1 INTRODUCTION

Periodontitis is a “chronic inflammatory disease associated with dysbiotic plaque biofilms and characterized by a progressive destruction of the tooth supporting apparatus”.1 Periodontitis affects 42.2% of the US population aged older than 30 years and 59.8% of those aged older than 65 years.2 According to the World Health Organization, periodontitis is the major cause of tooth loss in adults.3 Periodontitis pathogenesis is multifactorial with environmental, microbial, and host involvement affecting disease outcomes. Many systemic conditions have been associated with periodontitis, including diabetes mellitus, cardiovascular disease, and metabolic syndrome.4-11

Metabolic syndrome is a cluster of conditions that occur concomitantly and together they increase the risk of cardiovascular disease and double the risk of type 2 diabetes.12-15 Metabolic syndrome affects approximately 34% of the US population16 and 10% of US adolescents.17 The prevalence of metabolic syndrome also increases with age and varies with ethnicity and gender.18 Several definitions of metabolic syndrome exist and differ slightly depending on the issuing agency. The most commonly utilized definition is provided by the National Cholesterol Education Program Adult Treatment Panel III. This definition requires that the individual has at least three of the following risk factors: (a) increased abdominal circumference, (b) low plasma levels of high-density lipoprotein cholesterol, (c) increased values for plasma triglycerides, (d) elevated blood pressure, and (e) elevated glucose levels.19 Prediabetes is also accepted as part of metabolic syndrome because it is associated with insulin resistance and is highly predictive of new-onset type 2 diabetes.20

The predominant underlying risk factors for metabolic syndrome appear to be abdominal obesity and insulin resistance. Other associated conditions are physical inactivity, aging, and hormonal imbalance.21 Among the risk factors, visceral adiposity appears to be a primary trigger for most of the pathways involved in metabolic syndrome.22 The exact mechanisms behind this systemic response remain unclear, but there is evidence to suggest that the inflammatory state caused by metabolic syndrome is associated with endothelial dysfunction, which might contribute to the increased risk of cardiovascular disease and type 2 diabetes.23-25

Herein, we will focus on the association between metabolic syndrome and periodontitis; however, we will also include information on diabetes and cardiovascular disease since these two conditions are significantly intertwined with metabolic syndrome.

2 METABOLIC SYNDROME AND PERIODONTITIS 2.1 Association between metabolic syndrome and periodontitis

Considerable interest has been focused on the connection between periodontitis and metabolic syndrome because both of these conditions are associated with systemic inflammation and insulin resistance26, 27 and they can potentially influence one another.

To date, there have been several longitudinal and cross-sectional studies as well as a few meta-analyses evaluating the relationship between these two conditions. The vast majority of the data point to an association between metabolic syndrome and periodontitis10, 11, 54 (Table 1). The three meta-analyses31, 32, 55 were performed utilizing different parameters, but each of them found an association between metabolic syndrome and periodontitis, with an odds ratio ranging from 1.38 to 1.99. The meta-analysis by Gobin et al55 included 39 studies and demonstrated an association between periodontitis and metabolic syndrome with a crude odds ratio of 1.99 (95% confidence interval: 1.75-2.25) and an adjusted odds ratio of 1.46 (95% confidence interval: 1.31-1.61). The authors of this study also performed a subgroup analysis of different countries. The pooled odds ratio was 1.68 (95% confidence interval: 1.41-2) for Japan, 1.75 (95% confidence interval: 1.31-2.34) for the USA, 1.81 (95% confidence interval: 1.35-2.42) for Korea, and 2.29 (95% confidence interval: 1.53-3.41) for China.55 The meta-analysis conducted by Daudt et al,32 which included 26 studies with radiographic and clinical examination, also found an association between metabolic syndrome and periodontitis with an odds ratio of 1.38 (95% confidence interval: 1.26-1.51). The authors went on to suggest that patients with metabolic syndrome are 38% more likely to have periodontitis.32 The systematic review/meta-analysis by Nibali et al31 included 20 studies (one longitudinal study) and a total of 36 337 subjects. The authors concluded that there is a positive association between metabolic syndrome and periodontitis with an odds ratio of 1.71 (95% confidence interval: 1.42-2.03). A critical review by Watanabe and Cho56 also concluded that there is a positive association between metabolic syndrome and periodontitis. In addition, several animal studies utilizing different periodontitis models demonstrated that rodents with metabolic syndrome or obesity, as a result of being fed a high-fat diet, also exhibited exacerbated periodontal bone loss.57-59

TABLE 1. The role of metabolic syndrome in periodontitis Longitudinal studies Authors Duration (y) Age (y) Sample size

Metabolic syndrome

parameters

Periodontitis

parameters

Results Morita et al40 4 20 to 56 1023 BP, TG, HDL, TC, FPG, and BMI PD (CPI) Periodontitis was associated with a positive conversion of metabolic syndrome components Bullon et al41 3 20 to 44 188 Pregnancy, weight, BMI, BP, HbA1c, CRP, FPG, TG, TC, LDL, and HDL Plaque, BOP, PD, recession There is an association between periodontitis and metabolic syndrome Iwasaki et al35 3 ≥70 125 Abd obesity, BP, TG, HDL, and FPG CAL Metabolic syndrome may be a risk factor for periodontitis in older Japanese individuals Kaye et al42 33 760 FPG, BP, TG, WC, and HDL PD, CAL, ABL, tooth mobility Metabolic syndrome may play a role in the development or worsening of periodontitis Nascimento et al34 8 or 16 539 FPG, HDL, TG, WC, and BP BOP, PD, CAL Positive association between metabolic syndrome and periodontitis, when the multiple dimensions of both diseases were accounted in latent variables. When metabolic syndrome and periodontitis were treated as observed variables, no association was detected Sakurai et al43 2 ≥30 390 TG, HDL, BP, FPG, and WC CPI The prevalence of individuals with more positive metabolic syndrome components was higher in those with persistent/progressive periodontitis than in those with no/improved periodontitis Tegelberg et al44 15 1964 WC, TG, HDL, BP, and FPG PD and ABL Metabolic syndrome was associated in an exposure-dependent manner with periodontitis Adachi et al45 1 ≥35 136

WC, TG, HDL, BP, and FPG

CPI

There were no associations between periodontitis and the development of metabolic syndrome

Cross-sectional/case-control studies Authors Age of patients (y) Number of patients Metabolic syndrome parameters Perio Parameters Results Borges et al65 30 to 92 1315

BMI, dyslipidemia, BP and FPG

CPI

There were no associations between periodontitis and metabolic syndrome

Shimazaki et al28 40 to 79 584 Abd obesity, TG, HDL, BP, and FPG PD and CAL Metabolic syndrome increases risk of periodontitis D’Aiuto et al11 ≥17 13 677 WC, TG, HDL, BP, and insulin resistance BOP, PD Severe periodontitis is associated with metabolic syndrome in middle-aged individuals Khader et al37 ≥25 or above 156 WC, TG, HDL, TC, BP, and FPG PI, GI, PD, and CAL Patients with metabolic syndrome displayed more severe and extensive periodontitis compared with subjects without metabolic syndrome Li et al46 37 to 78 208 Abd obesity, TG, HDL, BP, and FPG/or T2DM CAL, PD, BOP, and PI Patients with metabolic syndrome had poor periodontal conditions, and periodontitis was associated with metabolic syndrome, independent of other risk factors Morita et al29 24 to 60 2478 WC, TG, HDL, TC, BP and FPG, HbA1c, and BMI CPI BMI, BP, TG, FPG, and HbA1c were significantly elevated in patients with PD of ≥ 4 mm. The adjusted odds ratio of the presence of periodontitis was 1.8 when the subjects with 2 positive components and without positive component were compared. And the odds ratio was 2.4 when the subjects with 3 or 4 positive components and without positive components were compared Kushiyama et al47 40 to 70 1070 Obesity, BP, HDL, TG, and FPG CPI The higher the number of metabolic syndrome components the higher the odds ratio of having more severe periodontitis Andriankaja et al30

20 to

>90

7431 Abd obesity, BP/or Med, TG, HDL and FPG/or Med PD The association between metabolic syndrome and periodontitis was significant in women. Abdominal obesity appeared to be the contributing metabolic factor for both genders Benguigui et al48 35 to 74 276 WC, TG, HDL, BP, and FPG PI, GI, PD, and CAL There is a relationship between metabolic disturbances and periodontitis, with insulin resistance playing a central role Han et al49 ≥18 1046 Abd obesity, TG, HDL, BP, and FPG BOP, PD, and calculus Metabolic syndrome might be associated with periodontitis. The association was confounded by age, gender, and smoking. Metabolic syndrome with high glucose and hypertension showed higher impact on this association Nesbitt et al10 mean: 56.8 ± 12 190 BP, WC, TG, and FPG ABL Patients with severe periodontitis were approximately 2.5% times more likely to have metabolic syndrome

Timonen et al63

30 to 64

2050

Abd obesity Insulin resistance, BP, and dyslipidemia

PD

Metabolic syndrome was associated with PD ≥ 4 mm (adjusted risk ratio 1.19), and with pockets ≥ 6 mm (adjusted risk ratio 1.5) Chen et al36 >18 253 WC, TG, HDL, TC, BP and FPG, or T2DM

PI, GI, and

PDI

Moderate-severe periodontitis is associated with metabolic syndrome in patients undergoing hemodialysis Kwon et al297 ≥19 7178 WC, TG, HDL, BP, and FPG PD Periodontitis is significantly associated with metabolic syndrome with an odds ratio of 1.55 Fukui et al298 34 to 77 6,421 TG, HDL, BP, FPG, HDL, BP, and obesity

PD and CAL

Periodontal status, particularly in individuals suspected to have untreated periodontal infection, is significantly associated with metabolic syndrome Furuta et al60 40 to 79 2370

WC, TG, BP

HDL, and FPG

PD, CAL, and BOP Gender differences appear to exist in the association between periodontitis and metabolic syndrome. Metabolic syndrome might have a stronger association with periodontitis in females compared with males Sora et al39 26 to 87 283 Abd obesity, BP, HDL, TG, and FPG (OGTT)

Plaque, PD, CAL, and

BOP

Metabolic syndrome is associated with the extent of severe periodontitis in this Gullah population with type 2 diabetes

LaMonte et al64

50 to 79

657

Abd obesity,

BP or Med, TG, FPG or Med and HDL

ABL, PD, and

CAL

A consistent association between metabolic syndrome and measures of periodontitis was not seen in this cohort of postmenopausal women Thanakun et al33 35 to 76 125 WC, TG, HDL, BP, and FPG

BOP, PD,

and CAL

Severe periodontitis was associated with metabolic syndrome (odds ratio 3.6) when 4-5 metabolic syndrome components were analyzed the odds ratio increased to 5.49 in this Thai population Minagawa et al9 ≥80 234

WC, FPG, BP,

and dyslipidemia

PD and CAL Metabolic syndrome was associated with the presence and severity of periodontitis (crude odds ratio 2.24)

Chen et al299

23 to 58 303 Abd obesity, BP, TG, HDL, and FPG CPI The prevalence of metabolic syndrome was sufficiently high to be a medical concern, and was associated with periodontitis Gomes-Filho et al50 24 to 89 419 WC, TG, HDL, BP, and FPG PD, CAL, and BOP Periodontitis is associated with metabolic syndrome

Musskopf et al51

18 to 81

363 WC, TG, HDL, BP, and FPG PI, GI, PD, CAL, and BOP There is a weak association among metabolic syndrome and periodontitis. The association is observed in the age group of 41-60 y Jaramillo et al52 651 TG, HDL, BP, BMI, and glucose tolerance GI, PI, PD, CAL, and BOP There is a positive association between metabolic syndrome and periodontitis. The adjusted odds ratio is 2.72. Glucose sensitivity is a strongly associated component Kikui et al53 mean: 66.4 1856 BP and/or Med, HDL, TG and/or Med, FPG/and Abd obesity CPI Metabolic syndrome and lower HDL cholesterol are associated with periodontitis. Subjects with 2 or more metabolic syndrome components had a significantly higher prevalence of periodontitis Kim et al300 50 to 94 5078 BMI, WC, BP, FPG, HDL, and TG

PD and

CAL

Increasing the severity of periodontitis was associated with the risk of prevalent metabolic syndrome in Korean adults Pham et al38 mean: 57.8 ± 5.7 412 BMI, WC, HDL, BP and FPG PI, GI, PD, CAL, and BOP More severe and extensive periodontitis was found in metabolic syndrome participants and increased with number of metabolic syndrome components. Participants with higher periodontal parameters had a higher risk of metabolic syndrome Campos et al54 122 with metabolic syndrome and 366 controls BP, TGs and LDL and/or WC PI, BOP, PD, and CAL There is an association between metabolic syndrome and periodontitis Abbreviations: Abd, abdominal; ABL, alveolar bone level; BMI, body mass index (kg/m2); BOP, bleeding on probing; BP, blood pressure; CAL, clinical attachment level; CPI, community periodontal index; CRP, C-reactive protein; FPG, fasting plasma glucose; GI, gingival bleeding index; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Med, medication; OGTT, oral glucose tolerance test; PD, probing depth; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TG, triglycerides; WC, waist circumference.

Evaluating the role of metabolic syndrome in periodontitis development and progression, Kaye et al35, 42 and Iwasaki et al35, 42 performed longitudinal studies and concluded that metabolic syndrome increases the risk of development and progression of periodontitis (Table 1). In fact, Iwasaki et al35, 42 concluded that patients with metabolic syndrome were 2.6 times more likely to develop periodontitis. Likewise, the more components of metabolic syndrome an individual exhibited, the more prevalent and extensive the presentation of the periodontitis.35, 38

Until now, very little has been known about the potential gender predilection in the association between metabolic syndrome and periodontitis, and definitive conclusions cannot be made. Nonetheless, among the three relevant studies published, two concluded that there is a stronger association between metabolic syndrome and periodontitis in women,30, 60 while the other study did not find a relationship between gender, metabolic syndrome, and periodontitis; however, Kushiyama et al47 did comment that their small sample size could have influenced their results. As it relates to age, Minagawa et al9 suggested that metabolic syndrome and periodontitis are linked in the elderly population, which is consistent with the prevalence of metabolic syndrome and periodontitis increasing with age.61, 62

Although the vast majority of studies concluded that there is an association between metabolic syndrome and periodontitis, several studies found weak or no associations between these two conditions34, 45, 51, 63-65 (Table 1). It is worth noting that most of these studies were cross-sectional in nature, with the longitudinal study spanning a period of 1 year; the study by Nascimento et al34 was performed on a relatively young population (31 years of age), whose age bracket has a comparatively low prevalence of periodontitis and metabolic syndrome. Additionally, in a 3-year longitudinal study, Kobayashi et al66 concluded that toothbrushing frequency is inversely related to the incidence of metabolic syndrome.

2.2 Influence of periodontitis on metabolic syndrome

Some studies have suggested that periodontitis can affect systemic conditions.67, 68 For example, periodontitis elevates the levels of several inflammatory mediators, such as C-reactive protein and interleukin-6.69, 70 Moreover, periodontal treatment can decrease circulating levels of inflammatory mediators.71, 72 Given this information, researchers have sought to evaluate the potential of periodontitis to affect metabolic syndrome.

The majority of studies concluded that periodontitis may contribute to the development or exacerbation of metabolic syndrome10, 40, 73 (Table 2). Nesbitt et al10 performed a cross-sectional study in 190 individuals evaluating periodontitis based on periodontal bone loss and concluded that periodontitis may contribute to the development of metabolic syndrome. Morita et al40 conducted a longitudinal study on 1023 adults and concluded that deeper periodontal pockets are associated with a positive conversion of one or more metabolic components during a 4-year period (odds ratio: 1.6; 95% confidence interval: 1.1-2.2). Moreover, Lopez et al73 suggested that reduction of periodontal inflammation reduces C-reactive protein levels in patients with metabolic syndrome.

TABLE 2. Effect of periodontitis on metabolic syndrome Authors Cross-sectional (CS) or longitudinal (L) Duration Age of patients (y) Number of patients

Metabolic syndrome

parameters

Periodontitis parameters

Results Kushiyama et al47 CS 40 to 70 1070 Obesity, BP, HDL, TG, and FPG

CPI