, 2Faculty of Dentistry, University of Costa Rica, Costa Rica   Submitted to Journal:   Frontiers in Oral Health   Specialty Section:   Cardiometabolic Health   Article type:   Original Research Article   Manuscript ID:   1447019   Received on:   10 Jun 2024   Revised on:   20 Jul 2024   Journal website link:   www.frontiersin.org In review http://www.frontiersin.org/           Scope Statement Limited information is available regarding the potential connection between systemic medication intake and periodontitis. Medication intake to treat noncommunicable diseases may reflect disease severity and may indirectly portray systemic chronic inflammation. Therefore, our aim was to analyze the relationship between the frequency of systemic medication intake and the severity (stage) together with the risk of progression (grade) of periodontitis, using a large database such as the electronic health records of patients attended at the Clinic of Periodontics of the University of Costa Rica, from 2019-2023. This study provides further indirect evidence of the link between systemic diseases and periodontitis. Thus, it becomes important in clinical practice, to identifty systemic factors such as medication intake. Characterizing systemic medication intake of patients with periodontitis, could have an important diagnostic value and therapeutic implications. Our results could assist practioners in providing a more accurate and personalized treatment plan for periodontal patients.       Conflict of interest statement   The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest       Credit Author Statement   Agatha Araya-Castillo: Investigation, Writing – review & editing. Ana Paula Solís-Rivera: Investigation, Writing – review & editing. Daniela Batista-Cárdenas: Formal Analysis, Writing – review & editing. Jeniffer Jiménez-Matarrita: Investigation, Writing – review & editing. Karol Ramírez: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Lucía Piedra-Hernández: Investigation, Supervision, Writing – review & editing. Luis Madriz-Montero: Supervision, Writing – review & editing. María Paula Arias-Campos: Investigation, Writing – review & editing.       Keywords   chronic diseases, Diabetes Mellitus, Drug Therapy, Medication intake, oralsystemic disease, Periodontitis       Abstract Word count: 279   Background/Purpose: Information on the systemic medication profiles of patients with periodontitis is limited. Therefore, this retrospective cross-sectional study aimed to analyze the relationship between the severity and rate of progression of periodontitis and systemic medication intake using a database of patients who attended the Clinic of Periodontics of the Faculty of Dentistry of the University of Costa Rica. Methods: Electronic health records of patients diagnosed with periodontitis based on the Classification of Periodontal and Peri-Implant Diseases and Conditions (2017) were evaluated. Individuals were further categorized based on the severity (stage) and rate of progression (grade). Data extracted from the patient records included age, sex, and self-reported medication intake. Results: In total, 930 records were included. Most of the studied population was middle-aged (36–64 years old); 43.01% were male, and 56.99% were female. Four hundred and fifty-seven patients (49.14%) reported taking at least one systemic medication for a chronic condition. Regarding the periodontal treatment phase, 62.37% underwent steps 1-3, and 37.63% underwent step 4. The most common systemic medications taken were for cardiovascular diseases (42.28%), followed by medications for diabetes (14.46%) and neurologic disorders (14.46%). Most patients (59.35 %) were diagnosed with Stage III periodontitis. Grade B (48.28%) was the most prevalent. Calcium channel blockers demonstrated a disease severity-dependent association with the periodontal stage (p=0.021). In addition, systemic medications for diabetes mellitus were associated with periodontal disease severity and rate of progression (all Ps <0.05). Conclusions: This study provides indirect evidence of the association between systemic diseases and periodontitis. The positive association between medications used to treat diabetes and the severity and rate of progression of periodontitis may be due to the underlying disease rather than the medications per se.       Funding information   Vice Rector’s Office for Research ordinary funds given to KR, Project C3304.       Funding statement In review   The author(s) declare that financial support was received for the research, authorship, and/or publication of this article.       Ethics statements   Studies involving animal subjects Generated Statement: No animal studies are presented in this manuscript.       Studies involving human subjects Generated Statement: The studies involving humans were approved by Scientifical Ethics Committee of the University of Costa Rica (CEC-283-2022). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.       Inclusion of identifiable human data Generated Statement: No potentially identifiable images or data are presented in this study.       Data availability statement Generated Statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.     In review 1 Article Title: Association of the severity and progression rate of periodontitis with 1 systemic medication intake 2 3 Daniela Batista-Cárdenas1† https://orcid.org/0000-0003-2632-5412 4 Agatha Araya-Castillo2 https://orcid.org/0009-0001-1004-0060 5 María Paula Arias-Campos2 https://orcid.org/0000-0002-00938678 6 Ana Paula Solís-Rivera2 https://orcid.org/0000-0003-2682-5660 7 Jeniffer Jiménez-Matarrita2 https://orcid.org/0009-000434802324 8 Lucía Piedra-Hernández2 https://orcid.org/0000-0001-5392-5179 9 Luis Madriz-Montero2 https://orcid.org/0000-0001-7700-4390 10 Karol Ramírez2†* https://orcid.org/0000-0002-4815-1049 11 12 1School of Statistics, University of Costa Rica, San Pedro, Montes de Oca, San José, 13 Costa Rica, 11801 14 15 2 Faculty of Dentistry, University of Costa Rica, Finca 3 "Instalaciones Deportivas", 16 Sabanilla, Montes de Oca, San José, Costa Rica 11502 17 18 †These authors share first authorship 19 20 *Correspondence: karol.ramirez@ucr.ac.cr 21 22 Keywords: chronic diseases, diabetes mellitus, drug therapy, medication intake, oral-23 systemic disease, periodontitis 24 25 Abstract 26 27 Background/Purpose: Information on the systemic medication profiles of patients with 28 periodontitis is limited. Therefore, this retrospective cross-sectional study aimed to 29 analyze the relationship between the severity and rate of progression of periodontitis 30 and systemic medication intake using a database of patients who attended the Clinic of 31 Periodontics of the Faculty of Dentistry of the University of Costa Rica. Methods: 32 Electronic health records of patients diagnosed with periodontitis based on the 33 Classification of Periodontal and Peri-Implant Diseases and Conditions (2017) were 34 evaluated. Individuals were further categorized based on the severity (stage) and rate of 35 progression (grade). Data extracted from the patient records included age, sex, and 36 self-reported medication intake. Results: In total, 930 records were included. Most of 37 the studied population was middle-aged (36–64 years old); 43.01% were male, and 38 56.99% were female. Four hundred and fifty-seven patients (49.14%) reported taking at 39 least one systemic medication for a chronic condition. Regarding the periodontal 40 treatment phase, 62.37% underwent steps 1-3, and 37.63% underwent step 4. The 41 most common systemic medications taken were for cardiovascular diseases (42.28%), 42 followed by medications for diabetes (14.46%) and neurologic disorders (14.46%). Most 43 patients (59.35 %) were diagnosed with Stage III periodontitis. Grade B (48.28%) was 44 the most prevalent. Calcium channel blockers demonstrated a disease severity-45 dependent association with the periodontal stage (p=0.021). In addition, systemic 46 In review 2 medications for diabetes mellitus were associated with periodontal disease severity and 47 rate of progression (all Ps <0.05). Conclusions: This study provides indirect evidence 48 of the association between systemic diseases and periodontitis. The positive 49 association between medications used to treat diabetes and the severity and rate of 50 progression of periodontitis may be due to the underlying disease rather than the 51 medications per se. 52 53 1 Introduction 54 55 Periodontal disease is a chronic inflammatory condition initiated by microbial pathogens 56 that destroy tooth-supporting components such as root cementum, periodontal ligament, 57 and alveolar bone(1). In addition to the clinical attachment loss, other characteristics of 58 periodontal disease include gingival bleeding, gingival margin recession, and 59 periodontal pockets. In more Advanced-stage periodontitis may cause tooth mobility and 60 loss if left untreated. Tooth loss may lead to masticatory dysfunction, speech alterations, 61 and altered nutritional status, negatively impacting personal quality of life(2,3). 62 63 Over the years, a bidirectional relationship has been established between diabetes and 64 periodontitis (4). However, evidence for a causal relationship between periodontitis and 65 other systemic diseases remains inconclusive. Nonetheless, consistent and robust 66 epidemiological studies have suggested that periodontitis is a risk factor for adverse 67 atherosclerotic cardiovascular disease events(5, 6). The association between 68 periodontitis and many other diseases and conditions, including obesity, adverse 69 pregnancy outcomes, respiratory disease, chronic kidney disease, rheumatoid arthritis, 70 cognitive impairment, metabolic syndrome, and cancer, has been widely investigated(7, 71 8). The oral microbiome of susceptible hosts plausibly may shift to dysbiosis, initiating 72 and promoting periodontal disease progression(9). 73 74 Research has focused on how specific systemic disease medications affect a healthy or 75 inflamed periodontium(10). Generally, dampening the inflammatory pathways involved 76 in the pathogenesis of periodontitis induces the oral side effects of drugs on the 77 periodontium. Some medications can modify inflammatory and immunological 78 responses of periodontal tissues to bacterial plaques(11). For example, gingival 79 overgrowth has been reported in individuals consuming antiepileptics, 80 immunosuppressants, and calcium channel blockers(12). Other drugs reported to affect 81 the periodontium include corticosteroids, nonsteroidal anti-inflammatory drugs, and 82 hormones(11). Systemic medications used to treat diabetes and hypertension are 83 associated with lower salivary flow rates. The amount and composition of saliva are 84 crucial first lines of defense against pathogens(13,14). Although xerostomia does not 85 cause periodontal disease, periodontal health may worsen in patients with dry mouth. 86 87 Limited information is available regarding the potential association between systemic 88 medication intake and periodontitis. Earlier studies have not established an association 89 between systemic medication intake and the severity and risk of periodontitis 90 progression. Medication intake to treat noncommunicable diseases may reflect disease 91 severity and indirectly portray the presence of systemic chronic inflammation. The 92 In review 3 current periodontal classification system can assess the association between staging, 93 grading, and systemic medication intake. Furthermore, studies evaluating the 94 periodontal state of Costa Ricans are scarce. Only one study describes the potential 95 effect of self-reported medications on oral health in older Costa Ricans(15), and no 96 studies have evaluated the relationship between the frequency of systemic medication 97 intake and periodontitis in Costa Ricans. Therefore, we aimed to analyze the 98 association between the frequency of systemic medication intake and the severity 99 (stage) and risk of progression (grade) of periodontitis using a large database, such as 100 the electronic health records (EHRs) of patients attending the Clinic of Periodontics at 101 the University of Costa Rica from 2019 to 2023. Characterizing the systemic medication 102 intake in patients with periodontitis may have important diagnostic and therapeutic 103 implications. Our results could assist practitioners in providing more accurate and 104 personalized treatment plans for patients with periodontitis. In other words, by providing 105 more information on the risk factors related to the severity and progression of 106 periodontitis, this targets bacterial biofilm disruptions, monitors patients’ overall health 107 status, and identifies individuals with a higher risk of periodontal disease progression. 108 109 2 Materials and methods 110 111 2.1 Study design 112 113 This retrospective cross-sectional study was conducted according to the Strengthening 114 the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (16). This 115 study was reviewed and approved by the Scientific Ethics Committee of the University 116 of Costa Rica (CEC-283-2022) and conducted in accordance with the Helsinki 117 Declaration of 1975, as revised in 2013. 118 119 We hypothesized that there is an association between systemic medication intake and 120 the severity (stage) and risk of progression (grade) of periodontitis. To test this 121 hypothesis, four student investigators (AAC, MPAC, APSR, and JJM) screened the 122 EHRs of adult patients who attended the Clinic of Periodontics of the Faculty of 123 Dentistry of the University of Costa Rica between January 2019 and December 2023. 124 125 2.2 Inclusion and exclusion criteria 126 127 Student investigators screened periodontal charts at the initial examination to select 128 samples that met the inclusion criteria of the study protocol. The student investigators 129 only included 1) patients with a diagnosis of periodontitis based on the classification 130 scheme in the 2017 World Workshop on the Classification of Periodontal and 131 Periimplant Diseases and Conditions(17), 2) patients aged 18 years and older, and 3) 132 patients with completed health history questionnaire in the electronic health record. 133 Exclusion criteria included: 1) patients diagnosed with gingivitis or those with healthy 134 periodontium. 135 136 2.3 Case definition of periodontitis 137 In review 4 We included EHRs of patients with periodontal diagnoses based on the 2017 World 138 Workshop on the Classification of Periodontal and Peri-Implant Diseases and 139 Conditions. Eight periodontal specialists at the Clinic of Periodontics of the University of 140 Costa Rica prepared the periodontal charts and performed the clinical examinations 141 registered in the EHRs between January 2019 and December 2023. 142 143 The selected EHRs were further grouped into the following categories based on the 144 severity and rate of periodontitis progression(18): 145 146 A. Severity of periodontitis: 147 (i) Stage I (interdental clinical attachment loss of 1–2 mm or radiographic bone loss of 148 <15%) 149 150 (ii) Stage II (interdental clinical attachment loss of 3–4 mm or radiographic bone loss of 151 15–33%) 152 153 (iii) Stage III (interdental clinical attachment loss of  5 mm or radiographic bone loss 154 extending to the middle third of the root and beyond. Showed 4 teeth loss due to 155 periodontitis) 156 157 (iv) Stage IV (interdental clinical attachment loss of  5 mm or radiographic bone loss 158 extending to the middle third of the root and beyond. Showed  5 teeth loss due to 159 periodontitis) 160 161 B. Rate of progression: 162 163 (i) Grade A: slow rate (no bone loss or attachment loss over five years or percentage of 164 bone loss/age is <0.25, affected are nonsmokers and those not diagnosed with 165 diabetes). 166 167 (ii) Grade B: Moderate rate (<2 mm bone loss or attachment loss over 5 years or 168 percentage of bone loss/age is 0.25–1.0, and risk factors are those who smoke <10 169 cigarettes/day and have glycated hemoglobin (HbA1c) of < 7.0%). 170 171 (iii) Grade C: rapid rate (2 mm bone loss or attachment loss over 5 years or 172 percentage of bone loss/age > 1, smoking +10 cigarettes/day, and HbA1c  7.0% in 173 patients with diabetes). 174 175 2.4 Data extraction 176 Data were extracted from the EHRs, including demographic characteristics (age and 177 sex), smoking status, baseline or self-reported history of systemic medication intake at 178 the initial visit, no systemic medication intake during the last 3 months as stated in the 179 EHR, stage of periodontal treatment according to the European Federation of 180 Periodontology (19,20), and gingival bleeding index (GBI) (21) before Step 1 of 181 periodontal therapy. Moreover, the plaque control record (PI) (22) was recorded before 182 Step 1 and after Step 2 of periodontal treatment. 183 In review 5 Baseline or first-visit self-reported intakes of systemic medications included those 184 reported by Wang et al.(23). Generic names of medications or international 185 nonproprietary names were used in the descriptive analysis to allow precise 186 identification and communication. Antibiotics, corticosteroids, non-steroidal anti-187 inflammatory drugs, non-oral routes of administration, or an intake history of less than 3 188 months were excluded from the regression analysis. We excluded antibiotics, 189 corticosteroids, and non-steroidal anti-inflammatory drugs since these medications are 190 already known to affect clinical indicators of inflammation. Furthermore, only systemic 191 medications administered orally were considered, since not all drugs offer non-oral 192 routes of administration. 193 194 2.5 Statistical analysis 195 196 Data were tabulated, and statistical analysis was conducted in R (Version 4.0.3; R Core 197 Team, 2020). Patient demographic and clinical characteristics are summarized as 198 means and standard deviations or medians and interquartile ranges for continuous 199 variables, as appropriate, and frequencies and percentages for categorical variables. To 200 assess normality, a Quantile Plot was used to compare the theoretical quantiles of the 201 data if they were perfectly distributed with normality and the quantiles of the measured 202 values. The Shapiro–Wilk Test was used, where the null hypothesis was that the 203 frequency distribution of the data was normally distributed. In this study, none of the 204 variables met the assumption of normality. 205 206 The Mann–Whitney–Wilcoxon and chi-square tests were used to compare non-normally 207 distributed and categorical outcomes, respectively. Associations between systemic 208 medication intake variables and periodontal disease severity and progression rates 209 were assessed using proportional odds regression models, with results presented as 210 Odds Ratios (ORs) and corresponding 95% confidence intervals (CIs). Specifically, a 211 multinomial ordinal logistic model was used to obtain ORs results. This method operates 212 with the cumulative probabilities of Y when k=n and this seeks to identify the cumulative 213 probability of being in different categorical combinations for the explained variable (Y), 214 which is conditioned by the influence of X. Fisher's exact test was used because one of 215 the expected frequencies was <5. Analysis of variance was used to detect differences in 216 numerical variables. Proportional odds ratios were assessed using Brant’s test. 217 Multivariable regression models were used to explore the above outcomes, adjusting for 218 the effects of age, sex, and smoking status at baseline. The p-values were corrected for 219 multiple comparisons by using Holm’s method. 220 221 3 Results 222 223 In total, 945 EHRs were reviewed. This study only included 930 EHRs of patients who 224 received periodontal treatment at the Clinic of Periodontics of the Faculty of Dentistry at 225 the University of Costa Rica. The 15 patient EHRs excluded from the analysis were 226 those diagnosed with gingivitis or had healthy periodontium (Figure 1). 227 228 In review 6 Table 1 summarizes the demographic characteristics and clinical indices of the study 229 population. Of the 930 included records, 56.99% and 43.01% were from female and 230 male patients, respectively (p<0.001). The patients were categorized by age into young 231 adults (aged 18–35 years; n = 8.82%), middle-aged adults (aged 36–64 years, n = 232 77.42%), and older adults (aged  65 years, n = 13.79%). For clarity, age categorization 233 was based on the definition of “adulthood” by the American Psychological Association 234 (24), with a slight modification. Young adults were categorized as persons aged 18 to 35 235 years, middle-aged adults from 36 to 64 years, and older people aged 65 years and 236 above. We modified the age range of young adulthood because most are legally 237 identified as adults at 18 years in Costa Rica. 238 239 Regarding cigarette smoking, 24.52% reported being active smokers, whereas 75.48% 240 did not smoke (p<0.001). Half the participants reported not taking any systemic 241 medication (50.86%), whereas the other half reported taking at least one medication to 242 treat chronic diseases (49.14% (p=0.600). In the periodontal treatment phase, 62.37% 243 of the patients underwent steps 1–3, and 37.63% received supportive periodontal care. 244 The initial GBI of the study population was 30.2223.14. The initial plaque index (PI) 245 was 65.6018.06, and the final PI reported after the treatment conclusion was 246 30.8218.46 (p<0.001). 247 248 Supplementary Table 1 shows the medication types and consumption prevalence. The 249 most common systemic medication reported was for cardiovascular disease (42.28 %), 250 followed by medications for neurological disorders (14.46 %) and diabetes mellitus 251 (14.46 %). Some patients reported consuming more than one medication to treat 252 chronic diseases. 253 254 Table 2 shows the demographic characteristics of the study population stratified by 255 periodontal disease severity (stage). Most patients were diagnosed with stage III 256 periodontitis (n = 552), followed by stage II periodontitis (n = 179), stage IV (n = 170), 257 and stage I (n = 29). Univariable comparison tests indicated significant differences 258 between the age groups (p<0.001). Middle-aged individuals were more likely to have 259 stages II, III, and IV periodontitis (p<0.001). Periodontal disease severity between the 260 sexes in the study population was not different (p=0.136). Differences in smoking status 261 were also detected (p = 0.021). People who smoked were diagnosed with stages III and 262 IV periodontitis. In addition, the GBI differed between the stages, indicating that patients 263 with stage IV periodontitis had the highest GBI index (p=0.022). Moreover, patients with 264 stage IV periodontitis had a significantly higher initial PI before and after periodontal 265 treatment (p<0.001, p=0.011, respectively). 266 267 The demographic characteristics of the included population stratified by periodontal 268 disease progression rates are shown in Table 3. Most included patients were diagnosed 269 with grade B periodontitis (n = 449). Univariable comparison tests indicated significant 270 differences in age categories at baseline between grades A, B, and C (p<0.001). Most 271 individuals in the grades B and C periodontitis groups were middle-aged (p<0.001). No 272 significant difference was found between sex and periodontal disease progression rate 273 (p = 0.295). Regarding periodontal indices, the mean GBI and initial PI were higher in 274 In review 7 patients diagnosed with grade C than in those with grades A and B (p<0.001 and 275 p=0.002, respectively). Furthermore, the GBI decreased significantly after periodontal 276 treatment at all the progression rates (p<0.001). 277 278 The association between systemic medication intake and the severity of periodontal 279 disease (stage) is presented in Table 4. Multivariable proportional odds regression 280 adjusted for age, sex, and smoking showed that calcium channel blocker usage was 281 significantly associated with periodontal disease severity (p=0.021). Patients diagnosed 282 with stages III and IV periodontitis reported consuming more systemic medications than 283 those diagnosed with periodontitis stages I and II. The same analysis demonstrated that 284 the intake of systemic medications for diabetes mellitus was significantly associated 285 with the severity of periodontal disease (p=0.001). No association was found between 286 the periodontitis stage and medication intake. Most ORs suggested a decreased risk or 287 inverse correlation between periodontal stage and medication intake. 288 289 The associations between systemic medication intake and periodontal disease 290 progression (grade) are shown in Table 5. Multivariable proportional odds regression, 291 adjusted for age, sex, and smoking, revealed that the intake of systemic medications for 292 diabetes mellitus (p = 0.009) was significantly associated with the periodontitis 293 progression rate. Individuals who used insulin and oral hypoglycemic agents were more 294 likely to have higher-grade periodontitis (p = 0.006 and p = 0.030, respectively). Most 295 ORs suggested a decreased risk/inverse correlation between the periodontal grade and 296 medication intake. The CIs of the antiacids, were affected due to the small sample size 297 of patients diagnosed with Grade A. With a greater sample size the confidence interval 298 would be narrower. If we had greater variability, the confidence interval would be wider. 299 This is why the singificant p value is contradicting the CIs. 300 301 4 Discussion 302 303 To our knowledge, this is the first study to evaluate the potential association between 304 systemic medication intake and periodontal disease severity and progression rate 305 based on the 2017 World Workshop on the Classification of Periodontal and Peri-306 Implant Diseases and Conditions. This retrospective investigation included 930 EHRs of 307 patients with periodontitis who reported their systemic medication intake. The results of 308 the present study indicate (i) a disease severity-dependent association between calcium 309 channel blockers and periodontal disease and no effect relating grade and (ii) an 310 association between systemic medications for diabetes mellitus and periodontal disease 311 severity and progression rate. 312 313 The results of the present study were in accordance with the 2017 Classification of 314 Periodontal and Peri-Implant Diseases and Conditions, in which periodontitis cases 315 were characterized using a two-vector system. The current classification of periodontal 316 disease is reliable for describing complex factors and has lower susceptibility than other 317 indices(25). Grade assessment involves identifying common risk factors for 318 periodontitis. Describing the progression rate of periodontitis is crucial in 319 epidemiological studies. The grade assessment describes basic demographic variables, 320 In review 8 current smoking status, number of cigarettes smoked per day, history of diabetes 321 diagnosis, and metabolic control(25,26). Furthermore, the current classification offers 322 standardized case definitions for population-based surveillance of periodontitis. 323 324 Regarding sociodemographic data, the age group with the highest prevalence, severity, 325 and rate of periodontitis progression in our analysis was middle-aged adults. Other 326 clinical studies have demonstrated an increase in the prevalence and severity of 327 periodontal disease with advancing age. This has been observed in adults aged 30–40 328 years, with increased exacerbations after 50 years(27–29). Globally, the incidence of 329 severe periodontitis peaks around 38 years(30). Middle-aged and older individuals are 330 more likely to develop periodontitis than young individuals because of multiple exposure 331 factors, such as smoking, alcohol consumption, brushing frequency, and dental 332 cleaning(31). 333 334 Most periodontal patients who attended our clinic were women. The scientific literature 335 reports that women are more likely to visit their dentist and receive professional dental 336 care than men(32,33). Additionally, the periodontium undergoes an exaggerated 337 inflammatory response to plaque, modified by female hormonal fluctuations during 338 puberty and pregnancy, as oral contraceptive side effects and at the postmenopausal 339 stage(34). Periodontitis has a higher prevalence and greater severity in men than in 340 women(35,36). Two large cross-sectional epidemiological investigations provided 341 evidence of sexual dimorphism in destructive periodontal diseases(37,38). Moreover, 342 poorer oral hygiene behaviors have been reported in males compared to females(39). 343 However, no clear relationship between sex and periodontitis has been identified. 344 345 Smoking is recognized as a risk factor for the onset, severity, and progression of 346 periodontal disease(40–42). Current evidence indicates that smoking markedly 347 influences multiple immunoinflammatory responses that contribute to dysbiosis in 348 susceptible hosts and likely influences the severity and rate of progression of 349 periodontitis(18,43,44). In line with well-established evidence, smoking was associated 350 with the diagnosis of periodontitis stages III and IV, together with grade C in the current 351 study. Most of our study population were nonsmokers, probably because the General 352 Law on Tobacco Control and its Harmful Effects on Health, No. 9028, regulates smoking 353 in public areas in Costa Rica. Moreover, the prevalence and consumption of tobacco 354 cigarettes have decreased over the last few years owing to massive antismoking 355 campaigns in Costa Rica(45). 356 357 The most common type of medication consumed by the study population was drugs 358 used to treat cardiovascular diseases. In Costa Rica, cardiovascular diseases are the 359 leading cause of death among non-communicable diseases, and high blood pressure 360 has been associated with a 29% mortality rate(46). In the present investigation, patients 361 diagnosed with stage III and IV periodontitis had a more frequent intake of calcium 362 channel blockers. The association between calcium channel blockers and periodontal 363 disease severity may be due to the influence of drug-induced gingival overgrowth (47). 364 The mechanism underlying gingival overgrowth may be the stimulation of fibroblast 365 proliferation and collagen production (48). To clarify, the present study did not include 366 In review 9 patients with a diagnosis of periodontal health or gingival diseases and conditions. The 367 latter includes drug-influenced gingival enlargement. 368 369 Two other studies (23, 49) have also reported an association between calcium channel 370 blockers and periodontitis. Contrary to our results, these studies found a positive 371 association with other medications to treat cardiovascular diseases and periodontitis, 372 which can be explained by the differences between our study design and those of the 373 research participants. For example, a retrospective case-control study of patients seen 374 in the Graduate Periodontics Clinic, School of Dentistry, University of Michigan, reported 375 that the frequency of intake of ACE inhibitors, and diuretics was significantly higher in 376 patients with periodontal disease than in healthy individuals(23). Recently, another 377 study evaluating individuals from the greater Stockholm area, Sweden, reported a 378 possible relationship between taking systemic medications, such as anticoagulants, 379 ACE inhibitors, statins, and periodontitis stages III and IV(9). A longitudinal, database 380 case-control study concluded that patients with periodontitis purchased more than 19 381 different subgroups of medications compared with healthy periodontal individuals, 382 including calcium channel blockers, agents acting on the renin-angiotensin system, and 383 statins (49). 384 385 The second most common type of systemic medication reported in this study was 386 neurological disorders and diabetes mellitus. However, no association was found 387 between the use of medications to treat neurological disorders and periodontitis 388 severity. One of our limitations was that there are more than 1000 neurological 389 disorders to consider, and we only collected data on three types of medications used to 390 treat these conditions from the EHRs. Wang et al. found that patients with periodontitis 391 were more likely to consume antidepressants, anticonvulsants, and antipsychotic drugs 392 than periodontally healthy controls(23). These researchers found a severity-dependent 393 association with anticonvulsants. Contrastingly, Frankenhaeuser et al. reported no 394 association between periodontitis and drug use(49). Future studies on the link between 395 neurological disorders and periodontitis are required, considering the high incidence 396 and detrimental effects of these conditions on the general population. Untreated 397 periodontitis may induce a sustained systemic inflammatory stimulus that constantly 398 activates microglia, causing neuroinflammation(50). 399 400 The prevalence of diabetes mellitus in Costa Rica is 14.8%, which is comparable to that 401 in developed countries(51). Costa Rica’s Social Security Fund covers approximately 402 90% of its population. Most patients are treated at the primary care level, and access to 403 antidiabetic medications is limited to sulfonylureas, metformin, and human insulin(51). 404 Diabetes mellitus exacerbates the severity of periodontal disease(52–56). Additionally, 405 individuals with mild/moderate and severe periodontitis have higher HbA1c plasma 406 levels than individuals without periodontitis(57). We found that in agreement with our 407 hypothesis, insulin and hypoglycemic agents demonstrated a disease severity-408 dependent association when comparing periodontitis staging. Underlying diabetes is 409 more likely to be associated with periodontitis severity than the medications analyzed. 410 411 In review 10 Concerning the progression rate, the present study found a positive association 412 between the consumption of drugs to treat diabetes and a higher grade of periodontitis. 413 Insulin and oral hypoglycemic agents were associated with Grade C periodontitis 414 because the current classification of periodontal disease includes HbA1c levels and 415 smoking status as modifying factors that should be considered when determining the 416 grading process. Diabetes Mellitus is a major risk factor for periodontitis 417 progression(58,59). A recent consensus has designated diabetes and periodontitis as 418 comorbidities that accelerate each other’s development and progression(60). Extensive 419 evidence has indicated that periodontitis affects blood sugar control in patients with type 420 2 diabetes and aggravates diabetes-related complications(61–63). Consequently, 421 periodontal treatment alone beneficially affects HbA1c levels and reduces inflammation. 422 In addition, the promotion of diabetes control interventions, such as individual lifestyle 423 counseling, dietary changes, and oral health education, are recommended for patients 424 undergoing periodontitis therapy(20). 425 426 The present study had several strengths. We evaluated a large sample of patients 427 diagnosed with periodontal disease at the Clinic of Periodontics of the Faculty of 428 Dentistry at the University of Costa Rica. Of these patients, 50.86% reported not taking 429 any medications, and 49.14% reported taking at least one medication to treat a 430 systemic disease. Both groups allowed us to conduct detailed analyses. Using the 431 current classification of periodontal disease, we found a link between a few systemic 432 medications and the severity and progression rate of periodontitis. Previous studies 433 have used pocket depth as a determinant, which may not entirely reflect the actual 434 severity of periodontal disease. Another novelty is that our study targeted middle-aged 435 individuals (35–64 years old). In addition, we included confounding factors such as 436 smoking, age, and sex. However, we did not have enough information in the EHRs on 437 other risk factors, such as stress and family history, for all patients included in the study. 438 Therefore, we did not control for these variables. 439 440 Another limitation of our study is the association between the intake of two or more 441 systemic medications and periodontal state. Hence, it would be interesting to conduct a 442 follow-up study to analyze these possible associations. Another limitation was that not 443 all patients reported the dose and dosage information in their medication profiles at their 444 initial visit. Thus, this information was missing, and we could not further analyze these 445 variables. Substantial variability in the dose of medications probably exists between 446 patients. However, we did not assess the self-reported duration, underuse, or overuse 447 of medications. Pharmacodynamic drug-drug interactions and periodontal disease are 448 areas that have been sparsely studied. In a susceptible host, drug-drug interactions 449 may act as predisposing and precipitating factors that trigger the onset and progression 450 of periodontitis. 451 452 Conclusions 453 454 Within the limitations of this retrospective cross-sectional study, we suggest a 455 relationship between the systemic medications used to control diabetes and severity 456 and progression grade of periodontitis. It seems probable that the underlying chronic 457 In review 11 disease, in this case, diabetes, is more likely to be associated with periodontitis staging 458 and grading than the medications analyzed per se. We found increased odds for 459 medications for diabetes mellitus to both stage and grade, but decreased odds for 460 insulin and oral hypoglycemic agents. This may be explained by the fact that the overall 461 group included both treatments, insulin and oral hypoglycemic agents, adding the 462 probabilities of both medications. It’s important to keep in mind that there were patients 463 that self-reported taking both drugs to control diabetes mellitus. 464 465 The same occurrence can be seen with medications for cardiovascular diseases and 466 stage. Increased odds for systemic medications for cardiovascular diseases was 467 assessed for rate of progression, but decreased odds were found when the 468 medicaments were analyzed individually, except for calcium channel blockers. The 469 overall group included all medicaments to treat cardiovascular diseases, adding each 470 drug’s probability. Moreover, there were patients that reported taking more than one 471 medication to treat cardiovascular disease. 472 473 Our findings highlight the inextricable connection between oral and systemic general 474 health and provide further evidence for dental and medical professionals to consider the 475 indirect implications of systemic medications in the management and needs of 476 periodontal patients. 477 478 Conflicts of Interest Statement: The authors have no conflicts of interest relevant to 479 this article. 480 481 Authors contributions: KR conceived the study. AAC, MPAC, JJM, APSR, LPH, and 482 KR collected the data. DBC and KR analysis of raw data. KR, DBC, and LMM 483 interpreted the results. KR wrote the first draft of the manuscript. All authors have read 484 and approved the final manuscript. 485 486 Funding: Vice Rector’s Office for Research ordinary funds given to KR, Project C3304. 487 488 Acknowledgements: We would like to thank Dr. Alejandro Sáenz-Gutiérrez, Ms. 489 Thania Martínez-Ramírez, and Ms. Sofía Méndez-Madriz for their assistance accessing 490 the electronic health records. 491 492 Availability of data and materials: The datasets used and/or analyzed during the 493 current study are available from the corresponding author on reasonable request. 494 495 Ethics approval and consent to participate: Scientifical Ethics Committee of the 496 University of Costa Rica (CEC-283-2022). 497 498 499 References 500 501 1. Listgarten MA. Pathogenesis of periodontitis. J Clin Periodontol. (1986) 13(5):418–502 25. doi:10.1111/j.1600-051X.1986.tb01485.x 503 In review 12 2. Bortoluzzi M, Traebert J, Lasta R, Da Rosa T, Capella D, Presta A. Tooth loss, 504 chewing ability and quality of life. Contemp Clin Dent. 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(2010) 55(4):472–4. 695 doi:10.1111/j.1834-7819.2010.01273.x 696 62. Teeuw WJ, Gerdes VE, Loos BG. Effect of periodontal treatment on glycemic control 697 of diabetic patients: a systematic review and meta-analysis. Diabetes Care. (2010) 698 33(2):421-7. doi: 10.2337/dc09-1378 699 63. Baeza M, Morales A, Cisterna C, Cavalla F, Jara G, Isamitt Y, Pino P, Gamonal J. 700 Effect of periodontal treatment in patients with periodontitis and diabetes: systematic 701 review and meta-analysis. J Appl Oral Sci. (2020) 28:e20190248. doi: 10.1590/1678-702 7757-2019-0248 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 In review 17 Tables 732 733 Table 1. Demographic characteristics and clinical indices of the study population 734 No. Percentage p-Value* Overall Demographic characteristics 930 100 Age (years) 18–35 (young) 82 8.82 <0.001 36–64 (middle-aged) 720 77.42 ≥65 (older adults) 128 13.79 Sex Male 400 43.01 <0.001 Female 530 56.99 Smoking Yes 228 24.52 <0.001 No 702 75.48 Systemic medication No medication 473 50.86 0.600 Medication 457 49.14 Treatment status Step 1,2,3 580 62.37 SPC 350 37.63 Periodontal Indices** Mean SD p-Value** Gingival bleeding 30.22 23.14 Initial plaque index 65.60 18.06 <0.001 Final plaque index 30.82 18.46 No: Number; SPC: Supported periodontal care; SD: standard deviation 735 *Chi-square test **Wilcoxon test 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 In review 18 Table 2. Demographic characteristics of the study population by stage 758 Demographic Characteristics Stage I No. (%) n = 29 Stage II No. (%) n = 179 Stage III No. (%) n = 552 Stage IV No. (%) n = 170 p-Value* Age (years) 18–35 (young) 15 (51.72) 31 (17.32) 34 (6.16) 2 (1.18) <0.001 36–64 (middle-aged) 14 (48.28) 133 (74.30) 439 (79.53) 134 (78.82) ≥65 (older adults) 0 (0.00) 15 (8.38) 79 (14.31) 34 (20.00) Sex Male 18 (62.07) 76 (42.46) 228 (41.30) 78 (45.88) 0.136 Female 11 (37.93) 103 (57.54) 324 (58.70) 92 (54.12) Smoking Yes 3 (10.34) 39 (21.79) 131 (23.73) 55 (32.35) 0.021 No 26 (89.66) 140 (78.21) 421 (76.27) 115 (67.65) Periodontal Indices Stage I Mean (SD) Stage II Mean (SD) Stage III Mean (SD) Stage IV Mean (SD) p-Value** Gingival bleeding 26.65 (19.42) 28.72 (23.80) 29.40 (22.07) 35.07 (25.78) 0.022 Initial plaque index 58.51 (17.55) 64.15 (18.61) 64.99 (17.97) 70.33 (17.03) <0.001 Final plaque index 27.26 (12.85) 28.09 (12.86) 30.82 (19.71) 34.32 (19.58) 0.011 No.: Number; %: percentage; n: sample size; SD: standard deviation 759 * chi-squared test; ** Mann–Whitney–Wilcoxon test 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 In review 19 Table 3. Demographic characteristics and periodontal indices of the study 785 population by disease progression rate 786 Demographic Characteristics Grade A No. (%) n = 62 Grade B No. (%) n = 449 Grade C No. (%) n = 419 p-Value* Age (years) 18-35 (young) 15 (24.19) 40 (8.91) 27 (6.44) <0.001 36-64 (middle-aged) 44 (70.97) 331 (73.72) 345 (82.34) ≥65 (older adults) 3 (4.84) 78 (17.37) 47 (11.22) Sex Male 30 (48.39) 182 (40.53) 188 (44.87) 0.295 Female 32 (51.61) 267 (59.47) 231 (55.13) Smoking Yes 9 (14.52) 93 (20.71) 126 (30.07) <0.001 No 53 (85.48) 356 (79.29) 293 (69.93) Periodontal Indices Grade A Mean (SD) Grade B Mean (SD) Grade C Mean (SD) p-Value** Gingival bleeding 23.55 (21.57) 27.92 (22.36) 33.68 (23.70) <0.001 Initial plaque index 59.59 (17.60) 64.72 (18.28) 67.44 (17.67) 0.002 Final plaque index 27.98 (14.71) 28.86 (18.88) 33.34 (18.24) <0.001 No.: Number; %: percentage; n: sample size; SD standard deviation 787 * chi-squared test; ** Mann–Whitney–Wilcoxon test 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 In review 20 810 Table 4. Association between systemic medications and periodontitis stage 811 812 No.: Number; %: percentage; n: sample size; CI: confidence interval 813 * Fisher’s exact test. 814 815 816 817 818 819 820 821 822 823 824 825 826 Systemic medication intake Overall Stage I No. (%) n = 29 Stage II No. (%) n = 179 Stage III No. (%) n = 552 Stage IV No. (%) n = 170 Odds ratio (95% CI) p-Value* No medication 473 17 (58.62) 103 (57.54) 268 (48.55) 85 (50.00) 1.24 (0.96, 1.59) 0.162 Medications for cardiovascular diseases 457 10 (34.48) 44 (24.58) 185 (33.51) 65 (38.24) 1.39 (1.06, 1.81) 0.043 ACE inhibitors 225 8 (27.59) 32 (17.88) 137 (24.82) 48 (28.24) 0.74 (0.55, 1.00) 0.113 Calcium channel blockers 66 0 (0.00) 9 (5.03) 36 (6.52) 21 (12.35) 0.47 (0.28, 0.76) 0.021 Diuretics 71 1 (3.45) 9 (5.03) 50 (9.06) 11 (6.47) 0.83 (0.52, 1.34) 0.281 Anticoagulants 0 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0.00 (0.00,0.00) NA Blood-lipid lowering medications 98 1 (3.45) 18 (10.06) 58 (10.51) 21 (12.35) 0.80 (0.53, 1.20) 0.594 Alpha 2 antagonists 39 0 (0.00) 8 (4.47) 20 (3.62) 11 (6.47) 0.66 (0.35, 1.25) 0.317 Platelet antiaggregant 48 1 (3.45) 6 (3.35) 28 (5.07) 13 (7.65) 0.58 (0.33, 1.03) 0.331 Medications for neurologic disorders 104 0 (0.00) 22 (12.29) 63 (11.41) 19 (11.18) 1.06 (0.71, 1.59) 0.224 Antidepressants 79 0 (0.00) 21 (11.73) 42 (7.61) 16 (9.41) 1.05 (0.67, 1.65) 0.112 Anticonvulsants 17 0 (0.00) 3 (1.68) 10 (1.81) 4 (2.35) 0.72 (0.28, 1.85) 0.934 Antipsychotic drugs 27 0 (0.00) 9 (5.03) 15 (2.72) 3 (1.76) 1.67 (0.80, 3.50) 0.274 Medications for diabetes mellitus 104 3 (10.34) 8 (4.47) 64 (11.59) 29 (17.06) 2.05 (1.37, 3.07) 0.001 Insulin 19 1 (3.45) 0 (0.00) 10 (1.81) 8 (4.70) 0.28 (0.12, 0.69) 0.010 Oral hypoglycemic agents 98 3 (10.34) 8 (4.47) 60 (10.87) 27 (15.88) 0.50 (0.33, 0.76) 0.004 Medications for gastric pathologies/disorders 91 1 (3.45) 13 (7.26) 63 (11.41) 14 (8.24) 1.15 (0.75, 1.76) 0.243 Antiacids 86 1 (3.45) 13 (7.26) 58 (10.51) 14 (8.24) 0.86 (0.56, 1.33) 0.446 Proton pump inhibitors 5 0 (0.00) 0 (0.00) 5 (0.90) 0 (0.00) 0.88 (0.16, 4.96) 0.542 Medication for respiratory conditions/asthma 53 3 (10.34) 13 (7.26) 31 (5.62) 6 (3.53) 0.61 (0.36, 1.04) 0.257 Bronchodilators 53 3 (10.34) 13 (7.26) 31 (5.62) 6 (3.53) 0.61 (0.36, 1.04) 0.257 Thyroid disease 63 0 (0.00) 9 (5.03) 45 (8.15) 9 (5.29) 0.86 (0.52, 1.42) 0.202 In review 21 Table 5. Association between systemic medications and disease progression rate 827 (Grade) 828 829 Systemic medication intake Overall Grade A No. (%) n = 62 Grade B No. (%) n = 449 Grade C No. (%) n = 419 Odd ratio (95% CI) p- Value* No medication 473 33 (53.22) 222 (49.44) 218 (52.03) 1.06 (0.83, 1.36) 0.696 Medications for cardiovascular diseases 457 19 (30.64) 151 (33.63) 134 (31.98) 0.92 (0.71, 1.20) 0.825 ACE inhibitors 225 15 (24.19) 112 (24.94) 98 (23.39) 1.07 (0.80, 1.43) 0.877 Calcium block channels 66 3 (4.84) 30 (6.68) 33 (7.88) 0.79 (0.49, 1.29) 0.678 Diuretics 71 3 (4.84) 41 (9.13) 27 (6.44) 1.23 (0.77, 1.96) 0.257 Anticoagulants 0 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00, 0.00) NA Blood-lipid lowering medications 98 10 (16.13) 42 (9.35) 46 (10.98) 1.01 (0.67, 1.51) 0.226 Alpha 2 antagonists 39 1 (1.61) 18 (4.01) 20 (4.77) 0.73 (0.39, 1.37) 0.613 Platelet antiaggregant 48 1 (1.61) 24 (5.34) 23 (5.49) 0.82 (0.46, 1.44) 0.530 Medications for neurologic disorders 104 6 (9.68) 53 (11.80) 45 (10.74) 0.92 (0.62, 1.36) 0.879 Antidepressants 79 6 (9.68) 41 (9.13) 32 (7.64) 1.22 (0.78, 1.90) 0.671 Anticonvulsants 17 1 (1.61) 7 (1.56) 9 (2.15) 0.74 (0.29, 1.89) 0.855 Antipsychotic drugs 27 2 (3.22) 15 (3.34) 10 (2.39) 1.35 (0.64, 2.85) 0.665 Medications for diabetes mellitus 104 3 (4.34) 40 (8.91) 61 (14.56) 1.82 (1.21, 2.73) 0.009 Insulin 19 1 (1.61) 3 (0.67) 15 (3.58) 0.22 (0.07, 0.67) 0.006 Oral hypoglycemic agents 98 3 (4.84) 39 (8.68) 56 (13.36) 0.57 (0.37, 0.86) 0.030 Medications for gastric pathologies/disorders 91 1 (1.61) 54 (12.03) 36 (8.59) 0.89 (0.59, 1.35) 0.013 Antiacids 86 1 (1.61) 52 (11.58) 33 (7.88) 1.13 (0.74, 1.74) 0.014 Proton pump inhibitors 5 0 (0.00) 2 (0.44) 3 (0.72) 0.51 (0.09, 3.07) 0.771 Medication for respiratory conditions/asthma 53 6 (9.68) 25 (5.57) 22 (5.25) 0.76 (0.44, 1.30) 0.340 Bronchodilators 53 6 (9.68) 25 (5.57) 22 (5.25) 0.76 (0.44, 1.30) 0.340 Thyroid disease 63 4 (6.45) 31 (6.90) 28 (6.68) 1.02 (0.62, 1.67) 1.000 No.: Number; %: percentage; n: sample size 830 CI: confidence interval; * Fisher’s exact test. 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 In review Figure 1.JPEG In review