Periodontal Inflammation and Diabetes: a two way relationship

Kaumudi Joshipura BDS, MS, ScD

Center for Clinical Research and Health PromotionSchool of Dental MedicineUniversity of Puerto Rico

Harvard University

2

Periodontitis Caries

Tooth loss

Common Risk FactorsAgeSmokingObesity, DiabetesPhysical ActivityGeneticsRaceAlcoholComorbidityMedications

Systemic Inflammation Nutrition (Body Composition,

(Biomarkers) Dietary intake; Nutritional Status) Dyslipidemia

Adverse Pregnancy Outcomes

Obesity

CHDPAD

Stroke

Diabetes

Kidney DiseaseCancer

Fluoride

Access to Care

HypertensionAtherosclerosis

Microbes

Pre-eclampsiaGestationalDiabetes

Pre-diabetes

Arterial Stiffness

Biological Pathways: Periodontal Disease, Systemic Inflammation and Cardiometabolic Conditions

Dental Caries • Cavities are holes or structural damage to the teeth.

• There may be no symptoms, but if present, may include:– Toothache or painful sensation

in the teeth, especially after consuming sweet drinks or hot or cold food

• Risk factors include: –Poor oral hygiene –Fermentable carbohydrates

Periodontitis• It is an infection and

inflammation affecting the soft tissues and bone that support the teeth.

• Periodontitis occurs when infection and inflammation of the gums (gingivitis) progresses to involve other surrounding tissues.

Healthy Gingiva

Periodontal Disease

Healthy gingiva Periodontal Pocket

Pocket Depth

Attachment Level

6mm 6mm

Bone Loss

Gingival RecessionCauses:

• Periodontal Disease• Traumatic tooth cleaning

technique• Local irritants (plaque or

calculus)• Orthodontic tipping • Provisional crowns • Extraction of adjacent

teeth • Occlusal forces

9

U.S. Adults Periodontal Disease Prevalence (≥1 site Pocket Depth ≥4mm)

NHANES III, 1988-94

Adapted: Burt and Eklund, 2005

NHANES III, 1988-94

U.S. Adults Cumulative Periodontal Disease Severity ≥1 site Attachment Loss by Age

Adapted: Burt and Eklund, 2005

Established risk factors

• Microbes• Age • Male gender • Race • Genetic factors

• Tobacco • Diabetes • Malnutrition • Systemic

disease

Potential novel risk factors • Obesity • Physical activity • Alcohol• Calcium • Vitamin D • Antioxidants, fiber, other…..

Predictors of Periodontal Disease

These act indirectly through other risk factors:• Education• Employment • Income• Regular dental visits• Marital status• Dental insurance

Prognostic factors• Plaque control • Triclosan • Scaling and root planing • Other professional treatment

Impact of Periodontal Disease

Periodontal Disease

Bad Breath

Recession

Mobility

Root Caries

Hypersensitivity

Aesthetics

Systemic Diseases

Tooth Loss

Chewing Difficulty

DietPain

Systemic Inflammation

Biological Pathways: Periodontal Disease, Systemic Inflammation and Insulin Resistance

Periodontal Disease

Major Common Risk FactorsAge Physical ActivityGenetics DietSmoking Obesity

Type 2 Diabetes*

β-Cell Dysfunction Insulin resistance

Glucose Abnormalities

Dyslipidemia (HDL, TG) Adiponectin

Systemic Inflammation (CRP, Il-6, TNF-∞)

Diabetes

Metabolic Syndrome and Periodontitis

Authors Population Results OR (95% CI)

Morita, T., et al.2009

Tokyo, JapanN= 2478 adult Age: 43.3 years

Any vs. No positive component OR =1.8 (96% CI = 1.4-2.3)

≥ 3 vs. No positive componentOR= 2.4 (96 % CI = 1.7-2.7)

Li, P., et al.2009

ChineseN= 208 adults

OR = 9.9 (95% CI: 1.50 - 65.24) attachment loss >33% to 67% of sites

OR = 15.6 (95% CI: 2.20 -110.43) attachment loss >67% of sites

D'Aiuto, F., et al.2008

NHANES IIIN=13,994

Aged ≥ 17 yr

Severe periodontitis vs. No periodontitisOR = 2.31 (95% CI 1.13-4.73)

10% increase in gingival bleeding, OR = 1.12 (95% CI 1.07-1.18)

10% increase in periodontal pockets, OR = 1.13 (95% CI 1.03-1.24)

Components of metabolic syndrome

• Abdominal obesity• Atherogenic dyslipidemia 

• Hypertension 

• Insulin Resistance/Diabetes

Association between Obesity and Periodontitis

Authors Population Results OR (95% CI)

Al-Zahrani et al. 2003

NHANES III N=13,665

Ages: 18-90 yrs

BMI > 30 vs. BMI 18.5-24.9 (ref)60-90 yrs: OR 1.20 (0.89-1.61)

WC: >88 cm women; >102 cm men60-90 yrs: OR 1.14 (0.86-1.50)

Borges-Yanez et al. 2006

MexicoN=473

Ages: > 60 yrsBMI > 30 kg/m2

OR=0.93 (0.85-1.02)

Linden et al. 2007MenUK

N=1,362Ages: 60-70 yrs

Low –threshold:BMI>30 kg/m2: OR:1.77 (1.20–2.63)>30% Wt gain: OR=1.33 (0.95-1.86)

High-threshold:BMI >30 kg/m2: OR:1.55 (0.82–2.93)>30% Wt gain: OR=1.65 (0.95-2.87)

Studies on Obesity and Periodontitis among older adults

Relationship between abdominal obesity and periodontitis in elderly Puerto Ricans

• Puerto Rican Elderly Dental Health Study (PREDHS)– Representative sample of adults age 70 and older San Juan Metropolitan area (N=183)

• Exposures: waist circumference, waist-to-hip ratio

• Outcome: moderate and severe periodontal disease

• Multivariate logistic regression

• Adjusted for age, gender, smoking, education, diabetes status, physical activity, total fruit and vegetable intake.

• Models for moderate and severe periodontitis additionally adjusted for number of teeth.

Relationship between obesity and periodontitis in elderly Puerto Ricans• Multivariate-adjusted

Moderate: OR=5.63 (1.44; 22.06)Severe: OR=1.12 (0.37; 3.41)Upper tertile % of sites with AL ≥ 3: OR=3.59 (1.37; 9.41)Upper tertile of Mean AL: OR=2.07 (0.84; 5.10)

• Multivariate-adjusted Moderate: OR=4.03 (0.92; 17.65) Severe: OR=1.98 (0.58; 6.80) Upper tertile % of sites with AL ≥ 3: OR=1.99 (0.74; 5.31) Upper tertile of Mean AL: OR=2.49 (0.91; 6.77)

Muñoz, IADR, 2009

Association between Dyslipidemia and Periodontitis

Periodontitis and Dyslipidemia

Joshipura et al, JDR 2004

No periodontal disease N

=377

Periodontal diseaseN = 91

% difference

p-value

LDL 108.5 120.0 11 0.001*

ApoB 117.6 129.0 9.7 0.002*

HDL 56.5 55.2 -2.4 0.68

Cholesterol 224.9 246.3 9.5 <0.001*

Clinical Trial for the Treatment of Periodontitis and Lipids

• Fifty patients (31 females and 19 males, age 36-66 yr) who had ≥ 3 pockets with a PD S:4 mm

• Groups: – Control: biochemical and periodontal evaluations– Treatment: periodontal treatment

• Measurements taken at baseline and end of study – Dental Assessment: PD, PI, GI, AL, BOP– Biochemical measurments: LDL, HDL, VLDL, TG

OZ, South Med J, 2007

Clinical Trial for the Treatment of Periodontitis and Lipids (cont.)

• Greater reduction of pocket depth and attachment loss in treatment group than in control group (11 % vs. 7% and 24.5% vs. 0%, respectively)

• Treatment Group: Significant reduction of 12.7% in total cholesterol and 25.7% in LDL compared with baseline values.

• Control Group: NS reduction 3.9% in total cholesterol and 2.5% in LDL

• There were also significant differences in total cholesterol and LDL levels between the two groups

OZ, South Med J, 2007

Periodontitis and Diabetes

Diabetes and Periodontal Disease

Oral care report 2001

Mechanisms for Diabetes-Perio Relationship

• Altered host response• Alterations in connective tissue and wound

healing • Microangiopathy• Alterations in gingival crevicular fluid• Altered subgingival microflora

(composition/virulence)• Hereditary predisposition

Taylor 2004 Compendium

Literature on Periodontitis and Diabetes

• Over 50 cross-sectional associations. Only few longitudinal studies

• A meta-analysis among type 2 diabetic patients showed an improvement after aggressive periodontal treatment, weighted mean difference of HbA1C before and after therapy of -0.40% (95% CI -0.77 to -0.04%, P = 0.03). Teeuw WJ, et al. Diabetes Care. 2010

Not clear if A1c improvement due to perio improvement or due to antibiotics

Periodontal Disease and Incidence of Type 2 Diabetes Mellitus

• The multivariate Cox RR for periodontitis (comparing moderate/severe vs. none/mild) and type 2 DM– 1.17 (0.97-1.42) in men vs. 1.20 (0.96 -1.50) in women

• Updated Periodontitis – 1.32 (1.15- 1.51) in men

• Tooth loss (≥1 vs. 0 teeth lost during follow-up):– 1.25 (1.12 -1.40) in men vs. 1.14 (1.06 - 1.22) in women

• The associations among men persisted among never smokers. • Confounders: age, smoking, family history of diabetes, physical

activity, body mass index, alcohol, diet (sugar-sweetened soft drinks, fiber, glycemic load and polyunsaturated: saturated fat ratio) and in women-menopause status and post-menopausal hormone use.

Joshipura, ADA, 2008

Periodontal Therapy and Insulin Resistance

• Only one clinical trial among type 2 diabetes patients showed that periodontal therapy was associated with decreased insulin resistance. Talbert J et al. J Dent Hyg. 2006

• Some RCTs showed positive findings; others showed no significant reduction in the level of plasma glucose.

• Inconsistent results from cross-sectional studies

Periodontitis as a risk factor for Diabetes

NHANES I • Periodontal pockets index 3 vs. Healthy

– OR = 2.26, 95% CI: 1.56-3.27

• Periodontal pocket index 4 vs. Healthy – OR = 1.71, 95% CI: 1.09-2.69

• Periodontal pocket index 5 vs. Healthy – OR = 1.50, 95% CI: 0.99-2.27

Demmer et al., Diabetes Care, 2008

Conclusions for Diabetes Periodontitis Association

• The association between periodontitis and type 2 diabetes is potentially bidirectional, but neither direction has been established

• Periodontal treatment including antibiotics could lead to improvement in HbA1c

• Periodontitis is associated with several risks factors for diabetes as well as with diabetes complications

• More well designed longitudinal studies and clinical trials are needed

Complications of Diabetes

• Microvascular complications include – Neuropathy– Nephropathy– Vision disorders

• Macrovascular complications include – Heart disease– Stroke – Peripheral vascular disease

• Periodontal disease is also considered a complication of diabetes

Complications of Diabetes

• Microvascular complications include – Neuropathy– Nephropathy– Vision disorders

• Macrovascular complications include – Heart disease– Stroke – Peripheral vascular disease

• Periodontal disease is also considered a complication of diabetes

Diseases Stroke (M) PAD (M) CHD (M) CHD (F)

Baseline Teeth Multivariate Relative Risks

25-32 1.0 1.0 1.0 1.0

17-24 1.6* 1.2 1.1 1.1

11-16 1.8* 1.4 1.4* 1.3

0-10 1.8* 1.1 1.4* 1.6*

Periodontal Disease 1.3* 1.3* 1.0 1.0

Incident Tooth Loss

During follow-up 1.3* 1.4* 0.9 -

Summary of our work in HPFS (Males) and NHS (Females) relating perio and CVD

HPFS Multivariate Results No

periodontal disease N

=377

Periodontal disease N = 91

% difference

p-value

CRP 0.47 0.61 30 0.02* Fibrinogen 286.5 288.4 1 0.61 Factor VII 99.7 101.0 1 0.36 IL -6 1.5 1.7 11.8 0.44 TNFR1 1129 1092 -3 0.22 TNFR2 1656 1610 -3 0.31 t-PA 15.9 17.6 11 0.001* vWF 109.0 121.4 11 0.001* LDL 108.5 120.0 11 0.001* ApoB 117.6 129.0 9.7 0.002* HDL 56.5 55.2 -2.4 0.68 Cholesterol 224.9 246.3 9.5 <0.001*

Joshipura et al, JDR 2004

NHS Results

No periodontal

disease N =229

Periodontal disease N = 152

% difference p-value

CRP 0.19 0.26 35.8 0.01* ICAM 332 356 7.4 0.02* VCAM 579 596 2.9 0.26 E-selectin 44 51 17.0 <0.001* Fibrinogen 295 307 4.0 0.17 IL -6 1.7 1.7 1.5 0.84 TNFR1 1222 1258 2.9 0.40 TNFR2 2248 2369 5.4 0.07 LDL (mg/dl) 133 144 8.2 0.04

Adjusting for age, smoking, BMI, physical activity, aspirin use, alcohol use, CHD case-control status and diabetes

Clinical Trials for Biomarkers

• Tonetti et al. NEJM.

Intensive vs. regular perio care 2-6 months

Flow-mediated dilation E-Selectin

• D’Aiuto et al. Am Heart J.

Intensive vs. regular perio care. 2-6 months

CRP, IL-6, Total Cholesterol and CVD composite scores

92%

96%

100%

104%

108%

112%

116%

Fruits Fruits withoutJuice

Vegetables Dietary fiber

None

1 to 10

11 to 16

17 to 24

25 to 32

Percentage of Edentulous Subjects' Dietary Intake

Hung, CDOE, 2005(Adjusting Age, Smoking and Physical Activity)

0

0.2

0.4

0.6

0.8

1

1.2

<3 3-4 4-5 5-6 6-8 >8

Fruit and Vegetable Intake (Servings/Day)

RR

an

d 9

5%

CI

Intake of total fruits and vegetables and risk of Ischemic stroke in the NHS and HPFS

Joshipura et al., JAMA, 1999

Future DirectionsOral and systemic association

• Additional cohort studies in different populations including developing countries

• Additional systemic outcomes

• Evaluate pathways with exposures, outcomes and mediators in the same models

• Evaluate role of periodontal microorganisms

• Evaluate role of genetic factors

• Clinical trials where feasible

Role of Physicians in Oral Health

•Emphasize prevention of oral disease and retention of teeth.•Age-specific advise•Annual Routine Physical:

• Include basic oral exam• Oral cancer visual screening• Referrals to dentist

•Systemic Disease, Treatments: Communicate impact on oral health to dentists and patients.•Control of diabetes.•Nutrition counseling for better oral and general health and recommend prosthesis when needed.

Dr. Alberto AscherioDr. Graham ColditzDr. Constant CrohinDr. Chester DouglassDr. Sue HankinsonDr. Frank HuDr. Hsin-Chia HungDr. Anwar MerchantDr. JoAnn MansonDr. Waranuch PitiphatDr. Eric RimmDr. Christine RitchieDr. Frank SpeizerDr. Walter Willett

AcknowledgementsGrants:R01DE12102R01DE017176BOHCR – DE1184 R03DE14004Office of Dietary Supplements, Florida Department of CitrusK-24 DE016884RCMI – G12 RR 03051RCMI CRCS21MD001830

Acknowledgements

PREDHS Team:Dr. Maria L. AguilarMichael BrunelleDr. Ana Luisa DávilaJenifer GuadalupeMonik JiménezSasha MartínezDr. Mauricio MonteroFrancisco MuñozVanesza RoblesDr. Enrique SantiagoJenifer TorresDr. Sona TumanyanYari Valle

SOALS Team:Dr. Cynthia PerezJennifer ColonJhezanuel GoncalvesGustavo SanchezKristian PoventudReinaldo DelizDr. Pedro HernandezOelisoa Andriankaja Dr. Cristina PalacioJose Luis VergaraBarbara GuzmanLaritza BerriosLumarie CuadradoAlberto CarreraDr. Maribel Campos