Periodontitis, Diabetes Mellitus, Cardiovascular Disease

W.J. Teeuw
 Summary, Discussion & Conclusion

Over the last decades, the relation between periodontitis, diabetes mellitus (DM) and
atherosclerotic cardiovascular disease (ACVD) has been extensively studied. Periodontitis
is a common chronic multifactorial inflammatory disease of the supporting structures of
the teeth and is a major cause of tooth loss (Pihlstrom et al., 2005). Besides the possibility
that systemic diseases, such as DM (Preshaw et al., 2012), may contribute to the onset
and/or progression of periodontitis, inflamed periodontal tissues open the possibility for
oral bacteria to enter the circulation and induce systemic inflammation. It is now widely
accepted that a low grade systemic inflammation contributes to metabolic dysregulation
(King, 2008, Pradhan et al., 2001) and atherogenesis (Kaptoge et al., 2010, Friedewald et
al., 2009). Although many investigations suggest several pathways that might explain the
link between periodontitis and DM, and periodontitis and ACVD, the biological
mechanisms, clinical relevance and implications of these interactions are still not well
understood. The aim of this thesis was to contribute to the understanding of the complex
relationship between these three disease states intricately caught in a Bermuda Triangle.

PERIODONTITIS AND DIABETES MELLITUS

DM and periodontitis are two chronic diseases that have long been considered to be
biologically linked in a bi-directional way (Llambes et al., 2015, Preshaw et al., 2012, Lalla
and Papapanou, 2011) (Figure 1).

Figure 1 The bi-directional link between diabetes mellitus and periodontitis. First, periodontitis is considered as a
complication of diabetes mellitus. Second, periodontitis, as a chronic inflammatory disease, might contribute to
an increased insulin resistance.

The DM periodontitis connection

Already in the nineties, periodontitis has been considered as complication of DM by the
former director of NIH/NIDCR (Le, 1993) (Figure 1). Thus, the initiation and progression

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of periodontitis could be indicative for metabolic dysregulation, and it has been suggested
that the dental setting might be suitable for diabetes screening (Lalla and Lamster, 2012).

Since recently plasma glycated hemoglobin (HbA1c) levels were proposed as a suitable
new marker for DM screening (American Diabetes Association, 2015) and a new validated
chairside-method for HbA1c testing was available, the hypothesis could be tested, that
periodontitis patients show an increased prevalence of suspected (pre)diabetes compared
to subjects without destructive periodontal disease (Chapter 2). Therefore, 126
mild/moderate periodontitis patients, 78 severe periodontitis patients and 109 subjects
without periodontitis were screened for DM, using the finger stick method and a validated
HbA1c dry spot analysis. Applying the ADA-guidelines for DM diagnosis (American
Diabetes Association, 2015), there was a significant overrepresentation of subjects with
suspected diabetes and prediabetes in the severe periodontitis group and the
mild/moderate periodontitis group, compared to the control group. Notably, 18.1%
suspected new diabetes patients (in addition to 7.7% already diagnosed) were found
among subjects with severe periodontitis compared to 9.9% and 8.5% in subjects with
mild/moderate periodontitis and controls, respectively. This confirms the assumption that
severe periodontitis could be one of the first signs of metabolic dysregulation and
undiagnosed DM and that the dental office, with particular focus on periodontitis patients,
proved to be a suitable location for screening for (pre)diabetes (Figure 2).

Early diagnosis and intervention of (pre)DM prevent the common micro- and macro-
vascular complications (Tian et al., 2014) and are cost-effective, by delaying or preventing
the direct medical costs of diabetes, including the costs of diabetes education and
nutritional counseling, glucose monitoring, treatment, surveillance for complications, and
treatment of complications (Herman et al., 2005). Owing to the absence of symptoms
and/or disease-related knowledge, DM often goes undetected, and approximately half of
people with DM are not aware of their status (Lee and Colagiuri, 2016). Therefore, risk
indicators for (pre)DM screening are needed and proposed (American Diabetes
Association, 2015). It is proposed here to include screening for DM in the dental office,
with particular focus on periodontitis. When a suspected case of DM is found, the
definitive diagnosis is made by the family physician and treatment can be initiated.
Reciprocally, this is also relevant for the successful treatment of periodontitis (Eke et al.,
2016, Garcia et al., 2015) (Figure 1, 2). It can be expected that, in the future, a good
collaboration between dentists and diabetologists will lead to the best periodontal and
diabetes care.

The periodontitis DM connection

There is a growing body of evidence supporting the fact that periodontal inflammation
adversely affects glycemic control (Engebretson and Kocher, 2013, Preshaw et al., 2012).

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 Summary, Discussion & Conclusion

One biological explanation might be the increased pro-inflammatory state due to

periodontitis (Schenkein and Loos, 2013), resulting in increased insulin resistance (King,
2008, Shoelson et al., 2006) (Figure 1). A systematic review (Chapter 3) presented in this
thesis was designed to explore the robustness of observations that periodontal treatment
affects glycemic control in patients with type 2 DM. Screening of the initially 639 identified
studies, using two online databases, resulted in 5 suitable papers. A total of 371 patients
were included in this analysis, with periodontitis as predictor and the actual absolute
change in HbA1c (HbA1c) as the outcome. The duration of follow-up was 3 to 9 months.
All studies described a research population with both periodontitis and type 2 DM, in
which glycemic control improved after periodontal therapy compared with a periodontitis
non-intervention control group (i.e. no periodontal treatment). A meta-analysis,
evaluating HbA1c before and after periodontal therapy, demonstrated a reduction of
0.40% in treatment groups favoring periodontal intervention, suggesting that periodontal
treatment leads to an improvement of glycemic control in patients with type 2 DM for at
least 3 months (Figure 2). The observed decrease of HbA1c is also clinically relevant, since
any decrease of HbA1c will result in less diabetic complications (Genuth et al., 2003,
Unger, 2008).

Although results of several more recent systematic reviews and meta-analyses

corroborate the findings of Chapter 3, the magnitude of reduction in HbA1c after
periodontal treatment varies (Engebretson and Kocher, 2013, Mauri-Obradors et al., 2015,
Sgolastra et al., 2013, Simpson et al., 2015, Teshome and Yitayeh, 2016), indicating that
the external validity might not be so high. This is also demonstrated by a recent, large
multi-centered single-blind, randomized controlled trial, which showed no differences in
HbA1c values between periodontally treated and non-treated subjects after six months
(Engebretson et al., 2013). Thus, to be able to translate the results from systematic
reviews and meta-analyses into guidelines for general practice, factors that explain the
large differences between individual trials need to be addressed. First, if periodontitis is
causally related to poorer metabolic control in DM patients, the amount of periodontal
inflammation that is present and removed by treatment, might influence the magnitude of
reduction in HbA1c levels. So far, there is no international consensus how to quantify the
amount of periodontal inflammation or how to measure the effect of reduction in
periodontal inflammation on metabolic control. Critically evaluating the present clinical
trials (Chen et al., 2012, Engebretson et al., 2013, Jones et al., 2007, Katagiri et al., 2009,
Kiran et al., 2005, Koromantzos et al., 2012, Moeintaghavi et al., 2012, Promsudthi et al.,
2005, Singh et al., 2008, Stewart et al., 2001, Sun et al., 2010, Sun et al., 2011, Telgi et al.,
2013), patients with various severities of periodontitis (mild, moderate and/or severe
periodontitis) are included and the periodontal treatment is often different, varying from
initial treatment with (Jones et al., 2007, Katagiri et al., 2009, Promsudthi et al., 2005,

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Singh et al., 2008, Sun et al., 2010, Sun et al., 2011) or without (Chen et al., 2012,
Engebretson et al., 2013, Kiran et al., 2005, Koromantzos et al., 2012, Moeintaghavi et al.,
2012, Singh et al., 2008, Stewart et al., 2001, Telgi et al., 2013) supportive antibiotics, with
(Sun et al., 2010, Sun et al., 2011) or without (Chen et al., 2012, Engebretson et al., 2013,
Jones et al., 2007, Katagiri et al., 2009, Kiran et al., 2005, Koromantzos et al., 2012,
Moeintaghavi et al., 2012, Promsudthi et al., 2005, Singh et al., 2008, Stewart et al., 2001,
Telgi et al., 2013) an additional surgical phase, and with (Koromantzos et al., 2012,
Moeintaghavi et al., 2012, Stewart et al., 2001, Sun et al., 2010, Sun et al., 2011) or
without (Chen et al., 2012, Engebretson et al., 2013, Jones et al., 2007, Katagiri et al.,
2009, Kiran et al., 2005, Promsudthi et al., 2005, Singh et al., 2008, Telgi et al., 2013)
extractions of hopeless teeth. Most of the treatment regimens were unsuccessful in
solving all periodontal problems, resulting in subjects with residual periodontal
inflammation at the end of the study period. Second, since metabolic dysregulation
negatively affects the periodontal treatment outcome (Lalla and Papapanou, 2011,
Llambes et al., 2015), the metabolic control of included subjects at baseline is important.
The metabolic regulation of subjects included in the present studies ranges from well
controlled (HbA1c <7%) to poorly uncontrolled (HbA1c >9.5%). So far, the influence of
variations in metabolic control on the clinical effects of periodontal treatment and back on
metabolic control has not been studied. Third, the various studies include patients with
varying levels of obesity and co-morbidities. These factors influence metabolic control and
may affect favorable effects of periodontal therapy in a negative way. Fourth, the
interaction between two complex diseases has been studied, meaning that several other
patient-related factors, such as genetics, lifestyle and biofilm composition might directly
or indirectly influence the metabolic control or periodontal treatment outcome or both.
None of these factors have been studied together in relation to periodontal treatment and
the effect on metabolic control.

To date, the current (Chapter 3) and newer reviews (Engebretson and Kocher, 2013,
Mauri-Obradors et al., 2015, Sgolastra et al., 2013, Simpson et al., 2015, Teshome and
Yitayeh, 2016) indicate positive effects of periodontal treatment on metabolic control in
type 2 DM patients. However, these studies do not completely prove a causal relationship,
i.e. that periodontitis is also involved in the causal chain of events in the initiation and
progression of type 2 DM. Nevertheless, all studies so far show that reducing periodontal
inflammation apparently helps to improve metabolic regulation in type 2 DM patients
(Figure 2). However, the systematic reviews and meta-analyses describing the effect of
treating a complex disease on the course of another complex disease is existent, but the
outcomes need to be interpreted with the above-mentioned shortcomings in mind.

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 Summary, Discussion & Conclusion

Figure 2 The relationship between periodontitis, diabetes mellitus and atherosclerotic cardiovascular disease,
depicted in outlines of the Bermuda Triangle. The studies in this thesis are mainly focused on the relationship
between periodontitis and diabetes mellitus (black-blue line) and periodontitis and atherosclerotic cardiovascular
disease (black-red line). The results suggest an associative (straight line) and/or a causative (arrow) relationship.
In this perspective, some studies also indirectly discuss other existent relationships (light-colored arrow).

Implementation of oral care in diabetes care

In general, standard diabetes care is focused on improving metabolic control, thereby
reducing insulin resistance, and thus prevention of complications (American Diabetes
Association, 2015, Rutten et al., 2013). In the Netherlands, diabetes patients are regularly
checked for common diabetes complications in a preventive manner, especially for
retinopathy, neuropathy and nephropathy (Rutten et al., 2013). Because of the above-
mentioned bi-directional relationship between DM and periodontitis, implementation of
oral care in diabetes care is desirable. Therefore, a first attempt has been made to

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investigate the possibility for internists to obtain current oral health information from the
dentist to complete the health assessment for their diabetes patients (Chapter 4). A total
of 889 DM patients were available. An oral health questionnaire (OHQ) for professional
use was developed. A chain was established from the internist to the patient and from the
patient to the dentist, and vice versa, or direct from the dentist to the internist. However,
a low response rate (<50%) for information on oral health of their patients with DM was
observed. The internists clearly were not used to incorporate questions about oral health
into their practice, and vice versa not all dentists were willing to fill out the OHQ.
Nevertheless, evaluation of the returned OHQs suggested that the OHQ could be a
valuable tool for identification of diabetes patients with poor oral health, especially
untreated periodontal disease. Indeed, as shown before (Chapter 3), proper treatment of
periodontitis can be helpful for diabetes management. However, the transfer of
information from the dentist to the internist is far from optimal and needs improvement.
Clearly, many factors might affect the mutual cooperative attitude of internists and
dentists, and as such need further investigation in prospective studies.

PERIODONTITIS AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

Several epidemiological studies demonstrated an independent association between

periodontitis and atherosclerotic cardiovascular disease (ACVD) (Lockhart et al., 2012).
Recently, also in the Netherlands, an association between periodontitis and ACVD has
been shown (Beukers et al., 2016). ACVD is a collective name for vascular pathologies in
which the process of atherogenesis is the underlying etiologic mechanism. A possible
explanation for the observed association between periodontitis and ACVD might be the
overlapping genetics (i.e. ANRIL, plasminogen) (Schaefer et al., 2015, Schaefer et al., 2013,
Schaefer et al., 2011) and lifestyle (i.e. smoking, overweight) (Suvan et al., 2011,
Warnakulasuriya et al., 2010) risk factors for both diseases. Next to these risk factors
between ACVD and periodontitis, a direct effect of periodontitis on ACVD has been
suggested and might also explain the observed association between both diseases.
Chronic metabolic or inflammatory diseases, such as DM, rheumatoid arthritis and
periodontitis, have been proposed to cause a pro-inflammatory state and may enhance
atherogenesis (Kammoun et al., 2014, Kraakman et al., 2016, Schenkein and Loos, 2013).
Several causal mechanisms have been proposed, whereby bacterial pathogens, antigens,
endotoxins, and/or inflammatory cytokines from the periodontal lesions contribute to the
process of atherogenesis and/or to thromboembolic events, thereby increasing the risk for
ACVD (Lockhart et al., 2012, Schenkein and Loos, 2013, Tonetti et al., 2013). Periodontal
therapy reduces periodontal inflammation and several treatment studies are highly
suggestive that this reduction results in lower levels of markers of systemic inflammation
(Bokhari et al., 2012, Sun et al., 2011) and improved vascular health (D'Aiuto et al., 2013).
In this perspective, C-reactive protein (CRP), an acute phase reactant, is often used as a

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biomarker for systemic inflammation. Thereby, CRP is a widely accepted key marker of
atherosclerosis and is strongly associated with an increased risk for ACVD (Geluk et al.,
2008, Ridker et al., 2010). On average periodontitis patients show elevated C-reactive
protein levels compared to controls (Paraskevas et al., 2008) and several studies indicated
that periodontal treatment might reduce CRP-levels (D'Aiuto et al., 2013), suggesting that
periodontitis causes an increased pro-inflammatory state and contributes to
atherosclerosis and an increased risk for ACVD.

To achieve better understanding of the association between periodontitis and ACVD, a

study was performed to explore whether genetic variation could explain the observed
increased systemic inflammation in periodontitis patients to some extent (Chapter 5).
Recently, ANRIL, a genetic risk factor for several conditions with inflammatory
components in Caucasians, and the strongest susceptibility locus for several types of
ACVD, like coronary artery disease (CAD), myocardial infarction, abdominal aortic
aneurysm and intracranial aneurysm (Deloukas et al., 2013, Helgadottir et al., 2008,
Schunkert et al., 2008) has been associated with periodontitis (Schaefer et al., 2013,
Schaefer et al., 2011). Furthermore, it has been speculated that genetic variation in ANRIL
may modulate inflammatory processes (Bochenek et al., 2013, Cunnington et al., 2010).
Therefore, the association between levels of CRP and the leading ACVD- and periodontitis-
associated ANRIL gene single nucleotide polymorphism (SNP) was investigated across
controls and periodontitis patients. From 171 healthy subjects from North European
descent (115 periodontitis and 56 controls), CRP levels were determined and subjects
were genotyped for the ANRIL SNP (rs1333048). In a multivariate analysis, periodontitis,
female gender, increasing BMI and homozygosity for the major allele (AA-genotype) of the
ANRIL SNP were significantly associated with elevated CRP plasma levels. This study is the
first to show that, in addition to gender and BMI, also a leading SNP in ANRIL is
explanatory for inter-individual variation in CRP levels in periodontitis patients of North
European descent.

Since CRP levels exhibit a continuous association with the risk of coronary heart disease,
ischemic stroke and vascular mortality (Kaptoge et al., 2010), these observations suggest
that the complex relationship between periodontitis and ACVD can also be modulated by
genetic variation in ANRIL (Figure 2). Interestingly, previous studies showed that
carriership of the minor allele (C-allele) of ANRIL is associated with ACVD and periodontitis
(Deloukas et al., 2013, Helgadottir et al., 2008, Schaefer et al., 2013, Schaefer et al., 2011,
Schaefer et al., 2009, Schunkert et al., 2008). In this study (Chapter 5), these findings were
corroborated; the minor allele was more frequent in periodontitis patients than controls.
Since chronic elevated CRP levels are considered as a prognostic risk marker for ACVD
(Geluk et al., 2008, Ridker et al., 2010), an association between the minor allele of ANRIL
and increased levels of CRP was expected. However, it was shown here, that, in the

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inflammatory disease periodontitis, carriage of the minor allele was associated with lower
plasma levels of CRP compared with those that were homozygous for the major allele (AA-
genotype). A possible explanation might be that, although chronic elevated CRP levels are
considered as a prognostic risk marker for ACVD (Geluk et al., 2008, Ridker et al., 2010), in
the initial phase of inflammation, due to a bacterial challenge, CRP might exert a
protective role (Du Clos, 2013). When opsonized to a surface, for instance a bacterium, it
can activate the classical pathway of the complement system (Holers, 2008, Mihlan et al.,
2011, Mold et al., 1984, Suankratay et al., 1998). In that sense, genetic variations
inhibiting a rise in CRP, might cause an increased susceptibility for chronic diseases, such
as periodontitis and ACVD. Because the current results are the first to suggest this
explanation, replication studies in other Caucasian and non-Caucasian periodontitis
patients, as well as biochemical studies are necessary to explain the role of ANRIL as
pleiotropic genetic locus affecting inflammatory pathways of different immune-mediated
diseases (Parkes et al., 2013), like periodontitis and ACVD.

To obtain further understanding of the association between periodontitis and the

cardiovascular condition, a study was initiated to investigate the relationship between
subclinical atherosclerosis and periodontitis using arterial stiffness (AS) as a recently
identified parameter for atherosclerosis (Liu et al., 2011) and ACVD (Greenland et al.,
2010) (Chapter 6). Pulse-wave velocity (PWV), a non-invasive chair-side function test for
AS, was measured in 57 periodontitis patients, without co-morbidity, and compared to 48
subjects from a reference group. Periodontitis patients showed a significantly increased
PWV compared to the reference group and this increase remained significant after
adjustments for ACVD risk factors; it can be concluded that periodontitis is associated with
increased AS. This confirms with another and new parameter the association of
periodontitis with ACVD (Lockhart et al., 2012) (Figure 2). Many studies have shown that
periodontal therapy may improve vascular health (D'Aiuto et al., 2013). Also described in
Chapter 6, 45 patients with periodontitis were followed for 6 months after periodontal
treatment, to explore a possible beneficial effect on arterial function. After periodontal
therapy, a reduction in AS (measured by PWV) was seen, but this failed significance.
Notably, systolic blood pressure was significantly reduced after periodontal therapy,
indicating an improved vascular health, despite the fact that this was not seen for AS.
Meanwhile, Vidal and co-workers showed a significantly reduced AS after periodontal
treatment in periodontitis patients with refractory hypertension (Vidal et al., 2013),
suggesting that especially subjects with co-morbidities, such as hypertension, benefit the
most from periodontal treatment.

Periodontal treatment and the atherosclerotic profile

To further explore the beneficial effects of periodontal treatment on the ACVD risk profile,
a systematic review and meta-analyses were designed (Chapter 7). From 3928 screened

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studies, using three online databases, 25 trials met the eligibility criteria: randomized
controlled trials (RCT) or clinical controlled trials (CCT) with periodontitis patients, in which
the intervention group received periodontal therapy and the non-intervention group
received no periodontal treatment. These trials enrolled 1748 periodontitis patients.
Seven trials enrolled periodontitis patients that were otherwise healthy, 18 trials recruited
periodontal patients with various co-morbidities, such as ACVD or DM. None of the
included trials used hard clinical endpoints of ACVD (i.e. clinical event, such as angina
pectoris, myocardial infarction, stroke, death), but only serum/plasma biomarkers or
surrogate clinical parameters for atherosclerotic disease (e.g. intima media thickness,
flow-mediated dilation, PWV). In fact, these latter clinical parameters reflect endothelial
function, a measure of the condition of the vascular system. Although assessed with
different methods, all trials, that studied endothelial function, showed improvement of
endothelial function after periodontal treatment (Higashi et al., 2009, Higashi et al., 2008,
Li et al., 2011, Tonetti et al., 2007). Moreover, the meta-analyses, presented in Chapter 7
demonstrated significant improvement in levels of biomarkers for ACVD, such as CRP,
interleukin-6, tumor necrosis factor-, fibrinogen, triglycerides, total cholesterol, high
density lipoprotein cholesterol and HbA1c, all favoring periodontal therapy.

Despite the above-mentioned positive effects, large differences between individual

controlled trials have been observed. Similar factors, like the amount of periodontal
inflammation at baseline, the treatment regime of periodontitis and patient
characteristics, as discussed in the other systematic review (Chapter 3), might explain the
observed heterogeneity. Therefore, sub-analyses including co-morbidity, smoking habits
and overweight have been performed, since these factors affect ACVD risk (Perk et al.,
2012), the periodontal treatment outcome (Lakkis et al., 2012, Warnakulasuriya et al.,
2010) or both. These sub-analyses show that for the majority of biomarkers for
atherosclerosis, a larger reduction after periodontal treatment could be observed in
patients with co-morbidity compared to otherwise healthy patients. In addition,
periodontitis patients without overweight or without smoking habits benefitted the most
from periodontal therapy, regarding the reduction in levels of biomarkers for
atherosclerosis. From the systematic review in Chapter 7 and corresponding meta-
analyses, it can be concluded, that periodontal treatment improves endothelial function
and reduces biomarkers of atherosclerotic disease (Figure 2), especially in those patients
already suffering from ACVD and/or DM. Notably, risk factors for ACVD and DM, like
overweight and smoking habits may frustrate the favorable effect of periodontal
treatment on the investigated parameters.

CRP in the oral cavity

As discussed above, CRP is a widely used biomarker for systemic inflammation and
increased risk for ACVD (Geluk et al., 2008, Ridker et al., 2010). In periodontitis, CRP levels

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in plasma and saliva correlate with the severity of periodontitis and after periodontal
treatment, CRP levels in both plasma and crevicular fluid decrease (Bertl et al., 2013,
D'Aiuto et al., 2013, Paraskevas et al., 2008, Torumtay et al., 2016). However, the actual
functional role of CRP in periodontitis and maintenance of oral health is unknown. It has
been shown that bacterium-bound CRP functions as opsonin, which enhances recognition
of bacteria by neutrophils and monocytes, and increases efficacy of phagocytosis as well
as cytokine production (Du Clos and Mold, 2004). Next to the possibility to activate the
complement cascade via the classical pathway, it has been shown that CRP can inhibit the
alternative complement pathway by recruiting factor H (Holers, 2008, Mihlan et al., 2011,
Mold et al., 1984, Suankratay et al., 1998). Factor H belongs to the group of complement
regulatory proteins and inhibits the alternative pathway amplification loop and the C5
convertase. In particular the latter is required for the formation of the membrane attack
complex, which can induce tissue damage (Du Clos and Mold, 2004). In this scenario, the
complement cascade is activated to enhance the clearance of invading bacteria, whereas
at the same time its deleterious effects on host tissues remain limited (Du Clos, 2013).
Therefore, it has been suggested that in the initial phase of inflammation, due to bacterial
challenge, the role of CRP might be protective (Du Clos, 2013).

In addition to CRP, it is known that salivary agglutinin (SAG) is a potential activator of the
complement cascade via the lectin pathway (Leito et al., 2011, Reichhardt et al., 2012). It
has been suggested that when SAG is bound to a bacterial surface, complement proteins
may bind to SAG and activate downstream complement pathways, while SAG in solution
might prevent complement proteins from binding to other surfaces, thereby inhibiting
further activation and subsequent inflammation (Leito et al., 2011, Reichhardt et al.,
2012).

Since the aberrant inflammatory response to the dental biofilm is suggested to be the
major factor determining the onset and/or progression of periodontitis (Loos et al., 2015),
all aspects of immune reactions need consideration. It has been postulated that the
complement system is an essential initiator of the inflammatory response and plays an
important role in the immune reactions in periodontitis (Hajishengallis et al., 2015). The
complement system can be activated via three different pathways: the classical pathway,
the lectin pathway and the alternative pathway. In particular, the classical pathway and
lectin pathway have a critical role in pathogen recognition and initiation of the
complement cascade (Merle et al., 2015). In this perspective, CRP and SAG may play a role
in maintaining oral health as well as in periodontitis by initiating the complement
pathway. Therefore the hypothesis was put forward that if CRP and SAG participate in
maintaining oral health and have a role in periodontitis by modulating the innate immune
responses to oral bacteria, CRP and SAG should be present in different ecological niches of
the oral cavity. An explorative study (Chapter 8) was performed to investigate the

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presence of CRP and SAG in the oral cavity in healthy and inflammatory (i.e. periodontitis)
conditions. Subsequently, since both the classical and lectin pathway lead to further
downstream activation of the complement system via complement protein C4, the
presence of C4 was also determined. Therefore, the presence of CRP, SAG and C4 was
determined in supragingival and subgingival plaque, saliva, and salivary cell fraction of 10
healthy subjects and 10 periodontitis patients and in saliva and salivary cell fraction of 10
edentulous subjects. The results showed that CRP, SAG and C4 were present in dental
plaque and in saliva of the oral cavity of controls, periodontitis patients and edentulous
subjects.

Knowing that CRP and SAG can modulate the innate immune responses to oral bacteria
and demonstrating the presence of CRP, SAG and C4 in supra- and subgingival plaque,
saliva and salivary cell fraction in healthy and inflammatory conditions, it can be suggested
that these proteins play a role in maintaining oral health and are part of various pathways
in the pathophysiology of periodontitis.

CONCLUSION
The research presented in this thesis contributes to the understanding of the complex
relationship between periodontitis and DM, and periodontitis and ACVD (Figure 2). It was
observed that a substantial number of suspected new DM patients could be found in
patients with periodontitis. Furthermore, periodontitis patients showed increased CRP
levels and more AS compared to controls, reflecting an increased atherosclerotic profile
and risk for ACVD. Moreover, periodontal treatment improves the levels of molecular and
clinical biomarkers for metabolic regulation and atherosclerosis. However, patient
characteristics, such as genetics, lifestyle and the presence of co-morbidities contribute to
the complexity of this relationship. Based on these observations and in agreement with a
recent consensus report of the joint EFP/AAP workshop on periodontitis and systemic
diseases, it is recommend that cardiologists, diabetologists and family physicians ask their
patients to be screened by dental care professionals for the presence of periodontitis. If
so, these patients should undergo periodontal therapy, which helps to improve their
metabolic status and lower their cardiovascular risk profile. This again may reduce the risk
for future occurrence of ACVD and DM related complications. In addition, it is proposed
that periodontists should consider that their patients with severe periodontitis may have
DM. Referral to the family physician or perhaps future point of care testing devices may
help with this. When a new case of DM is identified, treatment to improve metabolic
status can be initiated. Reciprocally, this will contribute to a successful treatment of
periodontitis.

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REFFERENCES

American Diabetes Association (2015) Classification and diagnosis of diabetes. Diabetes

Care 38 Suppl, S8-S16.
Bertl, K., Schoiber, A., Haririan, H., Laky, M., Steiner, I., Rausch, W. D., Andrukhov, O. &
Rausch-Fan, X. (2013) Non-surgical periodontal therapy influences salivary
melatonin levels. Clin Oral Investig 17, 1219-1225.
Beukers, N. G., van der Heijden, G. J., van Wijk, A. J. & Loos, B. G. (2016) Periodontitis is an
independent risk indicator for atherosclerotic cardiovascular diseases among 60
174 participants in a large dental school in the Netherlands. J Epidemiol
Community Health.
Bochenek, G., Hasler, R., El Mokhtari, N. E., Konig, I. R., Loos, B. G., Jepsen, S., Rosenstiel,
P., Schreiber, S. & Schaefer, A. S. (2013) The large non-coding RNA ANRIL, which
is associated with atherosclerosis, periodontitis and several forms of cancer,
regulates ADIPOR1, VAMP3 and C11ORF10. Hum Mol Genet 22, 4516-4527.
Bokhari, S. A., Khan, A. A., Butt, A. K., Azhar, M., Hanif, M., Izhar, M. & Tatakis, D. N. (2012)
Non-surgical periodontal therapy reduces coronary heart disease risk markers: a
randomized controlled trial. J Clin Periodontol 39, 1065-1074.
Chen, L., Luo, G., Xuan, D., Wei, B., Liu, F., Li, J. & Zhang, J. (2012) Effects of non-surgical
periodontal treatment on clinical response, serum inflammatory parameters, and
metabolic control in patients with type 2 diabetes: a randomized study. J
Periodontol 83, 435-443.
Cunnington, M. S., Santibanez Koref, M., Mayosi, B. M., Burn, J. & Keavney, B. (2010)
Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate
with ANRIL Expression. PLoS Genet 6, e1000899.
D'Aiuto, F., Orlandi, M. & Gunsolley, J. C. (2013) Evidence that periodontal treatment
improves biomarkers and CVD outcomes. J Clin Periodontol 40 Suppl 14, S85-105.
Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R.,
Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, B. A., Stirrups, K., Konig, I. R.,
Cazier, J. B., Johansson, A., Hall, A. S., Lee, J. Y., Willer, C. J., Chambers, J. C., Esko,
T., Folkersen, L., Goel, A., Grundberg, E., Havulinna, A. S., Ho, W. K., Hopewell, J.
C., Eriksson, N., Kleber, M. E., Kristiansson, K., Lundmark, P., Lyytikainen, L. P.,
Rafelt, S., Shungin, D., Strawbridge, R. J., Thorleifsson, G., Tikkanen, E., Van
Zuydam, N., Voight, B. F., Waite, L. L., Zhang, W., Ziegler, A., Absher, D., Altshuler,
D., Balmforth, A. J., Barroso, I., Braund, P. S., Burgdorf, C., Claudi-Boehm, S., Cox,
D., Dimitriou, M., Do, R., Consortium, D., Consortium, C., Doney, A. S., El
Mokhtari, N., Eriksson, P., Fischer, K., Fontanillas, P., Franco-Cereceda, A.,
Gigante, B., Groop, L., Gustafsson, S., Hager, J., Hallmans, G., Han, B. G., Hunt, S.
E., Kang, H. M., Illig, T., Kessler, T., Knowles, J. W., Kolovou, G., Kuusisto, J.,

236
 Summary, Discussion & Conclusion

Langenberg, C., Langford, C., Leander, K., Lokki, M. L., Lundmark, A., McCarthy,
M. I., Meisinger, C., Melander, O., Mihailov, E., Maouche, S., Morris, A. D., Muller-
Nurasyid, M., Mu, T. C., Nikus, K., Peden, J. F., Rayner, N. W., Rasheed, A.,
Rosinger, S., Rubin, D., Rumpf, M. P., Schafer, A., Sivananthan, M., Song, C.,
Stewart, A. F., Tan, S. T., Thorgeirsson, G., van der Schoot, C. E., Wagner, P. J.,
Wellcome Trust Case Control, C., Wells, G. A., Wild, P. S., Yang, T. P., Amouyel, P.,
Arveiler, D., Basart, H., Boehnke, M., Boerwinkle, E., Brambilla, P., Cambien, F.,
Cupples, A. L., de Faire, U., Dehghan, A., Diemert, P., Epstein, S. E., Evans, A.,
Ferrario, M. M., Ferrieres, J., Gauguier, D., Go, A. S., Goodall, A. H., Gudnason, V.,
Hazen, S. L., Holm, H., Iribarren, C., Jang, Y., Kahonen, M., Kee, F., Kim, H. S.,
Klopp, N., Koenig, W., Kratzer, W., Kuulasmaa, K., Laakso, M., Laaksonen, R., Lee,
J. Y., Lind, L., Ouwehand, W. H., Parish, S., Park, J. E., Pedersen, N. L., Peters, A.,
Quertermous, T., Rader, D. J., Salomaa, V., Schadt, E., Shah, S. H., Sinisalo, J.,
Stark, K., Stefansson, K., Tregouet, D. A., Virtamo, J., Wallentin, L., Wareham, N.,
Zimmermann, M. E., Nieminen, M. S., Hengstenberg, C., Sandhu, M. S., Pastinen,
T., Syvanen, A. C., Hovingh, G. K., Dedoussis, G., Franks, P. W., Lehtimaki, T.,
Metspalu, A., Zalloua, P. A., Siegbahn, A., Schreiber, S., Ripatti, S., Blankenberg, S.
S., Perola, M., Clarke, R., Boehm, B. O., O'Donnell, C., Reilly, M. P., Marz, W.,
Collins, R., Kathiresan, S., Hamsten, A., Kooner, J. S., Thorsteinsdottir, U., Danesh,
J., Palmer, C. N., Roberts, R., Watkins, H., Schunkert, H. & Samani, N. J. (2013)
Large-scale association analysis identifies new risk loci for coronary artery
disease. Nat Genet 45, 25-33.
Du Clos, T. W. (2013) Pentraxins: structure, function, and role in inflammation. ISRN
Inflamm 2013, 379040.
Du Clos, T. W. & Mold, C. (2004) C-reactive protein: an activator of innate immunity and a
modulator of adaptive immunity. Immunol Res 30, 261-277.
Eke, P. I., Wei, L., Thornton-Evans, G. O., Borrell, L. N., Borgnakke, W. S., Dye, B. & Genco,
R. J. (2016) Risk Indicators for Periodontitis in US Adults: NHANES 2009 to 2012. J
Periodontol 87, 1174-1185.
Engebretson, S. & Kocher, T. (2013) Evidence that periodontal treatment improves
diabetes outcomes: a systematic review and meta-analysis. J Clin Periodontol 40
Suppl 14, S153-163.
Engebretson, S. P., Hyman, L. G., Michalowicz, B. S., Schoenfeld, E. R., Gelato, M. C., Hou,
W., Seaquist, E. R., Reddy, M. S., Lewis, C. E., Oates, T. W., Tripathy, D., Katancik,
J. A., Orlander, P. R., Paquette, D. W., Hanson, N. Q. & Tsai, M. Y. (2013) The
effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons
with type 2 diabetes and chronic periodontitis: a randomized clinical trial. JAMA
310, 2523-2532.

237
Chapter 9

Friedewald, V. E., Kornman, K. S., Beck, J. D., Genco, R., Goldfine, A., Libby, P.,
Offenbacher, S., Ridker, P. M., Van Dyke, T. E., Roberts, W. C., American Journal
of, C. & Journal of, P. (2009) The American Journal of Cardiology and Journal of
Periodontology Editors' Consensus: periodontitis and atherosclerotic
cardiovascular disease. Am J Cardiol 104, 59-68.
Garcia, D., Tarima, S. & Okunseri, C. (2015) Periodontitis and glycemic control in diabetes:
NHANES 2009 to 2012. J Periodontol 86, 499-506.
Geluk, C. A., Post, W. J., Hillege, H. L., Tio, R. A., Tijssen, J. G., van Dijk, R. B., Dijk, W. A.,
Bakker, S. J., de Jong, P. E., van Gilst, W. H. & Zijlstra, F. (2008) C-reactive protein
and angiographic characteristics of stable and unstable coronary artery disease:
data from the prospective PREVEND cohort. Atherosclerosis 196, 372-382.
Genuth, S., Eastman, R., Kahn, R., Klein, R., Lachin, J., Lebovitz, H., Nathan, D., Vinicor, F. &
American Diabetes, A. (2003) Implications of the United kingdom prospective
diabetes study. Diabetes Care 26 Suppl 1, S28-32.
Greenland, P., Alpert, J. S., Beller, G. A., Benjamin, E. J., Budoff, M. J., Fayad, Z. A., Foster,
E., Hlatky, M. A., Hodgson, J. M., Kushner, F. G., Lauer, M. S., Shaw, L. J., Smith, S.
C., Jr., Taylor, A. J., Weintraub, W. S., Wenger, N. K., Jacobs, A. K., Smith, S. C., Jr.,
Anderson, J. L., Albert, N., Buller, C. E., Creager, M. A., Ettinger, S. M., Guyton, R.
A., Halperin, J. L., Hochman, J. S., Kushner, F. G., Nishimura, R., Ohman, E. M.,
Page, R. L., Stevenson, W. G., Tarkington, L. G., Yancy, C. W., American College of
Cardiology, F. & American Heart, A. (2010) 2010 ACCF/AHA guideline for
assessment of cardiovascular risk in asymptomatic adults: a report of the
American College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol 56, e50-103.
Hajishengallis, G., Maekawa, T., Abe, T., Hajishengallis, E. & Lambris, J. D. (2015)
Complement Involvement in Periodontitis: Molecular Mechanisms and Rational
Therapeutic Approaches. Adv Exp Med Biol 865, 57-74.
Helgadottir, A., Thorleifsson, G., Magnusson, K. P., Gretarsdottir, S., Steinthorsdottir, V.,
Manolescu, A., Jones, G. T., Rinkel, G. J., Blankensteijn, J. D., Ronkainen, A.,
Jaaskelainen, J. E., Kyo, Y., Lenk, G. M., Sakalihasan, N., Kostulas, K., Gottsater, A.,
Flex, A., Stefansson, H., Hansen, T., Andersen, G., Weinsheimer, S., Borch-
Johnsen, K., Jorgensen, T., Shah, S. H., Quyyumi, A. A., Granger, C. B., Reilly, M. P.,
Austin, H., Levey, A. I., Vaccarino, V., Palsdottir, E., Walters, G. B., Jonsdottir, T.,
Snorradottir, S., Magnusdottir, D., Gudmundsson, G., Ferrell, R. E.,
Sveinbjornsdottir, S., Hernesniemi, J., Niemela, M., Limet, R., Andersen, K.,
Sigurdsson, G., Benediktsson, R., Verhoeven, E. L., Teijink, J. A., Grobbee, D. E.,
Rader, D. J., Collier, D. A., Pedersen, O., Pola, R., Hillert, J., Lindblad, B.,
Valdimarsson, E. M., Magnadottir, H. B., Wijmenga, C., Tromp, G., Baas, A. F.,
Ruigrok, Y. M., van Rij, A. M., Kuivaniemi, H., Powell, J. T., Matthiasson, S. E.,

238
 Summary, Discussion & Conclusion

Gulcher, J. R., Thorgeirsson, G., Kong, A., Thorsteinsdottir, U. & Stefansson, K.

(2008) The same sequence variant on 9p21 associates with myocardial infarction,
abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 40, 217-224.
Herman, W. H., Hoerger, T. J., Brandle, M., Hicks, K., Sorensen, S., Zhang, P., Hamman, R.
F., Ackermann, R. T., Engelgau, M. M., Ratner, R. E. & Diabetes Prevention
Program Research, G. (2005) The cost-effectiveness of lifestyle modification or
metformin in preventing type 2 diabetes in adults with impaired glucose
tolerance. Ann Intern Med 142, 323-332.
Higashi, Y., Goto, C., Hidaka, T., Soga, J., Nakamura, S., Fujii, Y., Hata, T., Idei, N., Fujimura,
N., Chayama, K., Kihara, Y. & Taguchi, A. (2009) Oral infection-inflammatory
pathway, periodontitis, is a risk factor for endothelial dysfunction in patients with
coronary artery disease. Atherosclerosis 206, 604-610.
Higashi, Y., Goto, C., Jitsuiki, D., Umemura, T., Nishioka, K., Hidaka, T., Takemoto, H.,
Nakamura, S., Soga, J., Chayama, K., Yoshizumi, M. & Taguchi, A. (2008)
Periodontal infection is associated with endothelial dysfunction in healthy
subjects and hypertensive patients. Hypertension 51, 446-453.
Holers, V. M. (2008) The spectrum of complement alternative pathway-mediated diseases.
Immunol Rev 223, 300-316.
Jones, J. A., Miller, D. R., Wehler, C. J., Rich, S. E., Krall-Kaye, E. A., McCoy, L. C.,
Christiansen, C. L., Rothendler, J. A. & Garcia, R. I. (2007) Does periodontal care
improve glycemic control? The Department of Veterans Affairs Dental Diabetes
Study. J Clin Periodontol 34, 46-52.
Kammoun, H. L., Kraakman, M. J. & Febbraio, M. A. (2014) Adipose tissue inflammation in
glucose metabolism. Rev Endocr Metab Disord 15, 31-44.
Kaptoge, S., Di Angelantonio, E., Lowe, G., Pepys, M. B., Thompson, S. G., Collins, R. &
Danesh, J. (2010) C-reactive protein concentration and risk of coronary heart
disease, stroke, and mortality: an individual participant meta-analysis. Lancet
375, 132-140.
Katagiri, S., Nitta, H., Nagasawa, T., Uchimura, I., Izumiyama, H., Inagaki, K., Kikuchi, T.,
Noguchi, T., Kanazawa, M., Matsuo, A., Chiba, H., Nakamura, N., Kanamura, N.,
Inoue, S., Ishikawa, I. & Izumi, Y. (2009) Multi-center intervention study on
glycohemoglobin (HbA1c) and serum, high-sensitivity CRP (hs-CRP) after local
anti-infectious periodontal treatment in type 2 diabetic patients with periodontal
disease. Diabetes Res Clin Pract 83, 308-315.
King, G. L. (2008) The role of inflammatory cytokines in diabetes and its complications. J
Periodontol 79, 1527-1534.
Kiran, M., Arpak, N., Unsal, E. & Erdogan, M. F. (2005) The effect of improved periodontal
health on metabolic control in type 2 diabetes mellitus. J Clin Periodontol 32, 266-
272.

239
Chapter 9

Koromantzos, P. A., Makrilakis, K., Dereka, X., Offenbacher, S., Katsilambros, N., Vrotsos, I.
A. & Madianos, P. N. (2012) Effect of non-surgical periodontal therapy on C-
reactive protein, oxidative stress, and matrix metalloproteinase (MMP)-9 and
MMP-2 levels in patients with type 2 diabetes: a randomized controlled study. J
Periodontol 83, 3-10.
Kraakman, M. J., Dragoljevic, D., Kammoun, H. L. & Murphy, A. J. (2016) Is the risk of
cardiovascular disease altered with anti-inflammatory therapies? Insights from
rheumatoid arthritis. Clin Transl Immunology 5, e84.
Lakkis, D., Bissada, N. F., Saber, A., Khaitan, L., Palomo, L., Narendran, S. & Al-Zahrani, M.
S. (2012) Response to periodontal therapy in patients who had weight loss after
bariatric surgery and obese counterparts: a pilot study. J Periodontol 83, 684-689.
Lalla, E. & Lamster, I. B. (2012) Assessment and management of patients with diabetes
mellitus in the dental office. Dent Clin North Am 56, 819-829.
Lalla, E. & Papapanou, P. N. (2011) Diabetes mellitus and periodontitis: a tale of two
common interrelated diseases. Nat Rev Endocrinol 7, 738-748.
Lee, C. M. & Colagiuri, S. (2016) Population Approaches for Detecting Glucose Disorders.
Curr Diabetes Rev 12, 42-50.
Leito, J. T., Ligtenberg, A. J., van Houdt, M., van den Berg, T. K. & Wouters, D. (2011) The
bacteria binding glycoprotein salivary agglutinin (SAG/gp340) activates
complement via the lectin pathway. Mol Immunol 49, 185-190.
Li, X., Tse, H. F., Yiu, K. H., Li, L. S. & Jin, L. (2011) Effect of periodontal treatment on
circulating CD34(+) cells and peripheral vascular endothelial function: a
randomized controlled trial. J Clin Periodontol 38, 148-156.
Liu, C. S., Li, C. I., Shih, C. M., Lin, W. Y., Lin, C. H., Lai, S. W., Li, T. C. & Lin, C. C. (2011)
Arterial stiffness measured as pulse wave velocity is highly correlated with
coronary atherosclerosis in asymptomatic patients. J Atheroscler Thromb 18, 652-
658.
Llambes, F., Arias-Herrera, S. & Caffesse, R. (2015) Relationship between diabetes and
periodontal infection. World J Diabetes 6, 927-935.
Lockhart, P. B., Bolger, A. F., Papapanou, P. N., Osinbowale, O., Trevisan, M., Levison, M.
E., Taubert, K. A., Newburger, J. W., Gornik, H. L., Gewitz, M. H., Wilson, W. R.,
Smith, S. C., Jr., Baddour, L. M., American Heart Association Rheumatic Fever, E.,
Kawasaki Disease Committee of the Council on Cardiovascular Disease in the
Young, C. o. E., Prevention, C. o. P. V. D. & Council on Clinical, C. (2012)
Periodontal disease and atherosclerotic vascular disease: does the evidence
support an independent association?: a scientific statement from the American
Heart Association. Circulation 125, 2520-2544.
Le, H. (1993) Periodontal disease. The sixth complication of diabetes mellitus. Diabetes
Care 16, 329-334.

240
 Summary, Discussion & Conclusion

Loos, B. G., Papantonopoulos, G., Jepsen, S. & Laine, M. L. (2015) What is the Contribution
of Genetics to Periodontal Risk? Dent Clin North Am 59, 761-780.
Mauri-Obradors, E., Jane-Salas, E., Sabater-Recolons Mdel, M., Vinas, M. & Lopez-Lopez, J.
(2015) Effect of nonsurgical periodontal treatment on glycosylated hemoglobin in
diabetic patients: a systematic review. Odontology 103, 301-313.
Merle, N. S., Church, S. E., Fremeaux-Bacchi, V. & Roumenina, L. T. (2015) Complement
System Part I - Molecular Mechanisms of Activation and Regulation. Front
Immunol 6, 262.
Mihlan, M., Blom, A. M., Kupreishvili, K., Lauer, N., Stelzner, K., Bergstrom, F., Niessen, H.
W. & Zipfel, P. F. (2011) Monomeric C-reactive protein modulates classic
complement activation on necrotic cells. Faseb j 25, 4198-4210.
Moeintaghavi, A., Arab, H. R., Bozorgnia, Y., Kianoush, K. & Alizadeh, M. (2012) Non-
surgical periodontal therapy affects metabolic control in diabetics: a randomized
controlled clinical trial. Aust Dent J 57, 31-37.
Mold, C., Kingzette, M. & Gewurz, H. (1984) C-reactive protein inhibits pneumococcal
activation of the alternative pathway by increasing the interaction between
factor H and C3b. J Immunol 133, 882-885.
Paraskevas, S., Huizinga, J. D. & Loos, B. G. (2008) A systematic review and meta-analyses
on C-reactive protein in relation to periodontitis. J Clin Periodontol 35, 277-290.
Parkes, M., Cortes, A., van Heel, D. A. & Brown, M. A. (2013) Genetic insights into common
pathways and complex relationships among immune-mediated diseases. Nat Rev
Genet 14, 661-673.
Perk, J., De Backer, G., Gohlke, H., Graham, I., Reiner, Z., Verschuren, M., Albus, C.,
Benlian, P., Boysen, G., Cifkova, R., Deaton, C., Ebrahim, S., Fisher, M., Germano,
G., Hobbs, R., Hoes, A., Karadeniz, S., Mezzani, A., Prescott, E., Ryden, L., Scherer,
M., Syvanne, M., Scholte op Reimer, W. J., Vrints, C., Wood, D., Zamorano, J. L.,
Zannad, F., European Association for Cardiovascular, P., Rehabilitation &
Guidelines, E. S. C. C. f. P. (2012) European Guidelines on cardiovascular disease
prevention in clinical practice (version 2012). The Fifth Joint Task Force of the
European Society of Cardiology and Other Societies on Cardiovascular Disease
Prevention in Clinical Practice (constituted by representatives of nine societies
and by invited experts). Eur Heart J 33, 1635-1701.
Pihlstrom, B. L., Michalowicz, B. S. & Johnson, N. W. (2005) Periodontal diseases. Lancet
366, 1809-1820.
Pradhan, A. D., Manson, J. E., Rifai, N., Buring, J. E. & Ridker, P. M. (2001) C-reactive
protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286,
327-334.

241
Chapter 9

Preshaw, P. M., Alba, A. L., Herrera, D., Jepsen, S., Konstantinidis, A., Makrilakis, K. &
Taylor, R. (2012) Periodontitis and diabetes: a two-way relationship. Diabetologia
55, 21-31.
Promsudthi, A., Pimapansri, S., Deerochanawong, C. & Kanchanavasita, W. (2005) The
effect of periodontal therapy on uncontrolled type 2 diabetes mellitus in older
subjects. Oral Dis 11, 293-298.
Reichhardt, M. P., Loimaranta, V., Thiel, S., Finne, J., Meri, S. & Jarva, H. (2012) The salivary
scavenger and agglutinin binds MBL and regulates the lectin pathway of
complement in solution and on surfaces. Front Immunol 3, 205.
Ridker, P. M., MacFadyen, J., Libby, P. & Glynn, R. J. (2010) Relation of baseline high-
sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin
in the Justification for Use of statins in Prevention: an Intervention Trial
Evaluating Rosuvastatin (JUPITER). Am J Cardiol 106, 204-209.
Rutten, G. E. H. M., De Grauw, W. J. C., Nijpels, G., Houweling, S. T., Van de Laar, F. A., Bilo,
H. J., Holleman, F., Burgers, J. S., Wiersma, T. & Janssen, P. G. H. (2013) NHG-
Standaard Diabetes mellitus type 2 (derde herziening). Huisarts Wet 56, 512-525.
Schaefer, A. S., Bochenek, G., Jochens, A., Ellinghaus, D., Dommisch, H., Guzeldemir-
Akcakanat, E., Graetz, C., Harks, I., Jockel-Schneider, Y., Weinspach, K., Meyle, J.,
Eickholz, P., Linden, G. J., Cine, N., Nohutcu, R., Weiss, E., Houri-Haddad, Y., Iraqi,
F., Folwaczny, M., Noack, B., Strauch, K., Gieger, C., Waldenberger, M., Peters, A.,
Wijmenga, C., Yilmaz, E., Lieb, W., Rosenstiel, P., Doerfer, C., Bruckmann, C.,
Erdmann, J., Konig, I., Jepsen, S., Loos, B. G. & Schreiber, S. (2015) Genetic
evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery
disease and periodontitis. Circ Cardiovasc Genet 8, 159-167.
Schaefer, A. S., Bochenek, G., Manke, T., Nothnagel, M., Graetz, C., Thien, A., Jockel-
Schneider, Y., Harks, I., Staufenbiel, I., Wijmenga, C., Eberhard, J., Guzeldemir-
Akcakanat, E., Cine, N., Folwaczny, M., Noack, B., Meyle, J., Eickholz, P., Trombelli,
L., Scapoli, C., Nohutcu, R., Bruckmann, C., Doerfer, C., Jepsen, S., Loos, B. G. &
Schreiber, S. (2013) Validation of reported genetic risk factors for periodontitis in
a large-scale replication study. J Clin Periodontol 40, 563-572.
Schaefer, A. S., Richter, G. M., Dommisch, H., Reinartz, M., Nothnagel, M., Noack, B., Laine,
M. L., Folwaczny, M., Groessner-Schreiber, B., Loos, B. G., Jepsen, S. & Schreiber,
S. (2011) CDKN2BAS is associated with periodontitis in different European
populations and is activated by bacterial infection. J Med Genet 48, 38-47.
Schaefer, A. S., Richter, G. M., Groessner-Schreiber, B., Noack, B., Nothnagel, M., El
Mokhtari, N. E., Loos, B. G., Jepsen, S. & Schreiber, S. (2009) Identification of a
shared genetic susceptibility locus for coronary heart disease and periodontitis.
PLoS Genet 5, e1000378.

242
 Summary, Discussion & Conclusion

Schenkein, H. A. & Loos, B. G. (2013) Inflammatory mechanisms linking periodontal

diseases to cardiovascular diseases. J Clin Periodontol 40 Suppl 14, S51-69.
Schunkert, H., Gotz, A., Braund, P., McGinnis, R., Tregouet, D. A., Mangino, M., Linsel-
Nitschke, P., Cambien, F., Hengstenberg, C., Stark, K., Blankenberg, S., Tiret, L.,
Ducimetiere, P., Keniry, A., Ghori, M. J., Schreiber, S., El Mokhtari, N. E., Hall, A.
S., Dixon, R. J., Goodall, A. H., Liptau, H., Pollard, H., Schwarz, D. F., Hothorn, L. A.,
Wichmann, H. E., Konig, I. R., Fischer, M., Meisinger, C., Ouwehand, W., Deloukas,
P., Thompson, J. R., Erdmann, J., Ziegler, A., Samani, N. J. & Cardiogenics, C.
(2008) Repeated replication and a prospective meta-analysis of the association
between chromosome 9p21.3 and coronary artery disease. Circulation 117, 1675-
1684.
Sgolastra, F., Severino, M., Pietropaoli, D., Gatto, R. & Monaco, A. (2013) Effectiveness of
periodontal treatment to improve metabolic control in patients with chronic
periodontitis and type 2 diabetes: a meta-analysis of randomized clinical trials. J
Periodontol 84, 958-973.
Shoelson, S. E., Lee, J. & Goldfine, A. B. (2006) Inflammation and insulin resistance. J Clin
Invest 116, 1793-1801.
Simpson, T. C., Weldon, J. C., Worthington, H. V., Needleman, I., Wild, S. H., Moles, D. R.,
Stevenson, B., Furness, S. & Iheozor-Ejiofor, Z. (2015) Treatment of periodontal
disease for glycaemic control in people with diabetes mellitus. Cochrane
Database Syst Rev, CD004714.
Singh, S., Kumar, V., Kumar, S. & Subbappa, A. (2008) The effect of periodontal therapy on
the improvement of glycemic control in patients with type 2 diabetes mellitus: A
randomized controlled clinical trial. Int J Diabetes Dev Ctries 28, 38-44.
Stewart, J. E., Wager, K. A., Friedlander, A. H. & Zadeh, H. H. (2001) The effect of
periodontal treatment on glycemic control in patients with type 2 diabetes
mellitus. J Clin Periodontol 28, 306-310.
Suankratay, C., Mold, C., Zhang, Y., Potempa, L. A., Lint, T. F. & Gewurz, H. (1998)
Complement regulation in innate immunity and the acute-phase response:
inhibition of mannan-binding lectin-initiated complement cytolysis by C-reactive
protein (CRP). Clin Exp Immunol 113, 353-359.
Sun, W. L., Chen, L. L., Zhang, S. Z., Ren, Y. Z. & Qin, G. M. (2010) Changes of adiponectin
and inflammatory cytokines after periodontal intervention in type 2 diabetes
patients with periodontitis. Arch Oral Biol 55, 970-974.
Sun, W. L., Chen, L. L., Zhang, S. Z., Wu, Y. M., Ren, Y. Z. & Qin, G. M. (2011) Inflammatory
cytokines, adiponectin, insulin resistance and metabolic control after periodontal
intervention in patients with type 2 diabetes and chronic periodontitis. Intern
Med 50, 1569-1574.

243
Chapter 9

Suvan, J., D'Aiuto, F., Moles, D. R., Petrie, A. & Donos, N. (2011) Association between
overweight/obesity and periodontitis in adults. A systematic review. Obes Rev 12,
e381-404.
Telgi, R. L., Tandon, V., Tangade, P. S., Tirth, A., Kumar, S. & Yadav, V. (2013) Efficacy of
nonsurgical periodontal therapy on glycaemic control in type II diabetic patients:
a randomized controlled clinical trial. J Periodontal Implant Sci 43, 177-182.
Teshome, A. & Yitayeh, A. (2016) The effect of periodontal therapy on glycemic control
and fasting plasma glucose level in type 2 diabetic patients: systematic review
and meta-analysis. BMC Oral Health 17, 31.
Tian, L., Zhu, J., Liu, L., Liang, Y., Li, J. & Yang, Y. (2014) Prediabetes and short-term
outcomes in nondiabetic patients after acute ST-elevation myocardial infarction.
Cardiology 127, 55-61.
Tonetti, M. S., D'Aiuto, F., Nibali, L., Donald, A., Storry, C., Parkar, M., Suvan, J., Hingorani,
A. D., Vallance, P. & Deanfield, J. (2007) Treatment of periodontitis and
endothelial function. N Engl J Med 356, 911-920.
Tonetti, M. S., Van Dyke, T. E. & Working group 1 of the joint, E. F. P. A. A. P. w. (2013)
Periodontitis and atherosclerotic cardiovascular disease: consensus report of the
Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin
Periodontol 40 Suppl 14, S24-29.
Torumtay, G., Kirzioglu, F. Y., Ozturk Tonguc, M., Kale, B., Calapoglu, M. & Orhan, H. (2016)
Effects of periodontal treatment on inflammation and oxidative stress markers in
patients with metabolic syndrome. J Periodontal Res 51, 489-498.
Unger, J. (2008) Current strategies for evaluating, monitoring, and treating type 2 diabetes
mellitus. Am J Med 121, S3-8.
Vidal, F., Cordovil, I., Figueredo, C. M. & Fischer, R. G. (2013) Non-surgical periodontal
treatment reduces cardiovascular risk in refractory hypertensive patients: a pilot
study. J Clin Periodontol 40, 681-687.
Warnakulasuriya, S., Dietrich, T., Bornstein, M. M., Casals Peidro, E., Preshaw, P. M.,
Walter, C., Wennstrom, J. L. & Bergstrom, J. (2010) Oral health risks of tobacco
use and effects of cessation. Int Dent J 60, 7-30.

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