Diabetes and periodontitis: Bi-directional association in population-based 15-year retrospective cohorts

Abstract

Two-way relationship between periodontitis and diabetes was advocated; however, bidirectional observation in general population is still inconclusive. Using the Taiwan Health Insurance Database (covering over 99% of the entire population),11,011 patients with severe periodontitis were recruited from 2000 to 2015.After matching by age, sex, and index date, 11,011 patients with mild periodontitis and 11,011 non-periodontitis controls were registered. The outcome of T2DM was traced. Conversely, the development of periodontitis was traced in 157,798 patients with T2DM, and 157,798 non-diabetic controls enrolled. The risks of T2DM significantly increased in groups with severe and mild periodontitis, with the adjusted hazard ratio (aHR) and 95% confidence interval (CI) being 1.94 (1.49–2.63, p < 0.01) and 1.72 (1.24–2.52, p < 0.01), respectively. Patients with severe periodontitis had a high risk of having diabetes compared to those with mild periodontitis [aHR, 1.17 (95% CI 1.04–1.26, p < 0.001)]. Conversely, the risk of periodontitis increased significantly in patients with T2DM [1.99 (1.42–2.48, p < 0.01)]. However, the high risk was not observed for the outcome of mild periodontitis [0.97 (0.38–1.57, p = 0.462)]. We, therefore, suggested the bi-direction is between diabetes and severe periodontitis, but not in mild type.

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Diabetes and periodontitis: Bi-directional association in
population-based 15-year retrospective cohorts
Wu-Chien Chien
National Defense Medical Center
Earl Fu
Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
Chi-Hsiang Chung
National Defense Medical Center
Chia-Mao Cheng
Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
Hsiao-Pei Tu
Hsin-Sheng Junior College of Medical Care and Management
Wei-Cheng Lee
Tri-Service General Hospital
Wei-Liang Chen
Tri-Service General Hospital
Kuang-Chung Shih (  dentalab11@gmail.com )
Cheng Hsin General Hospital
Article
Keywords: Diabetes, Database, National health programs, Periodontitis
Posted Date: November 8th, 2022
DOI: https://doi.org/10.21203/rs.3.rs-2228878/v1
License:   This work is licensed under a Creative Commons Attribution 4.0 International License.  Read Full
License

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Abstract
Two-way relationship between periodontitis and diabetes was advocated; however, bidirectional observation in
general population is still inconclusive. Using the Taiwan Health Insurance Database (covering over 99% of the
entire population),11,011 patients with severe periodontitis were recruited from 2000 to 2015.After matching by age,
sex, and index date, 11,011 patients with mild periodontitis and 11,011 non-periodontitis controls were registered.
The outcome of T2DM was traced. Conversely, the development of periodontitis was traced in 157,798 patients with
T2DM, and 157,798 non-diabetic controls enrolled. The risks of T2DM signicantly increased in groups with severe
and mild periodontitis, with the adjusted hazard ratio (aHR) and 95% condence interval (CI) being 1.94 (1.49–2.63,
p
< 0.01) and 1.72 (1.24–2.52,
p
< 0.01), respectively. Patients with severe periodontitis had a high risk of having
diabetes compared to those with mild periodontitis [aHR, 1.17 (95% CI 1.04–1.26,
p
< 0.001)]. Conversely, the risk of
periodontitis increased signicantly in patients with T2DM [1.99 (1.42–2.48,
p
< 0.01)]. However, the high risk was
not observed for the outcome of mild periodontitis [0.97 (0.38–1.57,
p
= 0.462)]. We, therefore, suggested the bi-
direction is between diabetes and severe periodontitis, but not in mild type.
Introduction
Diabetes mellitus is a metabolic disease characterized by an increase in the blood glucose level. Periodontal
disease is a bacteria-induced chronic inammatory condition characterized by the breakdown of the tooth’s
supporting tissues. Diabetes can be considered a pandemic, causing signicant morbidity, mortality, and nancial
issues. In 2015, approximately 415 million individuals reportedly suffer from diabetes worldwide, and this number is
expected to increase each year1. Meanwhile, periodontal disease is recognized as the most prevalent inammatory
disease, with approximately 796 million cases of severe periodontitis recorded worldwide in 20172. Links between
diabetes and periodontitis have already been acknowledged. The majority of the studies have indicated that
diabetes increases the risk of periodontal inammation3-5; however, some studies have presented no such results6,7.
Clinical and epidemiological ndings have suggested that periodontal infection contributes to a poorer glycemic
control8-10, whereas the benets of periodontal therapy on glycemic conditions in periodontitis patients with
diabetes remain ambiguous11,12. The two-way relationship between periodontitis and diabetes was advocated far
past13. However, the bi-directional observations were much limited and inconclusive14-16. Two cohort studies
suggested the bi-directional14,15, but the third called into question the presence of a true bidirectional association16.
In this present study, by using the Taiwan Health Insurance Database, the development of type 2 diabetes mellitus
(T2DM) in patients with periodontitis (direction 1), and 2) the development of periodontitis in patients with T2DM
(direction 2) were tracked for 15 years.
Materials And Methods
Data sources
In this study, we used the data from the Longitudinal Health Insurance Database (LHID) in Taiwan (2000–2015),
which is a subset database selected randomly from the National Health Insurance Research Database (NHIRD). The
National Health Insurance (NHI) Program in Taiwan, which was launched in 1995, includes approximately 23
million beneciaries or more than 99% of the entire population in Taiwan17. The NHI program covers all necessary
medical care (including outpatient and inpatient), dental care, Chinese medicine, and prescription drugs. The LHID
contains information on health service utilization for approximately one million beneciaries who represent

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approximately 5% of the Taiwanese population. The NHIRD contains patient identication numbers, birthdays,
sexes, ICD-9-CM diagnostic codes (up to ve each), and outcomes.
Ethical statement
Data access and ethical approval for this study were approved by the Institutional Review Board of the Taipei Tzu
Chi Hospital (No. 09-W-043 approved with exempt review). The data were anonymized before they were obtained;
thus, The need for informed consent was waived by the Taipei Tzu Chi Hospital Ethics committee. All experiment
procedures complied with the ethical standards of the relevant national and institutional committees on human
experimentation and with the guidelines of the Declaration of Helsinki.
Study design and sampled participants
Direction 1, that is, tracing T2DM in patients with periodontitis, comprised patients who were newly diagnosed with
periodontitis from January 1, 2000, to December 31, 2015, according to the ICD-9-CM code 523.4. Each enrolled
periodontitis patient was required to have made at least three dental visits with the 523.4 code being led within the
previous 1 year. The periodontitis patients were then categorized into the mild and severe periodontitis groups as
described previously18-21. The patients who had NHI order code for sub-gingival curettage/root planning (91006-
91008C) or periodontal ap operation (91009B-91010B) were categorized into the severe periodontitis group,
whereas those without these treatment codes were categorized into the mild periodontitis group22. The exclusion
criteria for the study were as follows: the patients with periodontitis from January 1, 1998, to December 31, 1999;
the patients with T2DM from 1998 to 1999 or before their rst visit during which periodontitis was diagnosed; the
subjects aged <40 years; and those who had insucient medical information or withdrawal from the NHI program
throughout the 15-year study period (Fig.1). Among the 1,936,512 individuals, there were 11,011 periodontitis
patients enrolled in the severe periodontitis group. After matching for age, sex, and index date, 11,011 periodontitis
patients were included in the mild periodontitis group (same exclusion criteria and one-fold propensity score) (Fig.
1). Additionally, another 11,011 dental patients who were not diagnosed with periodontitis were categorized into the
non-periodontitis control group.
Direction 2, that is, tracking periodontitis in patients with T2DM who were taking ≥2 anti-diabetic medications,
consisted of patients who were selected from the medical claim data according to the ICD-9-CM code 250. Patients
who were diagnosed with T2DM or periodontitis from 1998 to 1999 and aged <40 years were excluded. In total,
157,798 patients with T2DM were enrolled in the diabetes group, whereas 157,798 participants were recruited in the
non-diabetes group. The outcome of periodontitis was then tracked. Besides, the outcome was subsequently
categorized into the severe periodontitis subgroup and the mild periodontitis subgroup.
The covariates included gender, age, insurance premium (<18,000, 18,000–34,999, and ≥35,000 NT$), urbanization
level of residence (levels 1–4), and level of care (hospital center, regional, and local hospitals). The urbanization
level of residence was based on the population and various other indicators. Briey, the urbanization level 1 was
dened as a population >1,250,000 and specic designation, while the levels 2, 3, and 4 as populations between
500,000 and 1,249,999; 149,999 and 499,999; and <149,999, respectively.
The baseline comorbidities included hypertension (ICD-9-CM codes: 401.1, 401.9, 402.10, 402.90, 404.10, 404.90,
405.1, and 405.9), hyperlipidemia (ICD-9 CM code: 272.x), coronary artery disease (CAD; ICD-9 CM code: 410–414),
obesity (ICD-9 CM codes: 278.00–278.01), smoking (ICD-9-CM code: 305.1), chronic obstructive pulmonary disease

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(COPD; ICD-9-CM codes: 490–496), and alcoholism (ICD-9-CM codes: 303 and 305.0); additionally, the revised
Charlson Comorbidity Index (CCI_R; CCI removed diabetes mellitus, hypertension, and CAD) was included.
Statistical analysis
Chi-square and Fisher’s exact tests were used to evaluate the differences between categorical variables, whereas the
t-test and the one-way analysis of variance with Scheffe’s post hoc test were used for continuous variables.
Multivariate Cox proportional hazards regression analysis was used to determine the risk of T2DM and periodontitis
(directions 1 and 2, respectively). The results were presented as hazard ratios (HRs) with 95% condence intervals
(CIs). Sensitivity analysis was further used to exclude the diagnosis of dementia in the rst 1 or 5 year(s) and to
eliminate any potential protopathic bias. The difference in the risk of outcome disease between the study and
reference groups was estimated using the Kaplan-Meier method and the log-rank test. A two-tailed
p
< 0.05 was
considered statistically signicant.
Results
Direction 1: Periodontitis, a risk factor for diabetes
At baseline, signicantly different characteristics were noted between groups(Supplementary Table S1).
Differences were observed for all variables exceptgender and age.At the end of the follow-up, 772 (7.01%) and 658
(5.98%) patients with periodontitis developeddiabetesin the severe and mild periodontitis groups, respectively,
compared with 490 (4.45%) participants in the non-periodontitis control group (
p
< 0.001) (Fig. 1; and Table S2,
Direction 1). The cumulative incidences for developingdiabetesdiffered between groups (
p
< 0.001; Fig. 2a).
Risk factors forT2DMin patients withperiodontitis
The patients in the severe and mild periodontitis groups tended to have a signicantly increased risk of
developingdiabetes(Table 1, Direction 1). The adjusted HRs (aHRs) were 1.94 (95% CI, 1.49–2.63;
p
< 0.001) and
1.72 (95% CI, 1.23–2.53;
p
< 0.001) for the severe and mild periodontitis groups, respectively (Table 1). Besides, the
participants who lived in places with high urbanization levels, who were treated in hospital centers/regional
hospitals, and had hypertension, hyperlipidemia, CAD, obesity, smoking, alcoholism, and greater CCI_R values were
associated with a higher risk of developingdiabetes. Nevertheless, gender, insured premium, and comorbidity
ofchronic obstructive pulmonary diseaseamong groupswere not signicantly associated with the risk of
developing diabetes.
Sensitivityof periodontitis as a risk factor forT2DM
The rates ofdiabeteswere 13.40 and 10.12 per 1,000 per 103 person-years in the severe and mild periodontitis
groups, respectively, which were signicantly greater than that in the non-periodontitis group (6.31 per 1,000 person-
years; Table 2, Direction 1). It was also observed that patients in the severe and mild periodontitis groups tended to
have a signicantly increased risk of developing diabetes, even though the data from the rst 1 or 5 years were
excluded. Moreover, the severe periodontitis patients had a high risk of having diabetes if the mild periodontitis
patients were used as the reference, despite the data exclusion or non-exclusion (1.17, 95% CI, 1.04–1.26, p < 0.001
for the non-excluded data).
Direction 2:T2DM, a risk factor for developing periodontitis

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The general characteristics of the diabetes and non-diabetes groups at the baseline were different, except for
gender, age, or insurance premium(Supplementary Table S1).At the end of follow-up,1,662 (1.05%)diabetic
patients have reportedly developed periodontitis compared with 430 (0.27%) participants in the non-diabetic control
group (
p
< 0.001) (Fig. 1; and Table S2, Direction 2). The difference was further noted in other variables except
gender and insured premium.The cumulative incidence of periodontitis in the diabetes group was signicantly
higher than that in the non-diabetes control group (Fig. 2b1). As per the outcomes of periodontitis subgroups
however, statistically different incidences between the groups of diabetes and non-diabetes were noticed for severe
periodontitis subgroup, but not for mild periodontitis (Fig. 2, b2, and b3).
Risks for developingperiodontitisinpatients withT2DM
Using the non-diabetes group as the reference, the aHR of developing periodontitis in the diabetes group was 1.99
(95% CI, 1.44–2.48;
p
< 0.001; Table 1, Direction 2). The elder patients who lived in areas of high urbanization levels
were attended to in the center/regional hospital; moreover, hypertension, hyperlipidemia, CAD, obesity, smoking,
alcoholism, and high CCI_R values tended to have a high risk of developing periodontitis. However, the statistical
signicance for an increased risk of developingthe outcome of periodontitis indiabetic patients was observed for
the severe periodontitis subgroup (aHRs: 2.08; 95% CI, 1.50–2.66;
p
< 0.001), but not for the mild periodontitis
subgroup (aHRs: 0.97; 95% CI, 0.38–1.57;
p
= 0.462) (Table 2).
SensitivityofT2DMas a risk factor for periodontitis
The rate of having periodontitis in the diabetes group (1.04 per 103 person-years) was determined to be signicantly
greater than that in the non-diabetes control group (0.16 per 103 person-years; Table 2, Direction 2). The diabetic
patients tended to have a signicantly increased risk of developing periodontitis. After subgrouping the outcome of
periodontitis, the rate of developing severe periodontitis was signicantly greater in the diabetes group than that in
the non-diabetes group (0.99 vs. 0.22 per 103 person-years). The aHRs was 2.08 (95% CI, 1.50–2.66;
p
< 0.001).
After the exclusion of the data from the rst 1 or 5 years, the greater rate and aHR in the diabetes group than that in
the non-diabetes group were repeated. However, the rate of developing mild periodontitis in the diabetes group did
not differ signicantly from that in the non-diabetes group (0.05 and 0.06 per 103 person-years, respectively). The
aHRs of 0.97 (95% CI, 0.38–1.57;
p
= 0.462) was obtained. No difference was also noticed after excluding the data
from the rst 1 or 5 years.
Discussion
This retrospective cohort study aimed to bi-directionally track the incidences of T2DM and periodontitis in aged
adults (>40 years old) who were chosen from the base population of Taiwan (Table 1, Fig. 1). As per our results, it
was found that the risk of developing T2DM increased in the patients with periodontitis compared to those non-
periodontitis control (Fig. 2a, Tables 1 and 2). In the same population, within the same observation period, the
patients with T2DM also had an increased risk of developing periodontitis (signicant greater risks noticed on the
Pt subgroup only) (Fig. 2b, Tables 1 and 2). In brief, in this nationally representative sample, the bi-directional
association between the two diseases was noticed during 15 years of tracking, similar to that previously reported
community study14. In that community study, T2DM was dened as having a history from the questionnaire or
fasting plasma glucose, and the periodontal status was assessed by the Community Periodontal Index of
Treatment Needs (CPITN). However, the simple screening based on the fasting glucose alone might ineffectively
detect an unacceptable number of subjects with glucose intolerance23. Whether CPITN could accurately reect the

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actual periodontal status of the sample population is also questioned24. Besides, the professional levels for those
examiners were not clearly dened. In the present study, the diagnosis of diabetes and periodontitis was performed
by board-certied endocrinologiest and dentists. The accuracy and validity of the diagnoses in NHIRD in Taiwan
were high25. Strategies to reduce the diagnosis bias were further selected25, such as the triple diagnoses of
periodontitis within the 1-year claim period and the taking more than two anti-diabetic medications required for
diabetic patients enrolling beside from the ICD-9-CM code of 250.
Inammation has been identied to be a known driver of insulin resistance26. Chronic dysregulation of the
peripheral cytokine pool is a characteristic pre-diabetic feature27. It has been determined that circulating mediators
such as
C-reactive protein (CRP)
, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, may be elevated in
periodontal diseases and correlated with the clinical periodontal parameters28. A longitudinal study reported that
the increase in HbA1c levels over a 5-year period in patients with periodontitis was highest in individuals with high
levels of CRP29. The role of systemic inammation as a mediator of the linkage between periodontitis and impaired
fasting glucose was found using the mediation analysis10. Systemic oxidative stress is elevated in patients with
diabetes and periodontitis26. It has been proposed that hyperactive neutrophils in the periodontium may be an
important source of reactive oxygen species, which then activates the pro-inammatory pathways and promotes
insulin resistance in patients with periodontitis and diabetes26. Another study reported that the markers of lipid
peroxidation in the gingival crevicular uid were correlated with the clinical parameters of periodontitis and the
levels of inammatory mediators in diabetic patients30.
The evidence of periodontal microorganisms having a direct impact on glycemic control or the diabetic state of the
patient might still be lacking; however, a recent study in mice demonstrated the translocation of
Porphyromonas
gingivalis
and gingipains to the pancreas, with alterations in the morphology of the islets in the pancreas31.
Following non-surgical periodontal therapy,
Porphyromonas gingivalis
was detected more frequently in patients
with increased HbA1c values compared with those with decreased values32. Furthermore,
Porphyromonas
gingivalis
with type II mbriae were detected only in patients with increased HbA1c levels.
Detailed pathogenesis of the high risk of developing periodontitis in diabetic patients remains under investigation;
however, studies reported that the cytokine levels in the gingival cervical uid, saliva, and/or gingival tissue of
diabetic patients with periodontitis were altered when compared with those in systemically healthy patients33. The
levels of TNF-α and IL-6 were signicantly increased in diabetic mice compared with those in normal mice after the
inoculation of
Porphyromonas gingivalis
34. The experiments with TNF-α inhibitors in the diabetic animal models of
periodontitis indicated that these changes may be the secondary effects of TNF-α35. In the present study, we found
that the diabetes as a risk factor for developing the severe periodontitis (aHRs: 2.08; 95% CI, 1.50–2.66;
p
< 0.001),
but not the mild periodontitis (aHRs: 0.97; 95% CI, 0.38–1.57;
p
= 0.462) (Table 2). The exact reason is still
unknown. However, studies have found the the diabetic patients with severe periodontitis have been shown to have
depressed neutrophil chemotaxis compared with diabetic individuals with mild periodontisis36, as well as defective
apoptosis of neutrophils37. These may lead to increased retention of neutrophils in the periodontal tissue and
leading to more tissue destruction by continued release of matrix metalloproteinases and reactive oxygen species.
In addition, the advanced glycation end products (AGEs) in the gingival tissues of diabetic patients with
periodontitis38 have been signicantly associated with the extent of periodontitis in diabetic individuals. Recently,
hyperglycemia and AGEs have been found to increase the lipopolysaccharide-induced production of IL-6 in human
gingival broblasts39. The interactions between AGEs and their receptors were signicantly higher in the inamed

Page 7/17
periodontal tissues of rats induced with hyperglycemia when compared with those in rats with normal blood
glucose levels40. Treatment using soluble receptors of AGE decreased the levels of TNF-α, IL-6, and
metalloproteinases in gingival tissues and suppressed alveolar bone loss in diabetic animals41.
It is generally believed that the presence of diabetes has no signicant effect on the composition of periodontal
microorganisms. Recently, the ndings of the shift in the subgingival microbiome suggest that diabetic patients are
more susceptible to shifts in the subgingival microbiome toward dysbiosis42. Besides,
Porphyromonas gingivalis
-
induced alveolar bone loss was noted to increase in diabetic mice when compared with non-diabetic controls; this
was accompanied by the enhanced expression of the AGEs and their receptors43.
This study has several limitations. First, like previous studies using the NHIRD on periodontal diseases, precise data
on the severity of periodontitis were unavailable. Second, other factors such as genetic, psychosocial, and detailed
environmental factors were excluded from the dataset. Third, the claims dataset did not include descriptions of the
metabolic or diabetic state of the patient. Fourth, there were only a few patients in the mild periodontitis subgroup.
Therefore, it is advisable to interpret the results of this study with caution. However, the strengths of the study are as
follows: First, this study included a large population, which allowed the results from this analysis to be generalized
to the entire population of Taiwan. Second, because the NHIRD provides continued coverage; hence, we could
follow the population trend for 15 years. Third, the accuracy and validity of the diagnoses in this study are high.
Conclusion
Using the data from the NHIRD of Taiwan, the relationship between periodontitis and diabetes was examined bi-
directionally. At the end of the 15-year follow-up, the cumulative incidences of T2DM among the two periodontitis
groups and non-periodontitis control group were determined to be statistically different (Direction 1). The aHRs were
1.94 and 1.72 for the severe and mild periodontitis groups, respectively. Besides, the risk of T2DM in the severe
periodontitis group was greater than that in the mild periodontitis group. In Direction 2, T2DM as a risk factor for
periodontitis was tested. An increased risk of developing periodontitis was observed among patients with T2DM
(aHR = 1.99, the development of periodontitis in the control participants without T2DM as the reference). However,
the greater risk was observed only for the outcome of the severe periodontitis subgroup but not of the mild
periodontitis subgroup. Based on the ndings of this retrospective cohort study, we suggested that the bi-directional
association was present between diabetes and severe periodontitis, but not in the mild type.
Declarations
Acknowledgments
We thank all the experts, the participating institutions, includingTri-Service General Hospital, National Defense
Medical Center, andTaipei Tzu Chi Hospital.
Funding
This study was partially supported by a research grant from Tri-Service General HospitalResearch Foundation
(TSGH-B-111018).
Competing interests

Page 8/17
The authors have no conicts of interest to declare.
Data Availability Statement
Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National
Health Insurance (NHI) Bureau. Due to legal restrictions imposed by the government of Taiwan in relation to the
“Personal Information Protection Act”, data cannot be made publicly available. Requests for data can be sent as a
formal proposal to the NHIRD (https://nhird.nhri.org.tw/en/).
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Tables
TABLE 1. Risks of periodontitis in DM groups and of DM in periodontitis groups determined by Cox regression

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 Direction 1: Periodontitis,
risk of DM Direction 2:DM, risk of periodontitis
Variables aHR
P
 Periodontitis,
overall Severe Subgroup Mild Subgroup
 (95% CI)   aHR (95%
CI)
P
aHR (95%
CI)
P
aHR
(95% CI)
P
Cohort,Non-
PReference        
Severe-P 1.94
(1.49-
2.63)
<0.001       
Mild-P 1.72
(1.23-
2.52)
<0.001       
Cohort,Non-
DM    Reference  Reference  Reference 
DM    1.99
(1.44-
2.48)
<0.001 2.08
(1.50-
2.66)
<0.001 0.97
(0.38-
1.57)
0.463
Male (F, ref)0.96
(0.47-
1.74)
0.570  1.11
(0.88-
1.76)
0.250 1.11
(0.87-
1.76)
0.253 1.12
(0.88-
1.76)
0.263
Age (years) 1.22
(1.08–
1.36)
<0.001 1.10
(1.01-
1.22)
0.044 1.11
(1.00–
1.22)
0.047 1.11
(1.01-
1.23)
0.042
IP (NTD103)        
<18 Reference   Reference  Reference  Reference 
18-35 1.27
(0.44-
1.93)
0.580  1.14
(0.38-
1.82)
0.530 1.15
(0.38-
1.83 )
0.540 1.14
(0.37-
1.80)
0.530
>35 1.42
(0.85–
1.97)
0.438  1.30
(0.62-
1.94)
0.472 1.33
(0.69-
1.95)
0.468 1.28
(0.56-
1.93)
0.489
Urbanization         
1 (Highest) 1.85
(1.24-
2.24)
<0.001 1.76
(1.26-
2.18)
<0.001 1.76
(1.25-
2.24)
<0.001 1.77
(1.28-
2.27)
<0.001
21.72
(1.18-
2.06)
<0.001 1.67
(1.23-
2.11)
<0.001 1.66
(1.21-
2.12)
<0.001 1.68
(1.25-
2.12)
<0.001
31.63
(1.16-
2.02)
<0.001 1.65
(1.18-
2.06)
<0.001 1.64
(1.15-
2.05)
<0.001 1.66
(1.19-
2.08)
<0.001
4 (Lowest) Reference   Reference  Reference  Reference 
Level of care         

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Center Hop. 2.40
(1.80-
3.07)
<0.001 2.24
(1.54-
2.89)
<0.001 2.26
(1.52-
2.91)
<0.001 2.23
(1.52-
2.86)
<0.001
Regional
Hop. 1.96
(1.43-
2.63)
<0.001 1.82
(1.23-
2.40)
<0.001 1.80
(1.21-
2.78)
<0.001 1.84
(1.18
-2.06)
<0.001
Local Hop. Reference   Reference  Reference  Reference 
HTN 1.97 (1.57
-2.45) <0.001 1.83
(1.46-
2.35)
<0.001 1.80
(1.45-
2.36)
<0.001 1.85
(1.46-
2.35)
<0.001
HLip 1.84
(1.41-2.18
)
<0.001 1.73
(1.27-
2.37)
<0.001 1.75
(1.28-
2.35)
<0.001 1.71
(1.26-
2.38)
<0.001
CAD 1.75
(1.27-2.17
)
<0.001 1.58
(1.33-
2.10)
<0.001 1.54
(1.24-
2.14)
<0.001 1.63
(1.43-
2.07)
<0.001
Obesity4.87
(2.16-
6.70)
<0.001 1.95
(1.48-
2.51)
<0.001 1.94
(1.43-
2.35)
<0.001 1.95
(1.48-
2.42)
<0.001
Smoking 1.35
(1.11-
1.51)
<0.001 1.25
(1.20-
1.64)
<0.001 1.48
(1.21–
1.67)
<0.001 1.38
(1.19-
1.61)
<0.001
COPD 1.20
(0.86-
1.48)
0.276  1.29
(0.41-
1.79)
0.530 1.39
(0.59–
1.98)
0.486 1.19
(0.24-
1.61)
0.587
Alcoholism 1.53
(1.30-
1.79)
<0.001 1.85
(1.34-
2.30)
<0.001 1.85
(1.33–
2.30)
<0.001 1.85
(1.39-
2.37)
<0.001
CCI_R 1.25
(1.06-1.70
)
<0.001 1.30
(1.10-
1.52)
<0.001 1.38
(1.10-
1.29)
<0.001 1.30
(1.10-
1.69)
<0.001
Abbreviation:aHR, adjusted hazard ratio; the adjusted variables listed in the table. CI, condent interval.
Severe-P, severe periodontitis. Mild-P, mild periodontitis. Non-P, no periodontitis. DM,diabetes mellitus. Non-
DM,without DM. IP, insured premium, 103 NTD. HTN, hypertension. HLip, hyperlipidemia. CAD, coronary artery
disease. COPD, chronic obstructive pulmonary disease. CCI_R, Charlson comorbidity index revised.
TABLE 2. Sensitivity of periodontitis or DM as the risk in the model.

Page 13/17
 Events Years Rate(/103PY s) aHR (95% CI) aHR (95% CI)
Direction 1: Periodontitis, risk of DM  
Severe-P group 772 57,601 13.40  1.94 (1.49-2.63)* 1.17(1.04-1.26)**
Mild-P group 658 65,012 10.12  1.72 (1.24-2.52)*  Reference
Non-P control 490 77,656 6.31  Reference  
Data in the rst year excluded   
Severe-P group 724 49,977 14.49  1.95 (1.49-2.64)* 1.18 (1.06-1.31)*
Mild-P group 631 59,701 10.57  1.74 (1.24-2.54)*  Reference
Non-P control 465 70,987 6.55  Reference  
Data in the rst 5 years excluded   
Severe-P group 509 32,402 15.71  1.96 (1.51-2.74)* 1.18 (1.07-1.35)*
Mild-P group 482 43,501 11.08  1.75 (1.26-2.54)*  Reference
Non-P control 399 58,732 6.79  Reference  
Direction 2: DM, risk of periodontitis 
DM group 1,662 1,599,752 1.04  1.99 (1.44-2.48)* 
Non-DM control 430 2,756,716 0.16  Reference  
Data in the rst year excluded    
DM group 1,493 1,294,201 1.15  2.01 (1.47-2.57)* 
Non-DM control 394 2,650,809 0.15  Reference  
Data in the rst 5 years excluded   
DM group 1,313 1,076,506 1.22  2.06 (1.50-2.65)* 
Non-DM control 323 1,918,852 0.17  Reference  
Subgroup A: DM, risk of severe periodontitis  
DM group 1,579 1,598,722 0.99  2.08 (1.50-2.66)* 
Non-DM control 370 1,678,127 0.22  Reference  
Data in the rst year excluded    
DM group 1,422 1,287,843 1.10  2.10 (1.58-2.68)* 
Non-DM control 339 1,370,244 0.25  Reference  

Data in the rst 5 years excluded    
DM group 1,254 1,065,244 1.18  2.16 (1.59-2.75)* 
Non-DM control 278 1,083,751 0.26  Reference  

Page 14/17
Subgroup B: DM, risk of mild periodontitis 
DM group 83 1,542,237 0.05  0.97 (0.38-1.57)  
Non-DM control 60 1,078,589 0.06  Reference  
Data in the rst year excluded    
DM group 71 1,291,022 0.05  0.97 (0.44-1.62)  
Non-DM control 55 972,682 0.06  Reference 
Data in the rst 5 years excluded   
DM group 59 1,142,575 0.05  0.98 (0.49-1.66)  
Non-DM control 45 835,101 0.05  Reference 
* and bold: signicant difference at
p
< 0.001.Abbreviation: PYs, person-years. aHR:, adjusted hazard ratio and
adjusted for the variables listed in Tables of 1 and 2. Severe-P, severe periodontitis. Mild-P, mild periodontitis. Non-P,
no periodontitis. DM, diabetes mellitus. Non-DM, without DM.
Figures

Page 15/17
Figure 1
Flowchart of the sample selection procedure from the NHIRD in Taiwan. (DM: type 2 diabetes mellitus; Non-DM: the
non-diabetes controls) (Diagnosis of periodontitis: ICD-9-CM 523.4 and ≥3 OPDs or IPDs in 1 year; the diagnosis of
severe periodontitis: NHI order codes 91006C–91008C and 91009B–91010B; the diagnosis of type 2 diabetes
mellitus: ICD-9-CM 250 and taking ≥2 anti-diabetics).

Page 16/17
Figure 2
Kaplan-Meier analysis of the association between periodontitis and DM.
The cumulative incidences of developing type 2 diabetes mellitus in the three periodontitis groups (a). The
cumulative incidences of developing periodontitis in the diabetes and non-diabetes groups (b): the incidences of
developing periodontitis, overall (b1), the outcome subgroups of severe periodontitis (b2) and mild periodontitis
(b3). (DM: type 2 diabetes mellitus; Non-DM: the non-diabetes controls).
Supplementary Files

Page 17/17
This is a list of supplementary les associated with this preprint. Click to download.
0TableSupplementarymaterials.docx