Periodontitis as a Potential Early Risk Indicator for Diabetes Mellitus, Atherosclerotic Cardiovascular Disease, Metabolic Syndrome and Obstructive Sleep Apnea Syndrome
Conditions: Diabetes Mellitus, Periodontal Diseases, Cardiovascular Diseases, Obstructive Sleep Apnea Syndrome
Sponsor: Academic Centre for Dentistry in Amsterdam

NL62337.029.17 / ParoSysACTA 
Periodontitis as signal for an underlying disease 
 
 
 
 
PROTOCOL TITLE  
‘Periodontitis as a potential early risk indicator for diabetes mellitus, atherosclerotic 
cardiovascular disease, metabolic syndrome and obstructive sleep apnea syndrome’ 
 
Protocol ID 
ParoSysACTA 
Short title 
Periodontitis as signal for an underlying disease 
EudraCT number  
NA  
Version 
4 
Date 
12-02-2018 
Coordinating 
investigator/project leader 
Dr. W.J. Teeuw 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Dr. W.J. Teeuw (W.Teeuw@acta.nl) 
Mevr. drs. M.X.F. Kosho (M.X.F.Kosho@acta.nl) 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Academic Centre for Dentistry Amsterdam 
(ACTA) 
Subsidising party 
Netherlands Enterprise Agency and Ministry of 
Economic Affairs 
Independent expert (s) 
Prof. dr. F.R. Rozema (Fred.Rozema@acta.nl) 
Laboratory sites  
Labonovum B.V. 
Anthony Cankrienstraat 9, 3065 NK Rotterdam 
(Dennis.C.W.Poland@gmail.com) 
Pharmacy  
Not applicable 
 
 

NL62337.029.17 / ParoSysACTA 
Periodontitis as signal for an underlying disease 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Prof. dr. A.J. Feilzer, Dean of the 
Academic Centre for Dentistry 
Amsterdam (ACTA) 
 
Head of Department: 
Prof. dr. B.G. Loos, Department of 
Periodontology (ACTA) 
 
 
Dr. W.J. Teeuw, Assistant-professor, 
periodontist, Chef de Clinique, 
Department of Periodontology 
 
 
 
 
 

NL62337.029.17 / ParoSysACTA 
Periodontitis as signal for an underlying disease 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 9 
2. 
OBJECTIVES ................................................................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................13 
4.1 
Population (base) ...................................................................................................13 
4.2 
Inclusion criteria .....................................................................................................13 
4.3 
Exclusion criteria ....................................................................................................13 
4.4 
Sample size calculation ..........................................................................................13 
5. 
TREATMENT OF SUBJECTS .......................................................................................14 
5.1 
Investigational product/treatment ............................................................................14 
5.2 
Use of co-intervention (if applicable) ......................................................................14 
5.3 
Escape medication (if applicable) ...........................................................................14 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................15 
6.1 
Name and description of investigational  product(s) ...............................................15 
6.2 
Summary of findings from non-clinical studies ........................................................15 
6.3 
Summary of findings from clinical studies ...............................................................15 
6.4 
Summary of known and potential risks and benefits ...............................................15 
6.5 
Description and justification of route of administration and dosage .........................15 
6.6 
Dosages, dosage modifications and method of administration ...............................15 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................15 
6.8 
Drug accountability .................................................................................................15 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................16 
7.1 
Name and description of non-investigational product(s) .........................................16 
7.2 
Summary of findings from non-clinical studies ........................................................16 
7.3 
Summary of findings from clinical studies ...............................................................16 
7.4 
Summary of known and potential risks and benefits ...............................................16 
7.5 
Description and justification of route of administration and dosage .........................16 
7.6 
Dosages, dosage modifications and method of administration ...............................16 
7.7 
Preparation and labelling of Non Investigational Medicinal Product ........................16 
7.8 
Drug accountability .................................................................................................16 
8. 
METHODS ....................................................................................................................17 
8.1 
Study parameters/endpoints ...................................................................................17 
8.1.1 
Main study parameter/endpoint .......................................................................17 
8.1.2 
Secondary study parameters/endpoints (if applicable) ....................................17 
8.1.3 
Other study parameters (if applicable) .............................................................17 
8.2 
Randomisation, blinding and treatment allocation ..................................................17 
8.3 
Study procedures ...................................................................................................17 
8.4 
Withdrawal of individual subjects ............................................................................19 
8.4.1 
Specific criteria for withdrawal (if applicable) ...................................................19 
8.5 
Replacement of individual subjects after withdrawal ...............................................19 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................19 
8.7 
Premature termination of the study .........................................................................19 

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9. 
SAFETY REPORTING ..................................................................................................20 
9.1 
Temporary halt for reasons of subject safety ..........................................................20 
9.2 
AEs, SAEs and SUSARs ........................................................................................20 
9.2.1 
Adverse events (AEs) ......................................................................................20 
9.2.2 
Serious adverse events (SAEs) .......................................................................20 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................21 
9.3 
Annual safety report ...............................................................................................22 
9.4 
Follow-up of adverse events ...................................................................................22 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..................................22 
10. 
STATISTICAL ANALYSIS ..........................................................................................23 
10.1 
Primary study parameter(s) ....................................................................................24 
10.2 
Secondary study parameter(s) ...............................................................................25 
10.3 
Other study parameters ..........................................................................................25 
10.4 
Interim analysis (if applicable) ................................................................................25 
11. 
ETHICAL CONSIDERATIONS ...................................................................................26 
11.1 
Regulation statement .............................................................................................26 
11.2 
Recruitment and consent........................................................................................26 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................27 
11.4 
Benefits and risks assessment, group relatedness .................................................27 
11.5 
Compensation for injury .........................................................................................27 
11.6 
Incentives (if applicable) .........................................................................................27 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................28 
12.1 
Handling and storage of data and documents ........................................................28 
12.2 
Monitoring and Quality Assurance ..........................................................................28 
12.3 
Amendments ..........................................................................................................28 
12.4 
Annual progress report ...........................................................................................29 
12.5 
Temporary halt and (prematurely) end of study report ............................................29 
12.6 
Public disclosure and publication policy ..................................................................30 
13. 
STRUCTURED RISK ANALYSIS...............................................................................32 
13.1 
Potential issues of concern .....................................................................................32 
13.2 
Synthesis ...............................................................................................................32 
14. 
REFERENCES ..........................................................................................................33 
APPENDIX 1: Criteria for the diagnosis of DM according the ADA guidelines (7) .................35 
APPENDIX 2: Categories for pre-DM according the ADA guidelines (7) ...............................36 
APPENDIX 3: The 10-year-risk chart of ASCVD (for patients without known ASCVD) (28) ..37 
APPENDIX 4: Criteria for diagnosis of Metabolic Syndrome (MetS) - NCEP ATP III (19) .....38 
APPENDIX 5: Case Definitions Periodontitis according to the CDC-AAP (23)……………….39 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
 
 
ACTA 
ADA 
ASCVD 
BMI 
CDC-AAP 
DM 
ESC 
HbA1c 
HDL-C 
IC 
IDF 
LDL-C 
MetS 
METC 
 
NHG 
 
NCEP 
ATP III 
 
OSA 
OSAS 
Sponsor 
 
 
 
 
STROBE 
WC 
WMO 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee 
(In Dutch, ABR = Algemene Beoordeling en Registratie) 
Academic Centre for Dentistry Amsterdam 
American Diabetes Association 
Atherosclerotic Cardiovascular Disease 
Body Mass Index 
Centers for Disease Control and Prevention 
Diabetes Mellitus 
European Society of Cardiology 
Glycated Haemoglobin 
High-density Lipoprotein Cholesterol 
Informed Consent 
International Diabetes Federation 
Low-density Lipoprotein Cholesterol 
Metabolic Syndrome 
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
Nederlands Huisartsen Genootschap (Dutch Family Physicians Clinical 
Practical Guidelines) 
National Cholesterol Education Program (NCEP) expert panel on 
detection, evaluation, and treatment of high blood cholesterol in adults 
(Adult Treatment Panel III) 
Obstructive Sleep Apnea  
Obstructive Sleep Apnea Syndrome 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
Strengthening the Reporting of Observational studies in Epidemiology 
Waist Circumference 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 

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SUMMARY 
 
Rationale: Diabetes Mellitus (DM), Atherosclerotic Cardiovascular Disease (ASCVD), 
Metabolic Syndrome (MetS) and Obstructive Sleep Apnea Syndrome (OSAS) are major 
health problems (1-3). However due to absence of symptoms and/or lack of knowledge, 
people are often unaware of having DM, ASCVD, MetS or OSAS while early treatment could 
prevent the progression of these diseases. Therefore, risk indicators for early detection of 
DM, ASCVD, MetS and OSAS are needed and proposed (4-8). 
 
Many studies demonstrate the association between oral diseases and DM and/or ASCVD  
(9, 10). The most observed chronic oral disease is periodontitis. Periodontitis is a common 
chronic multifactorial inflammatory disease of the supporting structures of the teeth (11). DM 
and ASCVD might, due to their pro-inflammatory state and alteration of the immune system, 
contribute to the onset and/or progression of periodontitis (12). Therefore periodontitis could 
be considered as an early sign of an underlying vascular and/or metabolic pathology (13). 
 
Some studies have also reported a positive association between periodontitis and MetS (14). 
The MetS prevalence in patients with periodontitis was shown to be higher than controls and 
MetS showed to be associated with severe periodontitis (15, 16). The association between 
periodontitis and OSAS is less established, however there is some evidence to a plausible 
association between periodontal disease and Obstructive Sleep Apnea (OSA) (8).  
 
Due to the broad overlap of objective biomarkers, in this study, subjects with or without 
periodontitis will be screened for determining the prevalence of (pre)DM, the 10-year-risk of 
ASCVD, the prevalence of MetS and the risk of OSAS. The screening will be based on 
clinical measures, specific blood markers determined by a developed finger stick analysis 
and three questionnaires. 
 
Notably, a recently published pilot paper from our research group presents the feasibility and 
preliminary results of proposed screening for (pre)DM; we found 18.1% new DM cases 
among subjects with severe periodontitis compared to 9.9% in mild/moderate periodontitis 
and 8.5% in controls (13).  
 
Objective: The aim of the proposed study is to screen for (pre)DM, an increased 10-year-risk 
of ASCVD, MetS and a high risk of OSAS in subjects with and without periodontitis.  
 
Study design: Cross-sectional study 

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Study population: In total 783 patients will be included (261 without periodontitis, 261 with 
mild/moderate periodontitis and 261 with severe periodontitis) at the Academic Centre for 
Dentistry Amsterdam (ACTA). The subjects with periodontitis that will be enrolled in this 
study are referred to the periodontal clinic for diagnosis and treatment of periodontitis. The 
subjects without periodontitis will be selected among individuals that visit the dental school 
for regular dental checkups. All subjects will be 18 years and older and are mainly 
inhabitants from Amsterdam and surrounding areas.  
 
Intervention (if applicable):  Subjects with and without periodontitis will undergo the 
following intervention: 
- 
General, medical and dental histories (standard procedure)  
- 
Clinical periodontal evaluation (standard procedure) 
- 
Dental x-rays, when indicated for periodontitis or other dental pathology (standard 
procedure) 
- 
Measurement of systolic and diastolic blood pressure (standard procedure) 
- 
Measurement of length and body weight, waist and neck circumference, a 
questionnaire for demographic characteristics, an International Physical Activity 
Questionnaire (IPAQ) and an OSAS risk questionnaire (extra procedure) 
- 
Plasma finger stick procedure (HemCol, Labonovum BV) for measuring biomarkers: A 
drop of blood is obtained with a finger stick (Greiner Bio-one Safety Lancet) and 
collected in a collection tube. The collection tube is sent to the laboratory for analysis 
by regular mail. (extra procedure) 
 
Main study parameters/endpoints: To investigate, within a dental setting, the differences 
between subjects with and without periodontitis in: 
- 
The prevalence of preDM and DM 
- 
The 10-year-risk of ASCVD 
- 
The prevalence of MetS 
- 
The risk of OSAS 
 
 
 
 
 
 

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Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: 
- 
The extra burden for the subjects with and without periodontitis will be three 
questionnaires, measurement of length, body weight, waist and neck circumference, 
and a finger stick procedure. 
- 
The risks associated with participation are negligible.  
- 
Possible benefit of participation will be early detection of health risks such as 
(pre)DM, ASCVD, MetS, OSAS and possibly a referral for further diagnosis and/or 
treatment at the family physician. 
 
 

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1. INTRODUCTION AND RATIONALE 
 
Diabetes Mellitus (DM), Atherosclerotic Cardiovascular Disease (ASCVD), Metabolic 
Syndrome (MetS) and Obstructive Sleep Apnea Syndrome (OSAS) are major health 
problems (1-3). However due to the absence of symptoms and/or disease-related 
knowledge, the pathology of DM, ASCVD, MetS and OSAS often goes undetected. 
Approximately one-third of the people with DM are not aware of their status (17). Another 
study has shown that the onset of DM appears approximately 4 to 7 years before clinical 
diagnosis (18). Research in Dutch OSAS patients showed that in 66% of the patients it took 
≥4 years before they were diagnosed with OSAS (4). Therefore, risk indicators for DM, 
ASCVD, MetS and OSAS are needed and proposed (4-8). In this respect the onset of 
several oral pathologies might be indicative. 
 
Many studies demonstrate the association between oral diseases and DM and/or ASCVD (9, 
10). The most observed chronic oral disease is periodontitis. For MetS and OSAS this 
association is less clear (8). However different studies have suggested an association 
between periodontitis and MetS (14-16) or between periodontitis and OSAS (8, 19). 
Periodontitis is a common chronic multifactorial inflammatory disease of the supporting 
structures of the teeth (root cementum, gingiva, periodontal ligament and alveolar bone). 
This condition is initiated and sustained by an aberrant host immune response against 
resident bacterial biofilms on the teeth and the tooth roots (11). Although the relative 
contribution of several causal factors may vary among patients, the uncontrolled 
inflammatory response upon bacterial accumulation seems the major factor determining the 
onset and/or progression of the periodontitis (12). In this respect, an increased pro-
inflammatory state caused by processes like atherosclerosis and metabolic dysregulation 
might contribute to the onset and/or progression of periodontitis. Therefore periodontitis 
could be considered as an early sign of an underlying vascular and/or metabolic pathology 
(13). With this knowledge, it has been suggested that dentists could help to screen for DM, 
the risk of ASCVD, MetS and the risk of OSAS. 
 
Notably, today there are several easy accessible and non-invasive techniques to screen for 
DM, ASCVD, MetS and OSAS. For DM there is the convenient Haemoglobin A1c (HbA1c) 
level, which is put forward by the American Diabetes Association (ADA) and International 
Diabetes Federation (IDF) as indicative of the metabolic state: prediabetes (HbA1c: 39-47 
mmol/mol) and diabetes (HbA1c: ≥48 mmol/mol) (5,6). For ASCVD there is the “10-year-risk” 
chart, based on age, gender, total cholesterol, HDL cholesterol (HDL-C), LDL cholesterol 
(LDL-C), systolic and diastolic blood pressure, smoking, presence of diabetes and 
rheumatoid arthritis (according to the NHG standards, which are the European Society of 
Cardiology guidelines modified to the Dutch population)(20). The diagnostic criteria for MetS 
are based on waist circumference (WC), triglycerides (TG), HDL-C, hypertension and 
dysglycemia (according to the NCEP ATP III) (21). For OSAS there is the recently developed 
OSAS risk questionnaire, which scores patients into a low, moderate or high risk category of 
having OSAS (22). 

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The majority of dental practices is not equipped for blood chemistry, however, today all 
plasma markers can be measured easily and accurately with help of a finger stick procedure 
(HemCol, Labonovum B.V., Rotterdam, The Netherlands). The measurement of the HbA1c 
and lipid by finger stick procedure is an elegant and essentially non-invasive way to screen 
for DM, ASCVD and MetS biomarkers. In addition, other demographic parameters (such as 
age, gender, smoking and rheumatoid arthritis) are known from the medical history and 
obtained with a questionnaire. Also systolic and diastolic blood pressure, Body Mass Index 
(BMI), Waist Circumference and N (WC) will be measured. A dental office, and in particular 
the dental office with a high volume of periodontitis patients, could be a suitable location for 
screening of individuals for early signs of DM, ASCVD, MetS and OSAS.  
 
The importance of early identification of subjects with increased risk for DM, ASCVD and 
MetS lies in the prevention of DM associated micro- and macrovascular complications, future 
coronary heart disease and/or cerebrovascular events. Early identification in OSAS patients 
would result in better medical and psychological conditions. Therefore, it contributes to an 
increased quality of life of our patients. The results of the current study should indicate the 
prevalence of DM and MetS and the prevalence of patients being at increased risk for 
ASCVD or OSAS. This may form the basis for further studies into general applicability and 
cost-effectiveness. 
 
Hypothesis 
- We put the hypothesis forward that periodontitis patients show an increased prevalence of 
(pre)DM, an increased 10-year-risk of ASCVD, an increased prevalence of MetS and an 
increased risk of OSAS compared with subjects without periodontitis. 
 
Notably, a recently published pilot paper from our group presented the feasibility and 
preliminary results of proposed screening for (pre)DM; we found 18.1% new DM cases 
among subjects with severe periodontitis compared to 9.9% in mild/moderate periodontitis 
and 8.5% in controls (13).  
 
 
 
 
 
 
 
 
 
 
 
 
 

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2. OBJECTIVES 
 
Primary Objective:  
To investigate, within a dental setting, the differences between subjects with and without 
periodontitis in:  
  -    The prevalence of preDM and DM (established cut-off values for HbA1c, appendix 1   
        and 2 (7))  
-    The 10-year-risk of ASCVD (“10-year-risk” chart, appendix 3 (20)) 
-    The prevalence of MetS (diagnostic criteria of NCEP ATP III, appendix 4 (21)) 
-    The risk of OSAS (OSAS risk questionnaire (22)) 
 
Secondary Objective(s):  
- 
To investigate the differences in (pre)DM prevalence, 10-year-risk of ASCVD, MetS 
prevalence and OSAS risk between mild/moderate and severe periodontitis patients 
 

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3. STUDY DESIGN 
A cross-sectional study will be performed with a duration of 24 months at the dental clinic of 
the Academic Centre for Dentistry Amsterdam (ACTA).  
 

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4. STUDY POPULATION 
4.1 Population (base)  
The research population will be drawn from the patients that visit the ACTA. These 
patients are particularly from Amsterdam and surrounding areas. The study subjects with 
periodontitis that will be enrolled in this study are referred to the periodontal clinic of ACTA 
for diagnosis and treatment of periodontitis. The control subjects without periodontitis will 
be selected among subjects that visit the dental school of ACTA for regular dental 
checkups. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
- 
Age ≥ 18 years 
- 
(Patient) referred for periodontitis  
- 
(Control) visiting the dental school for regular dental check-up without periodontitis 
- 
Able and willing to give written informed consent and comply with the requirements of 
the study protocol. 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
- 
None 
 
4.4 Sample size calculation 
The calculation of the sample size was based on a Chi2-test having an α<0.05 with 90% 
power and using the prevalence of diabetes of two groups (without periodontitis: 8.5%, 
severe periodontitis: 18.1%)(13). The required sample size is a minimum of 261 subjects 
per group. 
 
 
 

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5. TREATMENT OF SUBJECTS 
NA 
5.1 Investigational product/treatment 
NA 
5.2 Use of co-intervention (if applicable) 
NA 
5.3 Escape medication (if applicable) 
NA 

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6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational  product(s) 
NA 
6.2 Summary of findings from non-clinical studies 
NA 
6.3 Summary of findings from clinical studies 
NA 
6.4 Summary of known and potential risks and benefits 
NA 
6.5 Description and justification of route of administration and dosage 
NA 
6.6 Dosages, dosage modifications and method of administration 
NA 
6.7 Preparation and labelling of Investigational Medicinal Product 
NA 
6.8 Drug accountability 
NA 
 
 

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7. NON-INVESTIGATIONAL PRODUCT 
 
7.1 Name and description of non-investigational product(s) 
NA 
7.2 Summary of findings from non-clinical studies 
NA 
7.3 Summary of findings from clinical studies 
     NA 
7.4 Summary of known and potential risks and benefits 
NA 
7.5 Description and justification of route of administration and dosage 
NA 
7.6 Dosages, dosage modifications and method of administration 
NA 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
NA 
7.8 Drug accountability 
NA 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
To investigate, within a dental setting, the differences between subjects with and 
without periodontitis:  
- The prevalence of preDM and DM (established cut-off values for HbA1c, appendix 
1 and 2 (7))  
- The 10-year-risk of ASCVD (“10-year-risk” chart, appendix 3 (20)) 
- The prevalence of MetS (diagnostic criteria of NCEP ATP III, appendix 4 (21)) 
- The risk of OSAS (OSAS risk questionnaire (22)) 
8.1.2 Secondary study parameters/endpoints (if applicable) 
- To investigate the differences in (pre)DM prevalence, 10-year-risk of ASCVD, 
MetS prevalence and OSAS risk between mild/moderate and severe periodontitis 
patients. 
8.1.3 Other study parameters (if applicable) 
-    Other study parameters that will be obtained are sex, age, ethnicity (origin of 
parents), education level, smoking habits, diagnosis of hypertension, diagnosis of 
ASCVD, medical treatment for ASCVD, relatives with ASCVD, diagnosis of 
hypercholesterolemia, medical treatment for hypercholesterolemia, diagnosis of 
rheumatoid arthritis, diagnosis of DM, relatives with DM, history of periodontal 
treatment, height and body weight (for determining the BMI), neck and waist 
circumference, blood pressure, physical activity. 
 
 
8.2 Randomisation, blinding and treatment allocation 
NA 
 
8.3 Study procedures 
All subjects with periodontitis, diagnosed in a periodontology clinic, will be asked to 
participate. Subjects without periodontitis, visiting the dental school for a dental 
check-up, are selected and also asked to participate. The selection of subjects 
without periodontitis will be based on the following criteria: no interproximal alveolar 
bone loss on ≤1-year-old dental bitewing radiographs, no fulfillment of criteria for the 
classification of periodontitis according to the Centers for Disease Control and 
Prevention – American Academy of Periodontology (CDC-AAP) case definition 
(Appendix 5) (23). 
 
 

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Medical information, a periodontal chart (for periodontitis patients) or a periodontal 
screening index (for subjects without periodontitis) and a standard dental radiographic 
chart will be retrieved from the patient records. During the dental appointment blood 
will be obtained by a finger stick. Blood analysis will be performed to acquire data on 
the condition of the patients.  
 
A questionnaire about demographic characteristics will be filled in together with the 
periodontist or researcher, including the measurement of the systolic and diastolic 
blood pressure, body length and weight, waist and neck circumference. A 
questionnaire for assessment of the OSAS risk and a questionnaire about physical 
activity (IPAQ) will be asked to be filled in by the participant.    
 
At the dental appointment, all subjects (with or without periodontitis) will undergo the 
following assessments during the periodontal intake or regular dental check-up:   
1. General, medical and dental anamnesis (standard procedure)  
2. Clinical periodontal evaluation to define the presence and severity of periodontitis 
(standard procedure)  
3. Dental x-rays, when indicated for periodontitis or other dental pathology (standard 
procedure) 
4. Measurement of systolic and diastolic blood pressure (standard procedure) 
5. Measurement of length and body weight, waist and neck circumference, a 
questionnaire for demographic characteristics, an International Physical Activity 
Questionnaire (IPAQ) and an OSAS risk questionnaire. (extra procedure) 
6. Consecutive plasma finger stick procedure (HemCol, Labonovum B.V.) for 
measuring biomarkers: HbA1c, total cholesterol, LDL-C, HDL-C, triglycerides, C-
reactive protein (CRP), creatinine. A drop of blood is obtained with a finger stick 
(Greiner Bio-one Safety Lancet) and collected in a collection tube. The collection 
tube is sent to the laboratory for analysis by regular mail. (extra procedure) 
 
Ad 5. The questionnaire for demographic characteristics contains a question about 
the ethnicity of the subject. The ethnicity is an important factor that is associated with 
DM and ASCVD. According to the NHG standards, the Turkish, Moroccan or 
Surinam-Hindustan origin is one of the risk factors for the screening of DM (24). 
Furthermore, it is known that ethnic differences have an influence on the HbA1c 
value. Factors such as differences in hemoglobin glycation, red cell survival or non-
glycemic genetic determinants are being explored as determinants (25). 
 
People of the Dutch population with a Turkish, Moroccan and Surinam-Hindustan 
origin have more often DM than people with a Dutch origin (26, 27). Also the 
prevalence of cardiovascular complications in diabetes patients is higher in people 
from these ethnic minorities, especially from Surinam-Hindustan. Cardiovascular 
diseases were more often diagnosed in people of Turkish origin compared to people 
of Dutch origin (28). Our study population in Amsterdam and surrounding areas has a 

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variety of different ethnic groups. Because ethnicity is one of the factors, related to 
DM and ASCVD, it has to be taken into account as a variable when measuring the 
biomarkers for DM and ASCVD.  
 
All subjects will receive two letters with the result of the plasma finger stick procedure, 
on which the values of HbA1c, total cholesterol, LDL-C, HDL-C, triglycerides, CRP, 
creatinine will be reported. One letter is for the subject and the other letter is for their 
general practitioner (GP). The patient can decide to bring this letter to their GP. All 
subjects will be orally informed about their systolic and diastolic blood pressure by 
their dentist or researcher. When the blood values are above the known cut-off values 
and/or the 10-year risk of ASCVD is increased and/or the risk of OSAS is high, then 
the patient will be advised to visit the general practitioner for further diagnosis. An 
information brochure from the Thuisarts.nl, developed by the NHG, will be given when 
a high risk of cardiovascular diseases is suspected. Another information brochure 
from the Dutch Organization for Sleep Apnea about sleep apnea will be given when 
the risk of OSAS is increased. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. However, during informed consent, subjects will be informed that 
participation is not possible if they don’t want to be informed about the results of the 
finger stick procedure or questionnaires. The investigator can decide to withdraw a 
subject from the study for urgent medical reasons. 
8.4.1 
Specific criteria for withdrawal (if applicable) 
NA 
 
8.5 Replacement of individual subjects after withdrawal 
NA 
8.6 Follow-up of subjects withdrawn from treatment 
NA 
8.7 Premature termination of the study 
              NA 
         

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the finger stick procedure. All 
adverse events reported spontaneously by the subject or observed by the investigator 
or his staff will be recorded. 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events, except for the following SAEs: NA   
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 

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period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
NA 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 

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The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
9.3 Annual safety report 
     NA 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol  
 
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
     NA 
The advice(s) of the DSMB will only be sent to the sponsor of the study. Should the 
sponsor decide not to fully implement the advice of the DSMB, the sponsor will send the 
advice to the reviewing METC, including a note to substantiate why (part of) the advice of 
the DSMB will not be followed. 

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10. STATISTICAL ANALYSIS 
The prevalence of (pre)DM and MetS, the 10-year risk of ASCVD and the risk of OSAS 
will be presented in tables. First, one table will be generated describing the background 
variables, blood chemistry and demographic characteristics. Secondly, the prevalence of 
(pre)DM and MetS, the 10-year-risk of CVD and the OSAS risk will be reported in patients 
with and without periodontitis. 
 
According to the ADA guidelines HbA1c values will be classified as normal (<5.7% [<39 
mmol/mol]), preDM (5.7-6.4% [39-47 mmol/mol]) and DM (≥6.5% [≥48 mmol/mol]) (7). 
 
The 10-year risk of ASCVD  will be assessed with help of the risk table from the Dutch   
guideline on cardiovascular risk management (CVRM) according to the standards of the 
Dutch College of General Practitioners (NHG) (20).The NHG standards are derived from 
European Society of Cardiology guidelines and modified to the Dutch situation (6). 
 
According to the NCEP ATP III guidelines MetS is present if three of the 3 or more of the 
five criteria are met: elevated waist circumference over  102 cm (men) or  88 cm 
(women), triglyceride (TG) level over  1.7 mmol/L or being on drug treatment for elevated 
TG, high density lipoprotein cholesterol (HDL-C) level less than < 1.03 mmol/L (men) or  
< 1.3 mmol/L (women), blood pressure over 130/85 mmHg or on antihypertensive drug 
treatment, and blood glucose level over  5/6 mmol/L (21). 
 
The OSAS risk is calculated with help of a new questionnaire (PhilipsQ) which is 
constructed from body measurements (sex, age, BMI, neck circumference) and the most 
predictive questions of the following OSAS and sleep questionnaires: Berlin Questionnaire 
(BerlinQ), STOP Questionnaire (STOPQ) and Athens Insomnia Scale (AIS). An algorithm 
is developed to compute the individual estimated probability (p) that a subject will have 
OSAS: p(OSAS) = 1 / (1+e-X), where X = −6.322 + 2.828 × AIS + 2.745 × STOPBANGQ 
High + 0.965 × STOPBANGQ Intermediate + 4.640 × BerlinQ High + 1.584 × BerlinQ 
Intermediate + 0.790 × Age + 0.810 × BerlinQ Q-5. The final cutoff values were 
determined by exploratory logistic regression analyzes. The risk of OSAS will be classified 
as low (p[OSAS] < 35%), intermediate (p[OSAS] = 35-55%) and high (p[OSAS] > 55%) 
(22). 
 
The missing data from included subjects will be imputed using the expectation-
maximization method. Background variables, blood chemistry and demographic data 
between cases and controls will be analysed by Chi2-analyses or t-tests where 

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applicable. The primary and secondary outcome variables will be analysed both by 
univariate analysis and multivariate analysis (multiple logistic regression). The data will be 
analysed on an intention-to-treat basis (ITT).  
 
10.1 Primary study parameter(s) 
The cases and controls are a priori defined by inclusion and exclusion criteria. The 
STROBE guideline will be followed and a flow diagram will be generated of how many 
individuals have been screened, invited to participate, included and analysed (29). All 
initially included study subjects will form part of the data analysis (intention to treat). Type 
I error will be controlled by including a sufficient number of cases and controls to avoid 
multiplicities and to apply Bonferroni corrections where applicable. Secondly, we have 
determined the minimal sample size on the basis of an appropriate power calculation (see 
chapter 4.4). 
 
The prevalence of (pre)diabetes, the 10-year risk of ASCVD, the prevalence of MetS and 
the prevalences of OSAS risks (categorical variables) within the study population will be 
compared with parametric and non-parametric tests (ANOVA and Chi2-test). Where 
applicable, analyses will be corrected for multiple testing (Bonferroni). The significance 
level will be set to p<0.05. 
 
The prevalence of (pre)DM among cases and controls will be firstly reported without 
adjustment of any of potential covariates. In a second exploratory analysis we will adjust 
the prevalence for general and diabetes and ASCVD related characteristics of the study 
population: sex, age, ethnicity (origin of parents), education level, smoking habits, 
relatives with DM, history of periodontal treatment, diagnosis of hypertension, diagnosis 
of hypercholesterolemia, diagnosis of DM and the BMI, amount of physical activity. 
 
The 10-year risk of ASCVD will be calculated according to the algorithm from the ESC 
guidelines, which is adapted to the Dutch situation. No further adjustments will be done. 
 
The prevalence MetS will be calculated according to the criteria of the NCEP ATP III 
guidelines. No covariates will be included. 
 
The risk for OSAS will be assessed by the OSAS questionnaire. No further adjustments 
will be done. However, the results will be explored in relation to having periodontitis, the 

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background characteristics, the blood chemistry outcomes and having (pre)diabetes and 
the 10-year risk for ASCVD.  
 
10.2 Secondary study parameter(s)  
The secondary research aim is to investigate whether there are differences between 
severe periodontitis and mild/moderate periodontitis. As such, mild/moderate periodontitis 
will be labelled as “control” while severe periodontitis patients are labelled as “cases”. In 
secondary analyses exact procedures are followed as described above for the primary 
outcomes. 
 
10.3 Other study parameters 
Other study parameters that will be obtained and used as covariates are sex (M/F), age 
(years), ethnicity (origin of parents) (Europe/Non-Europe), education level (high/low), 
smoking habits (yes/no), diagnosis of hypertension (yes/no) , diagnosis of ASCVD 
(yes/no), medical treatment for ASCVD (yes/no), relatives with ASCVD (yes/no), diagnosis 
of hypercholesterolemia (yes/no), medical treatment for hypercholesterolemia (yes/no), 
diagnosis of rheumatoid arthritis (yes/no), diagnosis of DM (yes/no), relatives with DM 
(yes/no), history of periodontal treatment (yes/no), height (cm) and body weight (kg) (for 
determining the BMI), neck and waist circumference (cm), blood pressure (mmHg), 
physical activity (Metabolic Equivalent of Task). 
 
 
10.4 Interim analysis (if applicable) 
NA 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The procedures set out in this study protocol are designed to ensure that the investigator 
abide by the principles of the good clinical practice guidelines of the European 
Community and the Declaration of Helsinki (19-10-2013) and in accordance with the 
Medical Research Involving Human Subjects Act (WMO) in the conduct, evaluation and 
documentation of this study. The study will also be carried out in keeping with local legal 
requirements. 
11.2 Recruitment and consent 
Patients with periodontitis 
Patients with periodontitis, referred to the department of Periodontology (ACTA), will 
receive an information letter about the study from their dental practitioner (of ACTA) at 
least 1 week before their visit to the periodontal clinic. The dental practitioner is informed 
by the researcher about the study and the recruitment of patients. During the 
appointment, patients will be asked by the dental practitioner whether they want to 
participate with the study. Patients can give consent. The terms of the consent and when 
it was obtained will be documented in the case record form. After the informed consent, 
the dental practitioner or researcher will fill in the questionnaires with the patients and use 
the finger stick analysis.  
 
Control subjects 
Patients, visiting the dental clinic at ACTA for a regular dental checkup, will receive an 
information letter about the study from their dental practitioner (of ACTA) at least 1 week 
before their visit to the dental clinic. The dental practitioner is informed by the researcher 
about the study and the recruitment of patients. The dental practitioner performs the 
dental checkup. If the patient meets the inclusion criteria (see 8.3 Study procedures), 
then he/she will be asked by the dental practitioner (of ACTA) whether he/she wants to 
participate with the study. Patients can give consent. The terms of the consent and when 
it was obtained will be documented in the case record form. After the informed consent, 
the researcher will fill in the questionnaires with the patients and use the finger stick 
analysis.  
 
Before being admitted to the clinical study, the patient must consent to participate after 
the nature, scope and possible consequences of the clinical study have been explained in 
an information letter understandable to him/her. 
 

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In addition to the standard requirements that physicians are currently obliged to observe 
when providing information, all points on the information letter must be covered. The 
investigator will not undertake any investigation specifically required only for the clinical 
study until valid consent has been obtained. If the patient does not wish to know the 
result of the finger stick procedure, then he/she will not be included in the study. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
NA 
 
11.4 Benefits and risks assessment, group relatedness 
- 
The extra burden for the patients and control subjects will be three questionnaires, 
measurement of length, body weight, waist and neck circumference, and a finger 
stick procedure. 
- 
The risks associated with participation are negligible.  
- 
Possible benefit of participation will be early detection of health risks such as 
(pre)DM, ASCVD, MetS, OSAS and possibly a referral for further diagnosis and/or 
treatment at the family physician. 
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO.  
 
The sponsor (also) has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 
1. € 650.000,-- (i.e. six hundred and fifty thousand Euro) for death or injury for each 
subject  who participates in the research; 
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for 
each research;  
3. € 7.500.000,-- (i.e. seven million five hundred thousand Euro) each year for all 
researches together. 
All participants of this study will be informed about the insurance. 
 
11.6 Incentives (if applicable) 
NA 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
All patient names will be kept secret. The patient number during the study will identify 
patients throughout documentation and evaluation. At inclusion, each study subject 
receives a research number. Each questionnaire is coded with a patient number and a 
research number. The research number corresponds to the blood sample of the finger 
stick procedure. The tubes with the obtained blood will be sent to the chemical laboratory 
of Labonovum B.V. with the coded research number written on it. This laboratory will 
report the results of the finger stick procedure for each research number. This way the 
laboratory will not have any insight to individual data of our patients. 
 
The patients will be told that all study findings will be stored on computer and handled in 
strictest confidence. The investigator also agrees to allow these to be inspected on 
request. The investigator will maintain a personal list of patient numbers and patient 
names to enable records to be found at a later date. This personal list will be kept 
physically apart from the other data. The result of the finger stick procedure will be added 
to the medical history of the patient. Other documents and results, with individual patient 
numbers, will be kept for 15 years.  
 
12.2 Monitoring and Quality Assurance  
An independent monitor (quality officer) will monitor the study data according to Good 
Clinical Practice (GCP). During the selection of the study subjects, Informed Consents will 
be checked. In addition, Source Data Verification will be performed during onsite 
monitoring (checking whether the data of the Case Report Forms (questionnaires) are 
similar to the source data (patient status, lab results etc.). The intensity of this verification 
is related to the risk of the investigation. Data that also will be checked are the inclusion 
and exclusion criteria and the primary outcomes of the research. The monitor will also 
check whether all (S)AE’s and SUSAR’s are reported adequately within the time 
schedules as required by the law or regulations.  
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. The amendments will be submitted to the METC. All 
amendments will be notified to the METC that gave a favourable opinion. The starting 
date of the study will also be informed to the METC. 
 

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NA 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
12.5 Temporary halt and (prematurely) end of study report 
<The following text is applicable for studies without an investigational medicinal product.> 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 

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<The following text is applicable for studies with an investigational medicinal product.> 
NA 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
12.6 Public disclosure and publication policy 
The Consortium Agreement following the CCMO statement regarding publication policy of 
the study results is subscribed. 
 
8.9. Publication. Pursuant to the publication obligations set out in Section 5.12 of the TKI-
Allowance Agreement, the Parties must ensure open access (free of charge, online 
access for any user) to all scientific publications relating to its Foreground under the 
Project subject to the conditions hereunder. In particular, the Parties shall ensure open 
access to the deposited publication at the latest: (i) on publication, if an electronic version 
is available for free via the publisher, or (ii) within six months of publication in any other 
case.  A Party or Parties that intend to publish on the Foreground (jointly) owned by it 
shall provide the other Parties with the draft publication at least 30 (thirty) calendar days 
before publication. Any objection to the planned publication shall be made in writing to the 
Coordinator and the Party or Parties proposing the publication within 30 (thirty) calendar 
days upon receipt of the draft publication. If no objection is made within the time limit 
stated above, the Publication is permitted. For the avoidance of doubt, a Party shall not 
Publish Foreground or Background of another Party, even if such Foreground or 
Background is amalgamated with the Party’s own Foreground, without the other Party’s 
prior written approval. 
 
8.10. Objections to Publication. An objection has to include a precise request for 
necessary modifications and shall be considered justified only, if: 

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a. the proposed publication includes another Party’s Background, Foreground or other 
Confidential Information; or 
b. the objecting Party’s legitimate academic or commercial interests are harmed by the 
publication; 
c. the proposed publication includes patentable Foreground and the objecting Party 
anticipates that it wishes to exercise the Option. 
Upon receipt of an objection, the Parties involved shall discuss a solution in good faith. 
The objecting Party can request a publication delay of an additional period of 60 (sixty) 
calendar days (following the 30 day period referred to in clause 8.9). Upon expiration of 
the term, the publishing Party will be entitled to publish the proposed publication. 

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13. STRUCTURED RISK ANALYSIS  
NA 
13.1 Potential issues of concern 
 
a. Level of knowledge about mechanism of action 
NA 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
NA 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
NA 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
NA 
 
e. Analysis of potential effect 
NA 
 
f. Pharmacokinetic considerations 
NA 
 
g. Study population 
NA 
 
h. Interaction with other products 
NA 
 
i. Predictability of effect 
NA 
 
j. Can effects be managed? 
NA 
 
13.2 Synthesis 
NA 
 
 
 
 

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APPENDIX 1: Criteria for the diagnosis of DM according the ADA guidelines (7) 
 
 
 
 
 
 

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APPENDIX 2: Categories for pre-DM according the ADA guidelines (7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 3: The 10-year-risk chart of ASCVD (for patients without known ASCVD) 
(30)  
 
 

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APPENDIX 4: Criteria for diagnosis of Metabolic Syndrome (MetS) according to the 
NCEP ATP III (21) 
 
Measure (any 3 of 5 constitute 
diagnosis of metabolic syndrome) 
Categorical cutpoints 
Elevated waist circumference (WC) 
 102 cm in men 
 88 cm in women 
Elevated triglycerides (TG) 
 1.7 mmol/L  
or 
On drug treatment for elevated TG 
Reduced HDL-C 
< 1.03 mmol/L in men 
< 1.3 mmol/L in women  
or 
On drug treatment for reduced HDL-C 
Elevated blood pressure 
 130 mmHg systolic blood pressure  
or 
 85 mmHg diastolic blood pressure       
or 
On antihypertensive drug treatment in a 
patient with a history of hypertension 
Elevated fasting glucose  
 5.6 mmol/L  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 5 Case Definitions Periodontitis according to the CDC-AAP (23)