Association between metabolic syndrome and tooth loss

Original Contributions

Systematic Review Association between metabolic syndrome and tooth loss A systematic review and meta-analysis Marina Leite Souza, MSc; Carla Massignan, MSc; Karen Glazer Peres, DPH; Marco Aurélio Peres, DPH ABSTRACT Background. The authors conducted a systematic review and meta-analysis to verify the existence and level of scientific evidence concerning the association between metabolic syndrome (MetS), as the main exposure, and tooth loss (TL), as the outcome. Types of Studies Reviewed. Through electronic databases and partially through gray literature, the authors identified observational studies in adults. The authors used no date or language restrictions. The authors evaluated the studies’ methodological quality by using the Newcastle-Ottawa Scale. The authors conducted a random-effects model meta-analysis. The authors assessed the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation criteria. Results. Twelve studies met the eligibility criteria, and 9 were retained for the meta-analysis. Most were cross-sectional studies with good methodological quality. Participants with MetS had fewer teeth (standardized mean difference,
2.77; 95% confidence interval,
4.56 to
0.98) and an increased likelihood of lacking functional dentition (odds ratio, 2.37; 95% confidence interval, 1.89 to 2.96) than did those without MetS. The overall quality of evidence was very low. Conclusions and Practical Implications. Better-conducted longitudinal studies are necessary to establish a causal relationship between MetS and TL to inform the best strategies to prevent TL in populations with MetS. Key Words. Metabolic syndrome; tooth loss; systematic review; meta-analysis; epidemiology. JADA 2019:150(12):1027-1039 https://doi.org/10.1016/j.adaj.2019.07.023

M

etabolic syndrome (MetS) is a cluster of conditions that increase the risk of developing cardiovascular disease and type 2 diabetes. Among the components that characterize MetS are raised blood pressure, dyslipidemia (raised triglyceride and lowered highdensity lipoprotein [HDL] cholesterol levels), raised fasting glucose levels, and central obesity. Patients must have at least 3 of these abnormal findings to have a diagnosis of MetS. These factors separately contribute to the development of cardiovascular diseases and diabetes, but when they occur at the same time, the risk becomes greater.1 The global prevalence of MetS varies according to diagnostic criteria, age range, and population studied, and it is estimated to affect approximately one-quarter of the world’s population.2 Tooth loss (TL) is considered 1 of the worst oral health outcomes and can be related to a poor general health status,3 worsened quality of life,4 and increased stress and depressive symptoms.5 In addition, it may make chewing difficult6 and have an effect on eating patterns.7 The cumulative exposure to periodontal disease (PD) and caries is the main reason for TL in adults.8 Study results have supported an association between MetS and TL.9-11 This association can be the result of persistent low-grade inflammatory status12,13 and systemic oxidative stress.13 Oxidative stress leads to inflammation and can impair a normal physiological response to bacterial challenges, which increases the risk of developing PD13 or aggravates this oral disease, increasing the chance of developing TL.9 Oxidative stress may cause glandular inflammation, leading to hyposalivation, which increases the risk of developing caries14 and TL.15 Components of MetS, such as obesity,16

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dysglycemia,17 and hypertension,18 also are associated with reduced salivary flow, as is the use of antihypertensive agents.19 In addition, there are social and behavioral aspects common to MetS and poor oral health, such as low socioeconomic status, unhealthy eating habits, increasingly negligent self-care, and smoking.2 Moreover, the individual components of MetS, such as hypertension,20 obesity,21 and impaired glucose metabolism,22 also are related to TL. Although investigators have reported the association between MetS and TL previously,9,23 investigators in some studies have identified this association only in women24,25 or did not find an association.26 In addition, some research was limited to specific population groups, such as men,10,27 women,26 and older adults,28 and the diagnostic criteria for MetS and TL vary.29,30 Establishing the association between MetS and TL is challenging. Results of meta-analyses, including studies with different PD diagnostic criteria, have shown that participants with MetS are 71%31 and 38%32 more likely to have PD than are participants without this condition. However, the investigators in these studies could not establish the direction of this association, and they did not evaluate the outcome of TL, which may be a consequence of the exacerbated progression of PD. Besides that, TL is also a consequence of cumulative exposure to caries and its aggravation during the life course.33 To our knowledge, there are no systematic reviews and meta-analyses in which the investigators explore the association between MetS and TL, which is considered the worst outcome of oral diseases. Thus, although the association between MetS and TL has become an important theme of research in the scientific literature, there is no consensus regarding the topic. Therefore, in this systematic review, we aimed to verify the existence and level of scientific evidence concerning the potential association between MetS and TL. MetS was the main exposure, and TL was the main outcome. It is crucial to provide a summary of evidence regarding the association between MetS and TL to guide public policies and clinical assessment that approach the common risk factors of these diseases. ABBREVIATION KEY BMI: BP: F: FGIc: GRADE:

HDL: IDF:

JIS: M: MetS: MetS(L): MetS(D): NA: NCEP ATP III:

NOS: PD: TG: TL: WC:

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Body mass index. Blood pressure. Female. Fasting glucose levels. Grading of Recommendations Assessment, Development and Evaluation. High-density lipoprotein. International Diabetes Federation. Joint Interim Statement. Male. Metabolic syndrome. Without MetS. With MetS. Not applicable. National Cholesterol Education Program Adult Treatment Panel III. Newcastle-Ottawa Scale. Periodontal disease. Triglyceride. Tooth loss. Waist circumference.

METHODS We conducted a systematic review of the literature and meta-analysis. We planned the protocol according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols recommendations,34 and we registered the study at the International Prospective Register of Systematic Reviews under the CRD42018095880. The focused review question was: Is MetS positively associated with TL in adults? Eligibility criteria We used the criteria of population, exposition, comparison, outcomes, and type of studies to formulate the focused review question. The population was adults 18 years or older, the exposition was the presence of MetS, the comparison was the absence of MetS, the outcome was TL, and the type of studies was observational studies. Inclusion and exclusion criteria We included case-control, cross-sectional, and cohort studies in which the investigators assessed the association between MetS and TL in adults 18 years or older. The exclusion criteria were studies conducted in animals, case reports, reviews, opinions, and abstracts that duplicated published material; studies conducted in people younger than 18 years; studies in which the investigators did not assess the association between MetS and TL; studies in which the investigators did not evaluate the exposure (MetS) or outcome (TL) of interest; and studies lacking data on MetS or TL. Exposure The exposure was the presence of MetS. According to a Joint Interim Statement (JIS) of the International Diabetes Federation (IDF); National Heart, Lung, and Blood Institute; American Heart Association; and other organizations,1 MetS is defined when there are at least 3 of the following 5 risk factors: n fasting high triglyceride levels: 150 milligrams per deciliter or higher ( 1.7 millimoles per liter) or drug treatment for elevated triglyceride levels; n reduced HDL cholesterol levels: less than 40 mg/dL (< 1.0 mmol/L) in male patients and less than 50 mg/dL (< 1.3 mmol/L) in female patients or drug treatment for reduced HDL levels; n high blood pressure: systolic pressure of 130 millimeters of mercury or higher or diastolic pressure of 85 mm Hg or higher or antihypertensive drug treatment in a patient with a history of hypertension; JADA 150(12)

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high fasting blood glucose levels: 100 mg/dL or higher or drug treatment for elevated glucose levels as an alternate indicator; n high waist circumference (according to specific definitions of populations and countries). Although the JIS is the latest guideline for MetS, we considered all MetS criteria because the investigators specified and referenced them in the studies. n

Outcome TL was diagnosed clinically or self-reported according to the number of natural teeth, number of missing teeth (excluding third molars), lack of functional dentition, edentulism, complete TL in only 1 arch, or different criteria of TL. Functional dentition is conceptualized as a minimum number of natural teeth to have adequate dental function without the aid of prosthetic replacements.35,36 When the number of teeth is lower than this threshold, it can result in problems with chewing and, therefore, restriction of food and nutrient intake. Generally, this threshold is 21 teeth,35,36 but it also is considered when 20 teeth are retained.37 Edentulism is the complete loss of natural teeth. Search strategies We conducted a systematic search in the following electronic databases: Embase, Latin American and Caribbean Health Sciences Literature, LIVIVO, PubMed, Scopus, and Web of Science. We searched for titles and abstracts relevant to the review question. We adapted the search syntax to each database (Appendix 1, available online at the end of this article). We performed a partial search of gray literature by using ProQuest Dissertations and Theses, OpenGrey, and Google Scholar. We scanned the reference lists of the included studies to identify additional studies of relevance. We managed all references by using reference manager software (EndNote Basic, Clarivate Analytics) and removed duplicate hits. The end search date was June 13, 2018. We used no language or date restrictions. Data extraction and management Initially, 2 of us (M.L.S., C.M.) independently screened the studies on the basis of the titles and the abstracts derived from the search. We used Google Translator to translate the titles and abstracts not using the Roman or Latin alphabet. We discarded any study that did not fulfill the inclusion criteria. Subsequently, the same 2 reviewers (M.L.S., C.M.) retrieved the full text of relevant articles for further analysis and either included or excluded each from the review on the basis of the eligibility criteria. In this phase, collaborators with scientific experience helped us in the interpretation of the data included in selected articles written in languages not familiar to us. We handled disagreements about inclusion or exclusion through discussion and consensus among all 4 authors. The same 2 reviewers (M.L.S., C.M.) independently collected data and compared the results. They resolved any disagreement through discussion and consensus with the other authors (K.G.P., M.A.P.). The reviewers cross-checked all the retrieved information. We contacted the corresponding authors of all the included studies to provide additional data necessary to perform a meta-analysis. We sent 2 e-mails at a 15-day interval. For all included studies, we recorded structured information. The data we collected were study characteristics (authors, year of publication, country, study design, setting), population characteristics (sample size, participants’ age and sex), diagnostic criteria used for MetS and TL, measures of association, statistical analysis, and main conclusions. Two of us (M.L.S., C.M.) independently assessed the methodological quality of the included studies by using the Newcastle-Ottawa Scale (NOS)38 for observational studies. The scale assigns a score of 0 through 9 stars, with a greater number of stars indicating a higher-quality study. We measured the association between MetS and TL by using relative risk, prevalence ratio, odds ratio (OR), hazard ratio, or difference in means. Statistical analysis We conducted different meta-analyses considering the mean number of teeth counted and lack of functional dentition. The meta-analyses included cross-sectional and baseline data of cohort studies. Investigators in 1 study25 reported the mean number of teeth for men and women separately, so we treated it as 2 studies. We did not include 3 articles24,27,39 in the meta-analyses because they lacked

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data comparisons with other studies. We performed the meta-analyses with the aid of software (Review Manager, Version 5.3, Cochrane Collaboration). We used the random-effects model for the analyses because we sampled the studies in these analyses from a wide range of possible studies defined by specific inclusion and exclusion criteria, as outlined above. We evaluated heterogeneity among studies by using the I2 test (ratio of true heterogeneity to total observed variation) and s2 (among-study variance).40 To investigate heterogeneity, we performed sensitivity analyses both ways, removing successive studies to observe the effect on I2 and including only studies that received scores of 7 on the NOS. Levels of evidence We assessed the overall quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation criteria.41 We generated a summary-of-findings table by using online software (GRADEpro, McMaster University). RESULTS We followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.42 We also followed the recommendations of the Meta-Analysis of Observational Studies in Epidemiology43 for the report of this systematic review. Study selection We identified 2,750 citations from the search in the selected databases. After we removed duplicates, 1,237 articles remained. In addition, we considered 107 citations from gray literature. On the basis of the exclusion criteria, we excluded 1,197 articles from the databases and 105 from the gray literature after the review of titles and abstracts, resulting in 42 articles for full-text evaluation. After searching the reference lists in the chosen studies, we added another 2 articles. We compiled the reasons for exclusion in Appendix 244-47 (available online at the end of this article). Twelve studies met the eligibility criteria. Of these, only 9 were retained for the meta-analysis (Figure 1).42 Study characteristics The table9,10,23-30,39,48 describes the main characteristics of the studies included in the review. Most of them were cross-sectional, and 2 were cohort studies, 1 was a prospective study10 and another 1 was a retrospective study.9 The articles were published in 2015 and later, except for 1 study28 that was published in 2007. More than one-half of the studies were conducted in Asian countries. Ten were written in English and 2 in Korean.24,39 The sample size ranged widely from 363 participants48 through 12,131 participants.30 The diagnosis of MetS in all studies included measurements of blood pressure, anthropometric measures, and blood samples, but there was variation in the diagnostic criteria used: National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), JIS, and IDF. Kaye and colleagues10 classified participants according to the IDF and the NCEP ATP III criteria. In all articles, the investigators grouped participants according to the presence or absence of MetS (exposition). In addition, some investigators classified participants according to the number9,10,23,28 and types9,23-26,39 of MetS components. Investigators in almost all studies used oral examinations by trained professionals to assess the outcome (TL). Investigators in only 1 study28 used the self-report of participants. Study investigators presented the TL according to the number of teeth remaining or missing, categories,23,25,26,29,48 mean number of teeth,9,10,25,28,48 functional dentition,23,26,29,30 or edentulism.27,29 Quality of studies eTable 19,10,23-30,38,39,48 shows the quality assessment of the studies. Most of them had good methodological approaches. The main shortcomings included the lack of representativeness of the sample in the target population.9,10,27,28,48 The investigators controlled confounding variables, such as sociodemographic factors and smoking, in all studies. Results of individual studies In most studies, the investigators reported the association between MetS and TL. However, Ma and colleagues26 concluded that MetS was not an independent factor for having less than 20 remaining 1030

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Latin American and Caribbean Health Sciences Literature (n = 62)

Embase (n = 852)

LIVIVO (n = 609)

PubMed (n = 598)

Scopus (n = 369)

Web of Science (n = 260)

Identification

Records identified through database searching (n = 2,750)

Records after duplicates removed (n = 1,237)

OpenGrey (n = 0)

ProQuest (n = 7)

Google Scholar (n = 100)

Records screened from databases (n = 40)

Screening

Records screened from OpenGrey (n = 0)

Records screened from ProQuest (n = 0) Records screened from reference lists (n = 2)

Included

Eligibility

Full-text articles assessed for eligibility (n = 44)

Studies included in qualitative synthesis (n = 12)

Records screened from Google Scholar (n = 2)

Full articles excluded (n = 32) • Studies conducted in animals (n = 0) • Case reports, reviews, opinions, and abstracts that duplicated published material (n = 2) • Studies conducted in people younger than 18 years (n = 0) • Studies in which the investigators did not assess the association between MetS and TL (n = 21) • Studies in which the investigators did not evaluate the exposure (MetS) or outcome (TL) of interest (n = 5) • Studies lacking data on MetS or TL (n = 4)

Studies included in quantitative synthesis (n = 9)

Figure 1. Flow diagram of literature search and selection criteria.42 MetS: Metabolic syndrome. TL: Tooth loss.

teeth. Besides that, the investigators in the Korean studies identified an association between MetS and TL only in women.24,25 Kaye and colleagues10 observed that the hazards of TL tended to increase with each additional positive IDF or NCEP ATP III risk factor. Moreover, investigators in other studies also identified that a higher number of MetS components were associated independently with fewer teeth.23,28 Study results showed a significant association between the number of teeth and each component of MetS, such as hypertension,29,30,39 obesity,9,29,30 increased fasting glucose levels,29 and reduced HDL levels.29,30 Results in other studies indicated an association between TL and hypertension24,25 JADA 150(12)

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Table. Summary of descriptive characteristics of the 12 included articles.

STUDY CHARACTERISTICS

Study, Country

Study Design, Follow-Up

EXPOSURE CHARACTERISTICS (MetS*)

POPULATION CHARACTERISTICS

Aim

Setting

Holmlund and Colleagues,28 2007, Sweden

Municipality of Cross-sectional, NA{ To investigate how the number of remaining teeth Uppsala, Sweden relates to the presence of MetS and markers of inflammation

Hyvärinen and Colleagues,27 2015, Finland

Cross-sectional, NA To investigate the association of serum antibody levels against Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis and the number of missing teeth with MetS

Total No., M‡, F§ 1,016, 947 (self-reported number of teeth)

Age, Y (Mean or Range) 70

Type; Groups MetS(
)# MetS(þ)** Number of Components: 1 2 3 4 5

728 219

Medical examination, blood sample, and questionnaire; National Cholesterol Education Program Adult Treatment Panel III††

820 534

Blood sample and questionnaire; IDF§§

PAIS subcohort of the FINRISK 1997 study (a cardiovascular risk factor survey in Finland)

M: 1,354

45-74

MetS(
) MetS(þ)

Kang,24 2015, Cross-sectional, NA To identify a relationship Republic of Korea between MetS and periodontal disease with adult TL

Nationwide representative sample, in Fifth National Nutrition and Health Survey from 2010 and 2012

8,225, M: 3,553, F: 4,672

 40

MetS(
) MetS(þ) Types of abnormal components: BMI## HDL*** BP††† TG‡‡‡ FGlc§§§

Kang and Yul,39 Cross-sectional, NA To identify the relationship 2015, Republic of between MetS and oral Korea diseases

Korean National Health and Nutrition Examination Survey from 2010 and 2012

6,390, M: 2,675, F: 3,715

 40

MetS(
) MetS(þ) Types of abnormal components: BMI HDL BP TG FGlc

4,752 1,638

MetS(
) MetS(þ) WC### HDL BP TG FGlc No. of components

5,077 1,603 2,448 1,457 2,953 1,326 1,911 1.5 (1.3)‡‡

Tsai and Colleagues,23 2015, Taiwan

Cross-sectional, NA To examine the prevalence of the number of remaining teeth < 20 and associated risk factors among adults

Rural area of southwestern coast of Taiwan, September 2012-August 2013

6,680, M: 2,901, F: 3,779

42.5 (20-64)

Zhu and Hollis,29 2015, United States

Cross-sectional, NA To explore associations between the number of natural teeth and MetS

National survey

5,511, M: 2,872, F: 2,639

 20

Diagnosis; Criteria

No.

MetS(
) MetS(þ)

Medical examination; JIS{{{ with cut-off points of WC to Korean Population

Medical examination; JIS with cut-off points of WC to Korean Population

1,863 2,381 3,455 683 2,397

Medical examination, blood sample, and questionnaire; JIS for Asians

3,204 2,307

Medical examination, blood sample, and questionnaire; American Heart Association and National Heart, Lung, and Blood Institute****

* MetS: Metabolic syndrome. † TL: Tooth loss. ‡ M: Male. § F: Female. { NA: Not applicable. # MetS(
): Without MetS. ** MetS(þ): With MetS. †† Three of the following 5 criteria should be fulfilled: elevated triglyceride levels ( 150 milligrams per deciliter or drug treatment for elevated triglyceride levels), reduced high-density lipoprotein levels (< 40 mg/dL in men and < 50 mg/dL in women), elevated blood pressure (systolic blood pressure  130 millimeters of mercury, diastolic blood pressure  85 mm Hg, or antihypertensive drug treatment), and elevated fasting glucose levels ( 100 mg/dL); elevated waist circumference ( 102 centimeters in men and  88 cm in women). Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.49 ‡‡ Mean (standard deviation). §§ IDF: International Diabetes Federation. Waist circumference 94 cm or greater for men and greater than 80 cm for women of European origin plus any of 4 criteria: fasting serum glucose levels  100 mg/dL or antidiabetic drug use, systolic blood pressure  130 mm Hg or diastolic blood pressure  85 mm Hg or antihypertensive drug use, serum triglyceride levels  150 mg/ dL or hypertriglyceridemia drug use, and serum high-density lipoprotein levels < 40 mg/dL in men. Source: Grundy and colleagues.50 {{ OR: Odds ratio. ## BMI: Body mass index. *** HDL: High-density lipoprotein. ††† BP: Blood pressure. ‡‡‡ TG: Triglyceride. §§§ FGIc: Fasting glucose levels. {{{ JIS: Joint Interim Statement. Three of the following 5 criteria should be fulfilled: elevated TG levels ( 150 mg/dL or drug treatment for elevated TG levels), reduced HDL levels (< 40 mg/dL in men and < 50 mg/dL in women), elevated blood pressure (systolic blood pressure  130 mm Hg, diastolic blood pressure  85 mm Hg, or antihypertensive drug treatment), and elevated fasting glucose levels ( 100 mg/dL or drug treatment for elevated glucose levels); elevated waist circumference according to national or regional cut points. For Asian population should be  90 cm for men and  80 cm for women. For Korean population should be  90 cm for men and  85 cm for women. Sources: Alberti and colleagues,1 Lee and colleagues.51 ### WC: Waist circumference. **** Participants who met at least 3 of the following 5 criteria: high waist circumference ( 102 cm in men and  88 cm in women), high TG levels ( 1.7 millimoles per liter), low HDL cholesterol levels (< 1.03 mmol/L in men and < 1.3 mmol/L in women), high blood pressure ( 130 mm Hg systolic blood pressure,  85 mm Hg diastolic blood pressure, or current use of antihypertensive medications), and high fasting glucose levels ( 5.55 mmol/L or current use of hypoglycemic medications).

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Table. Continued

OUTCOME CHARACTERISTICS (TL†)

Type and Groups

No. 20.7 (7.2)‡‡ 17.7 (9.0)‡‡ P < .001

Mean number of teeth

Number of missing teeth 0-4 5-31 32

397 688 269

TL ¼ 0 TL > 1

RESULTS

Diagnosis Self-reported number of teeth, excluding third molars

Correlation coefficient
0.15

Clinical examination by a trained nurse

OR{{

996 5,394

Number of teeth < 20  20

1,085 5,595

Number of teeth 28 21-27 1-20 No teeth

1,826 2,110 1,062 513

Main Conclusions

Multiple regression; smoking and education level

The number of teeth was significantly lower in participants with MetS than in those without and was related significantly to the number of criteria included in the definition of MetS. TL was related significantly to MetS.

Logistic regression; age, serum total cholesterol level, family history of diabetes, prevalent diabetes, smoking, years of education, number of missing teeth, serum C-reactive protein level, and glutamyltransferase

> 4 missing teeth and complete edentulousness also were associated significantly with MetS.

Logistic regression; sex, age, education, income, residence, drinking, smoking, physical activity, oral examination, brushing after dinner, oral cavity, raw materials used

The OR of the group with abnormal BP in women increased 1.41-fold (95% CI, 1.10 to 1.82), and the OR of missing teeth in women with MetS increased 1.48-fold (95% CI, 1.07 to 2.04).

OR 1 1.47 1.09 (95% CI, 0.88 to 1.36) 1.08 (95% CI, 0.9 to 1.30) 1.25 (95% CI, 1.03 to 1.52) 1.29 (95% CI, 0.91 to 1.83) 1.04 (95% CI, 0.87 to 1.26)

Logistic regression; adjusted for general characteristics (sex, age, education, income, residence), health behaviors (drinking, smoking, physical activity), oral health behaviors (oral examination, brushing after dinner)

The high BP group had 1.25 times the missing teeth prevalence rate (95% CI, 1.00 to 1.37). The MetS group had 1.47 times the missing teeth prevalence rate (95% CI, 1.11 to 1.94).

Trained research assistants performed oral examinations, questionnaire

OR number of components 1.1 (95% CI, 1.04 to 1.16) M: 1.04 (95% CI, 0.96 to 1.14) F: 1.13 (95% CI, 1.06 to 1.21)

Multivariate logistic regression; unhealthy dietary habits, substance use, and component number of MetS

Greater number of MetS components (OR, 1.1; 95% CI, 1.04 to 1.16) were associated independently with a higher risk of < 20 teeth.

Oral examinations, number of teeth (excluding third molars)

OR, 1 OR, 1.32 (95% CI, 1.09 to 1.59) OR, 1.55 (95% CI, 1.22 to 1.98) OR, 1.79 (95% CI, 1.28 to 2.51)

Logistic regression; age, sex, race, ethnicity, ratio of family income to poverty, physical activity, smoking, and energy intake

The number of natural teeth was associated inversely with the presence of MetS.

Oral examination, presence or absence of each tooth (except third molar)

TL ¼ 0 TL  1

Statistical Analysis; Adjustments

Association

1 1.69 (95% confidence interval [CI], 1.26 to 2.27) 1.93 (95% CI, 1.30 to 2.86)

1.32 1.13 1.12 1.13 1.03 1.06

OR M: 1 (95% CI, 0.89 (95% CI, 0.84 (95% CI, 0.85 (95% CI, 0.87 (95% CI, 0.63 (95% CI, 0.81

Dentists performed oral examinations on the basis of World Health Organization standards

F: 1 to to to to to to

1.95) 1.51) 1.49) 1.47) 1.67) 1.39)

1.48 1.02 0.95 1.41 1.14 1.08

(95% (95% (95% (95% (95% (95%

CI, CI, CI, CI, CI, CI,

1.07 0.77 0.76 1.10 0.75 0.84

to to to to to to

2.04) 1.36) 1.20) 1.82) 1.74) 1.38)

and between TL and high triglyceride levels25 only in women. Investigators in the cohort studies identified that MetS is associated with the incidence of TL.9,10 Synthesis of results The authors10,48 of 2 of the included studies provided additional data to be included in the metaanalysis. We performed the meta-analysis regarding the outcome measures. First was the mean number of teeth. The analysis included 5 studies and comprised 6,855 participants. The outcome was the mean number of teeth, and the effect size was the standardized difference in means. The standardized difference in means was
2,77, which indicates that participants with MetS had, on average, fewer teethd2.77 fewer than those without MetS (Figure 2).9,10,25,28,48 The I2 statistic was

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Table. Continued EXPOSURE CHARACTERISTICS (MetS*)

POPULATION CHARACTERISTICS

STUDY CHARACTERISTICS

Study Design, Study, Country Follow-Up

Aim

Furuta and Colleagues,9 2016, Japan

Cohort retrospective, 5y

To examine whether MetS is a risk factor for TL

Kaye and Colleagues,10 2016, United States

Cohort prospective, follow-up was 17 (8)‡‡ y and ranged from 2-33 y

Setting

Total No., M‡, F§

Age, Y (Mean or Range) 42.7 (35-60)

Type; Groups

Workplace health examinations and dental records at a manufacturing company in Yokohama, Japan

2,107, M: 1,718, F: 389

To determine whether MetS predicts TL and worsening of periodontal disease

Department of Veterans Affairs Dental Longitudinal Study and Normative Aging Study

M: 760

Cross-sectional, To evaluate the relationship Kim and NA between TL and Colleagues,25 2016, MetS Republic of Korea

Korean National Health and Nutrition Examination Survey from 2012

3,589, M: 1,511, F: 2,078

 40

MetS(
) MetS(þ) Types of abnormal components: WC HDL BP TG FGlc

F: 2,547

35.4 (20-49)

MetS(
) MetS(þ) Types of abnormal components: WC HDL BP TG FGlc

61 (9)‡‡

Number of components: 0 1-2 3 Types of abnormal components: BMI HDL BP TG FGlc 0  3 components Obesity: BMI  25.0 MetS(
) MetS(þ) Number of components: 0 1 2 3 4 or 5

2,160 1,429

Musskopf, and Colleagues,48 2017, Brazil

Cross-sectional, To evaluate the association NA of MetS with periodontitis and TL

Department of Endocrinology and Metabolism of the Hospital de Clínicas de Porto Alegre from Federal University of Rio Grande do Sul, Porto Alegre, Brazil, dental clinic of the School of Dentistry of the Universidade Federal do Rio Grande do Sul

363, M: 132, F: 231

18-81

MetS(
) MetS(þ)

164 199

Cross-sectional, To explore the relationship Shin,30 2017, Republic of Korea NA between the number of natural teeth and MetS

Korean National Health and Nutrition Examination Survey from 2012-2014

12,131

 20

MetS(
) MetS(þ)

8,817 3,314

n

Medical examination, blood sample, and NCEP ATP III; IDF

424 336 82 124 195 190 169

Cross-sectional, To explore cardiometabolic risk Program for women in NA factors, oral health status, and rural region of Taiwan, associated factors among August 2014-July 2015 women of reproductive age

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Medical examination, blood sample, and questionnaire; JIS for Asians

892 911 304

Ma and Colleagues,26 2017, Taiwan

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Diagnosis; Criteria

No.

Medical examination, blood sample, and questionnaire; JIS for Asians

Medical examination, blood sample, and questionnaire; JIS for Asians

2,271 276 726 523 604 199 325

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Table. Continued

OUTCOME CHARACTERISTICS (TL†)

Type and Groups

No.

Mean number of teeth 27.3 (1.2)‡‡ 27.1 (1.6)‡‡ 27.0 (1.6)‡‡ TL > 1 TL ¼ 0 TL ¼ 1 TL ¼ 2 TL ¼ 3 TL ¼ 4 TL ¼ 5 Mean number of teeth

27 (10.8%) participants

Number of teeth < 20  20

F 24.5 (0.2)‡‡ 21.0 (0.3)‡‡ P < .001

209 2,338

Mean number of teeth Missing teeth < 6, 6

22.2 (5.9)‡‡ 18.7 (6.8)‡‡ P < .001

28 20-27 0-19

4,939 5,557 1,635

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Diagnosis

Association

Statistical Analysis; Adjustments

Main Conclusions

Oral examination, number of teeth at baseline (except third molars) minus at the follow-up examination

OR 1 1.12 (95% CI, 0.8 to 1.56) 1.54 (95% CI, 1.01 to 2.37) 1.46 (95% CI, 1.03 to 2.07) 1.23 (95% CI, 0.75 to 1.99) 1.01 (95% CI, 0.72 to 1.43) 0.95 (95% CI, 0.67 to 1.36) 0.94 (95% CI, 0.67 to 1.32) incidence rate ratio, 1.40 1.33

Logistic regression; age, sex, caries experience, attachment loss, oral hygiene status, number of teeth, toothbrushing frequency, smoking, occupational status

MetS was associated with the incidence of TL. Obesity was associated significantly with TL.

Oral examination, presence or absence of each tooth recorded at each examination

Hazard ratio IDF: 1.39 (95% CI 1.08 to 1.79) NCEP ATP III: 1.44 (95% CI 1.11 to 1.97)

Cox regression; age, education, smoking status, plaque level, and initial level of the appropriate periodontal disease measure

The presence of MetS predicted greater hazards of TL.

Multiple logistic regression; age, sex, BMI, smoking, alcohol consumption, regular exercise, education, household income, frequency of toothbrushing per day, and use a secondary oral product

Women with fewer remaining teeth had a higher prevalence of MetS.

1,880 179 32 11 4 1 27.0 (1.6)‡‡

Mean number of teeth 23 (6)‡‡ 22 (6)‡‡ 21 (6)‡‡ 21 (7)‡‡ 21 (6)‡‡

Mean number teeth M 24.1 (0.3)‡‡ 23.7 (0.3)‡‡ P < .273 Groups 28 20-27 0-19

RESULTS

Oral examination, number of teeth (excluding third molars)

OR 28 [Reference] 0-19 M: 1.202 (95% CI, 0.709 to 2.039) F: 1.784 (95% CI, 1.200 to 2.653) M: 0.641 (95% CI, 0.3 to 1.368) F: 2.141 (95% CI, 0.966 to 4.746) M: 1.137 (95% CI, 0.727 to 1.776) F: 1.451 (95% CI, 0.976 to 2.158) M: 1.05 (95% CI, 0.614 to 1.795) F: 1.571 (95% CI, 1.067 to 2.313) M: 1.125 (95% CI, 0.72 to 1.756) F: 1.535 (95% CI, 1.029 to 2.292) 1.268 (95% CI, 0.792 to 2.032) 0.949 (95% CI, 0.608 to 1.481)

20-27 0.897 (95% CI, 0.613 to 1.311) 1.480 (95% CI, 1.085 to 2.019) 0.968 (95% CI, 0.552 to 1.699) 1.882 (95% CI, 1.06 to 3.343) 0.91 (95% CI, 0.643 to 1.288) 1.197 (95% CI, 0.906 to 1.582) 0.979 (95% CI, 0.695 to 1.38) 1.41 (95% CI, 1.076 to 1.847) 1.097 (95% CI, 0.795 to 1.516) 1.476 (95% CI, 1.119 to 1.947) 0.945 (95% CI, 0.67 to 1.333) 1.071 (95% CI, 0.775 to 1.48)

Trained research assistants performed oral examinations, questionnaire

OR  20 [Reference] 1.16 (95% CI, 0.77 to 1.74) 1.27 (95% CI, 0.91 to 1.79) 1.18 (95% CI, 0.82 to 1.70) 0.95 (95% CI, 0.67 to 1.34) 0.86 (95% CI, 0.51 to 1.44) 1.09 (95% CI, 0.73 to 1.61)

Multivariate logistic regression

MetS was not an independent factor in having < 20 teeth.

Oral examinations, number of teeth (excluding third molars)

Prevalence ratio 1 1.23 (95% CI, 1.02 to 1.49)

Sex, age, smoking, years of education, and socioeconomic status

MetS was associated with TL (> 6 teeth). The associations between MetS and both periodontitis and TL were weak. The association was observed in the age group 41 through 60 years.

OR 1 1.19 1.37

Logistic regression; age, sex, income, education, toothbrushing frequency, periodontitis, smoking, drinking, physical activity, and diabetes mellitus

The number of teeth found was inversely proportional to the occurrence of MetS.

The number of existing permanent teeth was obtained after excluding missing teeth, impacted teeth, implants, and third molars Oral examinations, number of teeth (excluding missing teeth, impacted teeth, implants, and third molars)

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100% and showed considerable heterogeneity. The sensitivity analyses did not decrease the heterogeneity (eFigure 1,9,10,25,28,38,48 available online at the end of this article). Second was the lack of functional dentition. The analysis included 4 studies and comprised 26,869 participants. The outcome was the lack of functional dentition, and the effect size was the standardized mean difference in OR. The results of this meta-analysis revealed a positive association between MetS and lack of functional dentition, with an OR of 2.37 (95% confidence interval, 1.89 to 2.96) (Figure 3).23,26,29,30 We detected heterogeneity in this model (I2 ¼ 89%), and the s standard was 0.04. Results of the sensitivity analyses, in which we successively removed each study, produced a low effect on I2. When the meta-analysis included only studies receiving 7 or more NOS scores, the I2 decreased to 63%, and the OR increased to 2.83 (95% confidence interval, 2.48 to 3.23) (eFigure 2,23,26,29,30,38 available online at the end of this article). Confidence in cumulative evidence The overall quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation summary-of-findings table was very low. The explanations were selection bias in all primary studies, high heterogeneity in the meta-analysis of the mean number of teeth, and lack of functional dentition. eTable 241 shows the summary of findings. DISCUSSION MetS has an unquestionable negative effect on public health because it is associated with a high risk of developing diabetes and cardiovascular disease and, according to results from some studies,9,10 increases the risk of developing TL. In addition, our findings suggest that people with MetS have, on average, fewer teeth than do people without MetS and are more likely to lack functional dentition. This finding is of concern because the lack of functional dentition can result in problems with chewing6 and can have an effect on eating patterns, such as a decreased intake of fruits and vegetables and increased levels of cholesterol and saturated fats.7,52 Therefore, TL also can play a role in the development or worsening of obesity, hypertension, impaired glucose tolerance, and abnormal lipid metabolism, which are components of MetS. Besides that, TL also is related to poor general health status and reduced quality of life.4 Moreover, our results suggest that there is a possibility of MetS exacerbating the progression of oral diseases, such as caries and PD, given that participants with MetS had more severe TL. Investigators in some studies already have shown an association between MetS and the severity of PD,45,46,53 but they were unable to find a causal association. Regarding caries, there was a limited number of investigations addressing its relationship with MetS,44,47,54 and the investigators in these studies did not evaluate the direction of the association or whether MetS was associated with worsening of caries, including their depth or whether the lesions reached the dentin and roots. Investigators in studies with data of a nationwide representative sample from Korea identified an association between MetS and TL only in women. The same occurred when some components of MetS were associated individually with TL.24,25,39 This finding can be explained because systemic inflammation is accelerated in postmenopausal women with MetS,55 which increases the chance of TL. Also, results from some studies show that the effect of low socioeconomic status on the occurrence of MetS is higher in female than in male participants.56,57 Given that socioeconomic status also affects the occurrence of TL,58 socioeconomic status can be another possible explanation of the findings in the Korean studies. Our study has some limitations. The meta-analyses were significantly heterogeneous, although we were able to minimize the heterogeneity by performing sensitivity analyses. The heterogeneity was due to variability across the studies regarding the epidemiologic, nutritional, and demographic characteristics of the different countries. In addition, the variation in the age of participants (older than 18 years) could have contributed to heterogeneity. Concerning the exposure, we followed a pattern of grouping the participants according to the presence or absence of MetS. Besides that, the diagnostic criteria used to diagnose MetS varied. The main difference between these criteria is the cutoff points used for determining obesity. For example, for people of European descent, in the IDF criteria the cutoff point that defines high waist circumference is 94 centimeters or greater for men and 80 cm for women, whereas the NCEP ATP III uses a cutoff of 102 cm or greater for men and 88 cm for women. Moreover, the IDF criteria consider abdominal obesity as a component necessary for the diagnosis of MetS, whereas other criteria, such as NCEP ATP III and JIS, consider only the 1036

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With MetS Without MetS Standard Mean Difference Mean (SD) Total Mean (SD) Total Weight (%) IV, Random-Effects, 95% CI

Study or Subgroup Holmlund and Colleagues,28 2007

17.7 (9)

Furuta and Colleagues,9 2016 27 (1.6) 20.9 (5.6) Kaye and Colleagues,10 2016 25 23.7 (0.3) Kim and Colleagues, 2016 (Men) Kim and Colleagues,25 2016 (Women) 21 (0.3) 48 18.7 (6.8) Musskopf, and Colleagues, 2017 Total (95% CI)

219

20.7 (7.2)

728

16.7

–0.39 (–0.54 to –0.24)

304 336 522 907 199

27.3 (1.2) 892 21.8 (5.5) 424 24.1 (0.3) 989 24.5 (0.2) 1,171 22.2 (5.9) 164

16.7 16.7 16.7 16.7 16.7

–0.23 (–0.36 to –0.10) –0.16 (–0.31 to –0.02) –1.33 (–1.45 to –1.22) –14.07 (–14.51 to –13.63) –0.54 (–0.76 to –0.33)

2,487

4,368

100.0

–2.77 (–4.56 to –0.98)

2 2 2 Heterogeneity: τ = 4.99; χ5 = 3,801.67, P < .00001; I = 100%

Standard Mean Difference IV, Random-Effects, 95% CI

–10

Test for overall effect: z = 3.04 (P = .002)

–5 Favors MetS+

0

5 Favors MetS–

10

Figure 2. Forest plot for the meta-analysis of the mean number of teeth.9,10,25,28,48 Squares indicate the mean difference of single studies, and lines indicate the 95% confidence intervals (95% CI). Diamond shows the pooled estimates. The meta-analysis software rounded the decimal places. The triangle indicates the standard mean difference that cannot be plotted owing to its scale. CI: Confidence interval. IV: Inverse variance. MetS: Metabolic syndrome. SD: Standard deviation.

With MetS Events Total

Study or Subgroup Tsai and Colleagues,

23

2015

Zhu and Hollis,29 2015 Ma and Colleagues,26 2017 Shin,30 2017

Without MetS Odds Ratio Events Total Weight (%) M-H, Random-Effects, 95% CI

382

1,603

703

5,077

27.3

1.95 (1.69 to 2.24)

963

2,307

612

3,204

28.1

3.03 (2.69 to 3.42)

35

276

174

2,271

16.0

1.75 (1.19 to 2.58)

754

3,314

881

8,817

28.6

2.65 (2.38 to 2.95)

19,369

100.0

2.37 (1.89 to 2.96)

Total (95% CI)

7,500

Total events

2,134

Odds Ratio M-H, Random-Effects, 95% CI

2,370

2 2 2 Heterogeneity: τ = 0.04; χ3 = 26.46, P < .00001; I = 89%

Test for overall effect: z = 7.56 (P < .0001)

0.2

0.5

1

Favors MetS+

2

5

Favors MetS–

Figure 3. Forest plot for the meta-analysis of the lack of functional dentition.23,26,29,30 Squares indicate the odds ratio of single studies, and lines the 95% confidence intervals (95% CI). Diamond shows the pooled estimates. The meta-analysis software rounded the decimal places. CI: Confidence interval. MetS: Metabolic syndrome. M-H: Mantel-Haenszel.

presence of any 3 of the 5 risk factors, without a specific mandatory component.1 The investigators evaluated the outcome of TL in different ways, however, which made it difficult for us to compare the studies and group them in the same meta-analysis. Also, for this reason, we could not include all studies in the meta-analysis. Consequently, few studies remained in each analysis, which did not allow for the use of other strategies to reduce heterogeneity, such as meta-regression and subgroup analysis. All these aspects, therefore, can be considered limitations of the study. Investigators in only 2 studies showed the risk of developing TL (incidence) in participants with MetS because most of the selected studies were cross-sectional. This was 1 additional limitation that made it difficult to establish a relationship of cause and effect between MetS and TL. Thus, our findings suggest that further studies with a longitudinal design and use of appropriate causal modeling approaches are necessary. It also is essential that the studies follow a standard for measuring TL and MetS to allow more accurate comparisons between them. We recommend caution in generalizing our findings to a larger and more diverse population. Despite almost all included studies being of high methodological quality, the overall evidence was low because of the lack of study design and statistical analyses that allow the assessment of a causal relationship between MetS and TL. Besides that, the evidence downgraded further because some studies’ samples were not truly representative of the general population. The evidence quality was very low, and there is a possibility that the actual effects could be substantially different if more rigorous evidence becomes available. Despite this difficulty, the different settings of the included studies from diverse countries suggest that the association between Mets and TL is not context specific. To our knowledge, this is the first systematic review and meta-analysis in which the investigators explore the association between MetS and TL. This topic is new in the scientific literature, and almost all studies we selected were published after 2015, perhaps as a result of the increased prevalence of MetS in the past decade.2 Studying this topic is important because MetS and TL are prevalent conditions that negatively affect health and quality of life, increase the cost of health care systems, and exacerbate social JADA 150(12)

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problems and inequalities. Therefore, public policies that approach common risk factors regarding oral and general health appear to be a most promising strategy for health promotion and eventual prevention of these diseases. CONCLUSIONS Participants with MetS had, on average, fewer teeth and a greater chance of lacking functional dentition than did those with no MetS. The findings of this systematic review and meta-analysis suggest that MetS is associated positively with TL. However, because of the very low level of evidence, readers should use caution when considering these findings. Better-conducted longitudinal studies with use of appropriate causal modeling approaches are necessary to establish a causal relationship between MetS and TL. n SUPPLEMENTAL DATA Supplemental data related to this article can be found at: https://doi.org/10.1016/j.adaj.2019.07.023.

Ms. Leite Souza is a PhD student, postgraduate program in dentistry, Department of Dentistry, Federal University of Santa Catarina, Campus Universitário-Trindade, Florianópolis, Santa Catarina, Brazil 88040-900, e-mail [email protected]. Address correspondence to Ms. Leite Souza. Ms. Massignan is a PhD student, postgraduate program in dentistry, Federal University of Santa Catarina, Trindade, Florianópolis, Santa Catarina, Brazil. Ms. Glazer Peres is an associate professor, dentistry, School of Dentistry and Oral Health, Griffith University, Gold Coast, Queensland, Australia. Mr. Aurélio Peres is a professor, dental and oral health research, School of Dentistry and Oral Health, Griffith University, Gold Coast, Queensland,

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Australia and a professor, dental and oral health research, Menzies Health Institute Queensland and School of Dentistry and Oral Health, Gold Coast, Queensland, Australia. Disclosure. None of the authors reported any disclosures. Ms. Massignan is supported by Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (Foundation for Research and Innovation Support of Santa Catarina State) (FAPESC) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Coordination of Improvement of Higher Level Personnel) (CAPES).

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APPENDIX 1.

Search strategy (June 13, 2018). DATABASE

SEARCH

LILACS*

(tw†:((tw:(““perda de dente”“)) OR (tw:(““perda de dentes”“)) OR (tw:(““perda dental”“)) OR (tw:(““perda dentária”“)) OR (tw:(““Pérdida de Diente”“)) OR (tw:(““Tooth Loss”“)) OR (tw:(““teeth loss”“)) OR (tw:(““Tooth Extraction”“)) OR (tw:(““tooth Extractions”“)) OR (tw:(““Teeth Extraction”“)) OR (tw:(““teeth Extractions”“)) OR (tw:(““Extracción Dental”“)) OR (tw:(““Extração Dentária”“)) OR (tw:(““remaining teeth”“)) OR (tw:(““number of teeth”“)) OR (tw:(““number of natural teeth”“)) OR (tw:(““Arcada Edéntula”“)) OR (tw:(““arcada Edêntula”“)) OR (tw:(““Boca Edéntula”“)) OR (tw:(““boca Edêntula”“)) OR (tw:(““jaw, Edentulous”“)) OR (tw:(““edentulism”“)) OR (tw:(““edentulous”“)) OR (tw:(““toothless”“)) OR (tw:(““missing teeth”“)) OR (tw:(““mouth, Edentulous”“)))) AND (tw:((tw:(““Metabolic Syndrome”“)) OR (tw:(““Metabolic Syndromes”“)) OR (tw:(““syndrome x”“)) OR (tw:(““Insulin Resistance”“)) OR (tw:(““Resistencia a la Insulina”“)) OR (tw:(““Resistência à Insulina”“)) OR (tw:(obesity)) OR (tw:(obesidad)) OR (tw:(obesidade)) OR (tw:(““diabetes mellitus”“)) OR (tw:(hypertriglyceridemia)) OR (tw:(hyperlipidemia)) OR (tw:(hypercholesterolemia)) OR (tw:(hyperlipidemias)) OR (tw:(““Hyperlipoproteinemia Type IV”“)) OR (tw:(““Hiperlipoproteinemia Tipo IV”“)) OR (tw:(hipercolesterolemia)) OR (tw:(dyslipidemia)) OR (tw:(dislipidemias)) OR (tw:(dyslipidemias)) OR (tw:(hyperinsulinism)) OR (tw:(hyperglycemia)) OR (tw:(hypertension)) OR (tw:(hiperinsulinismo)) OR (tw:(hiperglucemia)) OR (tw:(hiperglicemia)) OR (tw:(hipertensión)) OR (tw:(hipertensão)))) AND (tw:((tw:(adult)) OR (tw:(adulto)) OR (tw:(““Middle Aged”“)) OR (tw:(““Mediana Edad”“)) OR (tw:(““Meia-Idade”“)) OR (tw:(aged)) OR (tw:(anciano)) OR (tw:(idoso)) OR (tw:(““Aged, 80 and over”“)) OR (tw:(““Anciano de 80 o más Años”“)) OR (tw:(““Idoso de 80 Anos ou mais”“)) OR (tw:(adults)) OR (tw:(““middle age”“)) OR (tw:(““aged people”“)) OR (tw:(““older age”“)) OR (tw:(““old age”“)) OR (tw:(elderly)) OR (tw:(““Aged, 80 and over”“)) OR (tw:(““Oldest Old”“)) OR (tw:(nonagenarians)) OR (tw:(nonagenarian)) OR (tw:(octogenarians)) OR (tw:(octogenarian)) OR (tw:(centenarians)) OR (tw:(centenarian)))) AND (instance:”“regional”“) AND (db‡:(““LILACS”“))

PubMed

((((““tooth loss”“ OR ““teeth loss”“ OR ““Tooth Extraction”“[MeSH§] OR ““Tooth Extraction”“ OR ““Tooth Extractions”“ OR ““Teeth Extraction”“ OR ““Teeth Extractions”“ OR ““remaining teeth”“ OR ““number of teeth”“ OR “number of natural teeth”“ OR ““edentulism”“ OR ““missing teeth”“ OR ““Mouth, Edentulous”“[MeSH] OR ““Edentulous”“ OR ““Toothless”“))) AND ((““Metabolic Syndrome”“[MeSH] OR ““Metabolic Syndrome”“ OR ““Metabolic Syndromes”“ OR ““metabolic syndrome”“ OR ““syndrome x”“ OR ““insulin resistance”“ OR ““obesity”“ OR ““diabetes mellitus”“ OR ““Hypertriglyceridemia”“ OR ““hyperlipidemia”“ OR ““hypercholesterolemia”“ OR ““hypocholesterolemia”“ OR ““dyslipidemia”“ OR ““hyperinsulinism”“ OR ““hyperglycemia”“ OR ““hypertension”“))) AND ((““adult”“[MeSH] OR ““adult”“ OR ““adults”“ OR ““middle aged”“[MeSH] OR ““middle aged”“ OR ““middle age”“ OR ““aged”“[MeSH] OR ““aged people”“ OR ““older age”“ OR ““old age”“ OR ““elderly”“ OR ““Aged, 80 and over”“[MeSH] OR ““Oldest Old”“ OR ““Nonagenarians”“ OR ““nonagenarian”“ OR ““Octogenarians”“ OR ““Octogenarian”“ OR ““Centenarians”“ OR ““Centenarian”“))

Scopus

(TITLE-ABS{-KEY ( ““tooth loss”“ OR ““teeth loss”“ OR ““Tooth Extraction”“ OR ““Tooth Extractions”“ OR ““Teeth Extraction”“ OR ““Teeth Extractions”“ OR ““remaining teeth”“ OR ““number of teeth”“ OR ““number of natural teeth”“ OR ““edentulism”“ OR ““missing teeth”“ OR ““Mouth, Edentulous”“ OR ““Edentulous”“ OR ““Toothless”“ ) ) AND ( TITLE-ABS-KEY ( ““Metabolic Syndrome”“ OR ““Metabolic Syndromes”“ OR ““metabolic syndrome”“ OR ““syndrome x”“ OR ““insulin resistance”“ OR ““obesity”“ OR ““diabetes mellitus”“ OR ““Hypertriglyceridemia”“ OR ““hyperlipidemia”“ OR ““hypercholesterolemia”“ OR ““hypocholesterolemia”“ OR ““dyslipidemia”“ OR ““hyperinsulinism”“ OR ““hyperglycemia”“ OR ““hypertension”“ ) ) AND ( TITLE-ABS-KEY ( ““adult”“ OR ““adults”“ OR ““middle aged”“ OR ““middle age”“ OR ““aged people”“ OR ““older age”“ OR ““old age”“ OR ““elderly”“ OR ““Aged, 80 and over”“ OR ““Oldest Old”“ OR ““Nonagenarians”“ OR ““nonagenarian”“ OR ““Octogenarians”“ OR ““Octogenarian”“ OR ““Centenarians”“ OR ““Centenarian”“ ) ) AND ( LIMIT-TO ( DOCTYPE# , ““ar”“** ) ) AND ( LIMIT-TO ( SUBJAREA†† , ““DENT”“‡‡ ) )

Web of Science

((TS§§¼(““tooth loss”“ OR ““teeth loss”“ OR ““Tooth Extraction”“ OR ““Tooth Extractions”“ OR ““Teeth Extraction”“ OR ““Teeth Extractions”“ OR ““remaining teeth”“ OR “number of teeth” OR “number of natural teeth” OR ““edentulism”“ OR “missing teeth”“ OR ““Mouth, Edentulous”“ OR ““Edentulous”“ OR ““Toothless”“)) AND (TS¼(““Metabolic Syndrome”“ OR ““Metabolic Syndromes”“ OR ““metabolic syndrome”“ OR ““syndrome x” OR ““insulin resistance”“ OR ““obesity”“ OR ““diabetes mellitus”“ OR ““Hypertriglyceridemia”“ OR ““hyperlipidemia”“ OR ““hypercholesterolemia”“ OR ““hypocholesterolemia”“ OR ““dyslipidemia”“ OR ““hyperinsulinism”“ OR ““hyperglycemia”“ OR ““hypertension”“)) AND (TS¼(““adult”“ OR ““adults”“ OR ““middle aged”“ OR ““middle age”“ OR ““aged people”“ OR ““older age”“ OR ““old age”“ OR ““elderly”“ OR ““Aged, 80 and over”“ OR ““Oldest Old”“ OR ““Nonagenarians”“ OR ““nonagenarian”“ OR ““Octogenarians”“ OR ““Octogenarian”“ OR ““Centenarians”“ OR ““Centenarian”“))) Refined by: DOCUMENT TYPES: ( ARTICLE )

Google Scholar

allintitle{{: (““number of teeth”“ OR ““tooth loss”“) AND (adults OR ““middle aged”“ OR ““middle age”“ OR ““aged people”“ OR ““older age”“ OR ““old age”“ OR ““elderly”“) AND ““metabolic syndrome”“

OpenGrey

(““tooth loss”“ OR ““teeth loss”“ OR ““Tooth Extraction”“ OR ““Tooth Extractions”“ OR ““Teeth Extraction”“ OR ““Teeth Extractions”“ OR ““remaining teeth”“ OR ““number of teeth”“ OR “number of natural teeth” OR “edentulism” OR “missing teeth” OR “Edentulous” OR “Toothless”) AND (“Metabolic Syndrome” OR “Metabolic Syndromes” OR “metabolic syndrome” OR “syndrome x” OR “insulin resistance” OR “obesity” OR “diabetes mellitus” OR “Hypertriglyceridemia” OR “hyperlipidemia” OR “hypercholesterolemia” OR “hypocholesterolemia” OR “dyslipidemia” OR “hyperinsulinism” OR “hyperglycemia” OR “hypertension”) AND (“adult” OR “adults” OR “middle aged” OR “middle age” OR “aged people” OR “older age” OR “old age” OR “elderly” OR “Nonagenarians” OR “nonagenarian” OR “Octogenarians” OR “Octogenarian” OR “Centenarians” OR “Centenarian”)

ProQuest noft##((“tooth loss” OR “teeth loss” OR “Tooth Extraction” OR “Tooth Extractions” OR “Teeth Extraction” OR “Teeth Extractions” OR “remaining teeth” Dissertations OR “number of teeth” OR “number of natural teeth” OR “edentulism” OR “missing teeth” OR “Edentulous” OR “Toothless”) AND (“Metabolic Syndrome” and Theses OR “Metabolic Syndromes” OR “metabolic syndrome” OR “syndrome x” OR “insulin resistance” OR “obesity” OR “diabetes mellitus” OR “Hypertriglyceridemia” OR “hyperlipidemia” OR “hypercholesterolemia” OR “hypocholesterolemia” OR “dyslipidemia” OR “hyperinsulinism” OR “hyperglycemia” OR “hypertension”) AND (“adult” OR “adults” OR “middle aged” OR “middle age” OR “aged people” OR “older age” OR “old age” OR “elderly” OR “Nonagenarians” OR “nonagenarian” OR “Octogenarians” OR “Octogenarian” OR “Centenarians” OR “Centenarian”)) Livivo

(“tooth loss” OR “teeth loss” OR “Tooth Extraction” OR “Tooth Extractions” OR “Teeth Extraction” OR “Teeth Extractions” OR “remaining teeth” OR “number of teeth” OR “number of natural teeth” OR “edentulism” OR “missing teeth” OR “Edentulous” OR “Toothless”) AND (“Metabolic Syndrome” OR “Metabolic Syndromes” OR “metabolic syndrome” OR “syndrome x” OR “insulin resistance” OR “obesity” OR “diabetes mellitus” OR “Hypertriglyceridemia” OR “hyperlipidemia” OR “hypercholesterolemia” OR “hypocholesterolemia” OR “dyslipidemia” OR “hyperinsulinism” OR “hyperglycemia” OR “hypertension”) AND (“adult” OR “adults” OR “middle aged” OR “middle age” OR “aged people” OR “older age” OR “old age” OR “elderly” OR “Nonagenarians” OR “nonagenarian” OR “Octogenarians” OR “Octogenarian” OR “Centenarians” OR “Centenarian”)

* LILACS: Latin American and Caribbean Health Sciences Literature. † tw: Words of titles, abstracts and subjects descriptors. ‡ db: Database. § MeSH: Medical Subject Headings. { ABS: Abstract. # DOCTYPE: Document type. ** ar: Article. †† SUBJAREA: Subject area. ‡‡ DENT: Dentistry. §§ TS: Topic. {{ allintitle: Filter to limit the search to the titles of articles. ## noft: Anywhere except full text.

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Continued DATABASE Embase

SEARCH (“tooth loss” OR “teeth loss” OR “Tooth Extraction” OR “Tooth Extractions” OR “Teeth Extraction” OR “Teeth Extractions” OR “remaining teeth” OR “number of teeth” OR “number of natural teeth” OR “edentulism” OR “missing teeth” OR “Edentulous” OR “Toothless”) AND (“Metabolic Syndrome” OR “Metabolic Syndromes” OR “metabolic syndrome” OR “syndrome x” OR “insulin resistance” OR “obesity” OR “diabetes mellitus” OR “Hypertriglyceridemia” OR “hyperlipidemia” OR “hypercholesterolemia” OR “hypocholesterolemia” OR “dyslipidemia” OR “hyperinsulinism” OR “hyperglycemia” OR “hypertension”) AND (“adult” OR “adults” OR “middle aged” OR “middle age” OR “aged people” OR “older age” OR “old age” OR “elderly” OR “Nonagenarians” OR “nonagenarian” OR “Octogenarians” OR “Octogenarian” OR “Centenarians” OR “Centenarian”)

Appendix 2. Articles excluded and the reasons for exclusion (n ¼ 31). STUDY

REASON FOR EXCLUSION*

Johansson and Colleagues,

e1

1994

2

Desvarieux and Colleagues,e2 2003 Taguchi and Colleagues, Okoro and Colleagues,

e3

e4

Borges and Colleagues,

2

2004

4

2005

e5

2

2007

2

Dietrich and Colleagues,e6 2008

2

Heitmann and Gamborg,e7 2008

2

Kushiyama and Colleagues,

e8

2009

2

Morita and Colleagues,e9 2009

2

Rodrigues,e10 2010

2 e11

2010

4

e12

2010

3

Syrjala and Colleagues,e13 2010

4

Lee and Colleagues,

Morita and Colleagues,

44

2010

2

e14

2011

2

Timonen and Colleagues, Nicolosi and Colleagues, Fukui and Colleagues,

45

2012

2

Holmlund and Lind,e15 2012

2

Cinar and Colleagues,e16 2013

2

Furuta and Colleagues, Tu and Colleagues,

e18

e17

2013

2

2013

2

Del Brutto and Colleagues,e19 2014

1

LaMonte and Colleagues,e20 2014

3

Lee and Colleagues,

e21

2014

2

e22

2014

2

Lim and Colleagues,

Meisel and Colleagues,e23 2014 Thanakun and Colleagues,

46

Minagawa and Colleagues,

4

2014

e24

3

2015

3

Ojima and Colleagues,47 2015 Kawashita and Colleagues, Lamster and Pagan,

13

Song and Colleagues,

e25

2 2017

3

2017 e26

1

2018

2

Han and Park,e27 2018

2

* The numbers indicate the reason for exclusion as follows: 1 indicates case reports, reviews, and opinions; 2 indicates no assessment of the association between metabolic syndrome and tooth loss; 3 indicates no report of the exposure or outcome of interest; and 4 indicates lack of data on metabolic syndrome or tooth loss.

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With MetS Study or Subgroup Holmlund and Colleagues,28 2007 10

Kaye and Colleagues,

25

Kim and Colleagues,

2016

2016 (Men) 48

2017

Standard Mean Difference IV, Random-Effects, 95% CI

728

20.0

–0.39 (–0.54 to –0.24)

424

20.0

–0.16 (–0.31 to –0.02)

24.1 (0.3)

989

20.0

–1.33 (–1.45 to –1.22)

907

24.5 (0.2)

1,171

19.9

–14.07 (–14.51 to –13.63)

199

22.2 (5.9)

164

20.0

–0.54 (–0.76 to –0.33)

3,476

100.0

–3.29 (–5.47 to –1.00)

Mean (SD)

Total

17.7 (9)

219

20.7 (7.2)

20.9 (5.6)

336

21.8 (5.5)

23.7 (0.3)

522

21 (0.3)

Kim and Colleagues,25 2016 (Women) Musskopf, and Colleagues,

Weight (%)

Total

Mean (SD)

18.7 (6.8)

Total (95% CI)

2,183 2

Heterogeneity: τ = 6.79;

χ24

Standard Mean Difference IV, Random-Effects, 95% CI

2

= 3,675.66, P < .00001; I = 100% –10

Test for overall effect: z = 2.82 (P = .005)

–5

0

Favors MetS+

5

10

Favors MetS–

A eFigure 1A. Forest plot for sensitivity analysis of the mean number of teeth with the study of Furuta and colleagues9 removed.10,25,28,48 The metaanalysis software rounded the decimal places. The triangle indicates the standard mean difference that cannot be plotted due to its scale. CI: Confidence interval. IV: Inverse variance. MetS: Metabolic syndrome. SD: Standard deviation.

Experimental Study or Subgroup

Mean (SD)

Furuta and Colleagues,9 2016 10

Kaye and Colleagues,

25

Kim and Colleagues,

2016

2016 (Men)

Control Mean (SD)

Total

Weight (%)

Standard Mean Difference IV, Random-Effects, 95% CI

27 (1.6)

304

27.3 (1.2)

892

20.0

–0.23 (–0.36 to –0.10)

20.9 (5.6)

336

21.8 (5.5)

424

20.0

–0.16 (–0.31 to –0.02)

23.7 (0.3)

522

24.1 (0.3)

989

20.0

–1.33 (–1.45 to –1.22)

21 (0.3)

907

24.5 (0.2)

1,171

19.9

–14.07 (–14.51 to –13.63)

199

22.2 (5.9)

164

20.0

–0.54 (–0.76 to –0.33)

3,640

100.0

–3.25 (–5.47 to –1.03)

Kim and Colleagues,25 2016 (Women) Musskopf, and Colleagues,48 2017

Total

18.7 (6.8)

Total (95% CI)

2,268

2 2 2 Heterogeneity: τ = 6.39; χ4 = 3,753.30, P < .00001; I = 100%

Standard Mean Difference IV, Random-Effects, 95% CI

–10

Test for overall effect: z = 2.87 (P = .004)

–5

0

Favors MetS+

5

10

Favors MetS–

B eFigure 1B. Forest plot for sensitivity analysis of the mean number of teeth with the study of Holmlund and colleagues28 removed.9,10,25,48 The metaanalysis software rounded the decimal places. The triangle indicates the standard mean difference that cannot be plotted due to its scale. CI: Confidence interval. IV: Inverse variance. SD: Standard deviation.

Experimental Study or Subgroup

Mean (SD)

Holmlund and Colleagues,28 2007

17.7 (9)

25

2016 (Men) 48

2017

Total

Weight (%)

Standard Mean Difference IV, Random-Effects, 95% CI

219

20.7 (7.2)

728

20.0

–0.39 (–0.54 to –0.24)

304

27.3 (1.2)

892

20.0

–0.23 (–0.36 to –0.10)

23.7 (0.3)

522

24.1 (0.3)

989

20.0

–1.33 (–1.45 to –1.22)

21 (0.3)

907

24.5 (0.2)

1,171

19.9

–14.07 (–14.51 to –13.63)

18.7 (6.8)

199

22.2 (5.9)

164

20.0

–0.54 (–0.76 to –0.33)

3,944

100.0

–3.30 (–5.53 to –1.07)

Kim and Colleagues,25 2016 (Women) Musskopf, and Colleagues,

Control Mean (SD)

27 (1.6)

Furuta and Colleagues,9 2016 Kim and Colleagues,

Total

Total (95% CI)

2,151

2 2 2 Heterogeneity: τ = 6.46; χ4 = 3,681.42, P < .00001; I = 100%

Test for overall effect: z = 2.90 (P = .004)

Standard Mean Difference IV, Random-Effects, 95% CI

–10

–5 Favors MetS+

0

5

10

Favors MetS–

C eFigure 1C. Forest plot for sensitivity analysis of the mean number of teeth with the study of Kaye and colleagues10 removed.9,25,28,48 The meta-analysis software rounded the decimal places. The triangle indicates the standard mean difference that cannot be plotted due to its scale. CI: Confidence interval. IV: Inverse variance. SD: Standard deviation.

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Experimental Study or Subgroup

Total

Mean (SD)

Holmlund and Colleagues,28 2007

17.7 (9)

10

2016

20.7 (7.2)

728

20.0

–0.39 (–0.54 to –0.24)

304

27.3 (1.2)

892

20.0

–0.23 (–0.36 to –0.10)

20.9 (5.6)

336

21.8 (5.5)

424

20.0

–0.16 (–0.31 to –0.02)

21 (0.3)

907

24.5 (0.2)

1,171

19.9

–14.07 (–14.51 to –13.63)

199

22.2 (5.9)

164

20.0

–0.54 (–0.76 to –0.33)

3,379

100.0

–3.07 (–5.44 to –0.69)

18.7 (6.8)

1,965

Total (95% CI) 2

Heterogeneity: τ = 7.31;

χ24

Standard Mean Difference Weight (%) IV, Random-Effects, 95% CI

219

Kim and Colleagues,25 2016 (Women) Musskopf, and Colleagues,48 2017

Total

27 (1.6)

Furuta and Colleagues,9 2016 Kaye and Colleagues,

Control Mean (SD)

Standard Mean Difference IV, Random-Effects, 95% CI

2

= 3,720.31, P < .00001; I = 100% –10

Test for overall effect: z = 2.53 (P = .01)

–5

0

Favors MetS+

5

10

Favors MetS–

D eFigure 1D. Forest plot for sensitivity analysis of the mean number of teeth with the study of Kim and colleagues25 (men) removed.9,10,25,28,48 The metaanalysis software rounded the decimal places. The triangle indicates the standard mean difference that cannot be plotted due to its scale. CI: Confidence interval. IV: Inverse variance. SD: Standard deviation.

Experimental Study or Subgroup

Total

Mean (SD)

Holmlund and Colleagues,

28

2007

17.7 (9)

10

2016

Kim and Colleagues,25 2016 (Men) 48

Musskopf, and Colleagues,

2017

Total

Standard Mean Difference Weight (%) IV, Random-Effects, 95% CI

219

20.7 (7.2)

728

20.0

–0.39 (–0.54 to –0.24)

27 (1.6)

304

27.3 (1.2)

892

20.1

–0.23 (–0.36 to –0.10)

20.9 (5.6)

336

21.8 (5.5)

424

20.1

–0.16 (–0.31 to –0.02)

23.7 (0.3)

522

24.1 (0.3)

989

20.2

–1.33 (–1.45 to –1.22)

18.7 (6.8)

199

22.2 (5.9)

164

19.7

–0.54 (–0.76 to –0.33)

3,197

100.0

–0.53 (–1.02 to –0.05)

Furuta and Colleagues,9 2016 Kaye and Colleagues,

Control Mean (SD)

1,580

Total (95% CI)

Heterogeneity: τ2 = 0.30; χ24 = 227.11, P < .00001; I2 = 98%

Standard Mean Difference IV, Random-Effects, 95% CI

–10

Test for overall effect: z = 2.14 (P = .03)

–5

0

Favors MetS+

5

10

Favors MetS–

E eFigure 1E. Forest plot for sensitivity analysis of the mean number of teeth with the study of Kim and colleagues25 (women) removed.9,10,25,28,48 The meta-analysis software rounded the decimal places. CI: Confidence interval. IV: Inverse variance. SD: Standard deviation.

Experimental Study or Subgroup

Total

Mean (SD) 28

Total

Standard Mean Difference Weight (%) IV, Random-Effects, 95% CI

219

20.7 (7.2)

728

20.0

–0.39 (–0.54 to –0.24)

27 (1.6)

304

27.3 (1.2)

892

20.0

–0.23 (–0.36 to –0.10)

Kaye and Colleagues,10 2016

20.9 (5.6)

336

21.8 (5.5)

424

20.0

–0.16 (–0.31 to –0.02)

Kim and Colleagues,25 2016 (Men)

23.7 (0.3)

522

24.1 (0.3)

989

20.0

–1.33 (–1.45 to –1.22)

21 (0.3)

907

24.5 (0.2)

1,171

19.9

–14.07 (–14.51 to –13.63)

4,204

100.0

–3.22 (–5.32 to –1.12)

Holmlund and Colleagues,

2007

17.7 (9)

Control Mean (SD)

Furuta and Colleagues,9 2016

25

Kim and Colleagues,

2016 (Women)

2,288

Total (95% CI) 2

Heterogeneity: τ = 5.72;

χ24

Standard Mean Difference IV, Random-Effects, 95% CI

2

= 3,790.80, P < .00001; I = 100%

Test for overall effect: z = 3.01 (P = .003)

–10

–5 Favors MetS+

0

5

10

Favors MetS–

F eFigure 1F. Forest plot for sensitivity analysis of the mean number of teeth with the study of Musskopf and colleagues48 removed.9,10,25,28 The metaanalysis software rounded the decimal places. The triangle indicates the standard mean difference that cannot be plotted due to its scale. CI: Confidence interval. IV: Inverse variance. SD: Standard deviation.

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Without MetS

With MetS Study or Subgroup

Mean (SD)

Furuta and Colleagues,9 2016 10

2016

Kaye and Colleagues,

25

2016 (Men)

25

2016 (Women)

Kim and Colleagues,

Kim and Colleagues,

Mean (SD)

Total

Total

Standard Mean Difference Weight (%) IV, Random-Effects, 95% CI

27 (1.6)

304

27.3 (1.2)

892

25.0

–0.23 (–0.36 to –0.10)

20.9 (5.6)

336

21.8 (5.5)

424

25.0

–0.16 (–0.31 to –0.02)

23.7 (0.3)

522

24.1 (0.3)

989

25.0

–1.33 (–1.45 to –1.22)

21 (0.3)

907

24.5 (0.2)

1,171

24.9

–14.07 (–14.51 to –13.63)

3,476

100.0

–3.93 (–6.66 to –1.21)

Total (95% CI)

2,069

Standard Mean Difference IV, Random-Effects, 95% CI

2 2 2 Heterogeneity: τ = 7.71; χ3 = 3,734.52, P < .00001; I = 100%

–10

Test for overall effect: z = 2.83 (P = .005)

–5

0

Favors MetS+

G

5

10

Favors MetS–

eFigure 1G. Forest plot for sensitivity analysis of the mean number of teeth including only studies9,10,25 that received scores of 7 or more on the Newcastle-Ottawa Scale.38 The meta-analysis software rounded the decimal places. The triangle indicates the standard mean difference that cannot be plotted due to its scale. The meta-analysis software rounded the decimal places. CI: Confidence interval. IV: Inverse variance. MetS: Metabolic syndrome. SD: Standard deviation.

With MetS Events Total

Study or Subgroup

Without MetS Events Total

Odds Ratio Weight (%) M-H, Random-Effects, 95% CI

Tsai and Colleagues,23 2015

382

1,603

703

5,077

32.5

Zhu and Hollis,29 2015

963

2,307

612

3,204

33.4

3.03 (2.69 to 3.42)

Shin,30 2017

754

3,314

881

8,817

34.1

2.65 (2.38 to 2.95)

17,098

100.0

2.51 (1.98 to 3.18)

Total (95% CI)

7,224

Total events

Odds Ratio M-H, Random-Effects, 95% CI

1.95 (1.69 to 2.24)

2,196

2,099

Heterogeneity: τ2 = 0.04; χ22 = 22.79, P < .00001; I2 = 91%

0.1

0.2

Test for overall effect: z = 7.59 (P < .00001)

0.5

1

Favors MetS+

2

5

10

Favors MetS–

A eFigure 2A. Forest plot for sensitivity analysis of the lack of functional dentition with the study of Ma and colleagues26 removed.23,29,30 The meta-analysis software rounded the decimal places. CI: Confidence interval. MetS: Metabolic syndrome. M-H: Mantel-Haenszel.

With MetS Study or Subgroup

Events

Tsai and Colleagues,23 2015 Zhu and Hollis,

29

2015

Ma and Colleagues,

26

Total

Without MetS Events

1,603

703

5,077

36.4

963

2,307

612

3,204

36.9

3.03 (2.69 to 3.42)

35

276

174

2,271

26.8

1.75 (1.19 to 2.58)

10,552

100.0

2.23 (1.55 to 3.20)

Total (95% CI)

4,186

Odds Ratio M-H, Random-Effects, 95% CI

Odds Ratio Weight (%) M-H, Random-Effects, 95% CI

382

2017

Total events

Total

1.95 (1.69 to 2.24)

1,489

1,380

Heterogeneity: τ2 = 0.09; χ22 = 25.39, P < .00001; I2 = 92%

0.1

0.2

Test for overall effect: z = 4.32 (P < .00001)

0.5

1

Favors MetS+

2

5

10

Favors MetS–

B eFigure 2B. Forest plot for sensitivity analysis of the lack of functional dentition with the study of Shin30 removed.23,26,29 The meta-analysis software rounded the decimal places. CI: Confidence interval. MetS: Metabolic syndrome. M-H: Mantel-Haenszel.

With MetS Events Total

Study or Subgroup Zhu and Hollis,

29

2015 26

Ma and Colleagues, Shin,30 2017

2017

2,307

612

3,204

41.2

3.03 (2.69 to 3.42)

35

276

174

2,271

16.1

1.75 (1.19 to 2.58)

754

3,314

881

5,897 1,752

Heterogeneity: τ2 = 0.02; χ22 = 8.23, P = .02; I2 = 76%

Odds Ratio M-H, Random-Effects, 95% CI

Odds Ratio Weight (%) M-H, Random-Effects, 95% CI

963

Total (95% CI) Total events

Without MetS Total Events

8,817

42.7

2.65 (2.38 to 2.95)

14,292

100.0

2.62 (2.17 to 3.17)

1,667 0.1

0.2

Test for overall effect: z = 10.00 (P < .00001)

0.5 Favors MetS+

1

2

5

10

Favors MetS–

C eFigure 2C. Forest plot for sensitivity analysis of the lack of functional dentition with the study of Tsai and colleagues23 removed.26,29,30 The metaanalysis software rounded the decimal places. CI: Confidence interval. MetS: Metabolic syndrome. M-H: Mantel-Haenszel.

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With MetS Events Total

Study or Subgroup Tsai and Colleagues, Ma and Colleagues,

23

26

Without MetS Total Events

2015

382

1,603

703

5,077

38.0

1.95 (1.69 to 2.24)

2017

35

276

174

2,271

22.2

1.75 (1.19 to 2.58)

754

3,314

881

8,817

39.8

2.65 (2.38 to 2.95)

16,165

100.0

2.15 (1.65 to 2.80)

Shin,30 2017 Total (95% CI)

5,193

Total events

Odds Ratio M-H, Random-Effects, 95% CI

Odds Ratio Weight (%) M-H, Random-Effects, 95% CI

1,758

1,171

Heterogeneity: τ2 = 0.04; χ22 = 14.12, P = .0009; I2 = 86%

0.1

0.2

Test for overall effect: z = 5.70 (P < .00001)

0.5

1

Favors MetS+

2

5

10

Favors MetS–

D eFigure 2D. Forest plot for sensitivity analysis of the lack of functional dentition with the study of Zhu and Hollis29 removed.23,26,30 The meta-analysis software rounded the decimal places. CI: Confidence interval. MetS: Metabolic syndrome. M-H: Mantel-Haenszel.

Study or Subgroup

With MetS Events Total

Without MetS Total Events

Odds Ratio Weight (%) M-H, Random-Effects, 95% CI

Zhu and Hollis,29 2015

963

2,307

612

3,204

47.7

3.03 (2.69 to 3.42)

Shin,30 2017

754

3,314

881

8,817

52.3

2.65 (2.38 to 2.95)

12,021

100.0

2.83 (2.48 to 3.23)

Total (95% CI)

5,621

Total events

Odds Ratio M-H, Random-Effects, 95% CI

1,493

1,717

Heterogeneity: τ2 = 0.01; χ21 = 2.67, P = .10; I2 = 63%

0.1

Test for overall effect: z = 15.48 (P < .00001)

0.2

0.5 Favors MetS+

E

1

2

5

10

Favors MetS–

eFigure 2E. Forest plot for sensitivity analysis of the lack of functional dentition including only studies29,30 that received scores of 7 or more on the Newcastle-Ottawa Scale.38 The meta-analysis software rounded the decimal places. CI: Confidence interval. MetS: Metabolic syndrome. M-H: MantelHaenszel.

e1. Johansson I, Tidehag P, Lundberg V, Hallmans G. Dental status, diet and cardiovascular risk factors in middle-aged people in northern Sweden. Community Dent Oral Epidemiol. 1994;22(6):431-436. e2. Desvarieux M, Demmer RT, Rundek T, et al. Relationship between periodontal disease, tooth loss, and carotid artery plaque: the oral infections and vascular disease epidemiology study (INVEST). Stroke. 2003; 34(9):2120-2125. e3. Taguchi A, Sanada M, Suei Y, et al. Tooth loss is associated with an increased risk of hypertension in postmenopausal women. Hypertension. 2004;43(6):12971300. e4. Okoro CA, Balluz LS, Eke PI, et al. Tooth loss and heart disease: findings from the Behavioral Risk Factor Surveillance System. Am J Prev Med. 2005;29(5):50-56. e5. Borges PK, Gimeno SG, Tomita NE, Ferreira SR. Prevalence and characteristics associated with metabolic syndrome in Japanese-Brazilians with and without periodontal disease [in Portuguese]. Cad Saude Publica. 2007; 23(3):657-668. e6. Dietrich T, Jimenez M, Krall Kaye EA, Vokonas PS, Garcia RI. Age-dependent associations between chronic periodontitis/edentulism and risk of coronary heart disease. Circulation. 2008;117(13):1668-1674. e7. Heitmann BL, Gamborg M. Remaining teeth, cardiovascular morbidity and death among adult Danes. Prev Med. 2008;47(2):156-160. e8. Kushiyama M, Shimazaki Y, Yamashita Y. Relationship between metabolic syndrome and periodontal disease in Japanese adults. J Periodontol. 2009;80(10): 1610-1615. e9. Morita T, Ogawa Y, Takada K, et al. Association between periodontal disease and metabolic syndrome. J Public Health Dent. 2009;69(4):248-253. e10. Rodrigues DCO. Periodontite Severa Como um Indicador Para Diagnóstico Precoce de Síndrome Metabólica [dissertation]. Rio de Janeiro, Brazil: Universidade do Estado do Rio de Janeiro; 2010. Available at: http://www. bdtd.uerj.br/tde_busca/arquivo.php?codArquivo¼2464. Accessed August 13, 2019.

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e11. Lee HK, Lee KD, Merchant AT, et al. More missing teeth are associated with poorer general health in the rural Korean elderly. Arch Gerontol Geriatr. 2010; 50(1):30-33. e12. Morita T, Yamazaki Y, Mita A, et al. A cohort study on the association between periodontal disease and the development of metabolic syndrome. J Periodontol. 2010;81(4):512-519. e13. Syrjala AM, Ylostalo P, Hartikainen S, Sulkava R, Knuuttila M. Number of teeth and selected cardiovascular risk factors among elderly people. Gerodontology. 2010; 27(3):189-192. 44. Timonen P, Niskanen M, Suominen-Taipale L, Jula A, Knuuttila M, Ylöstalo P. Metabolic syndrome, periodontal infection, and dental caries. J Dent Res. 2010; 89(10):1068-1073. e14. Nicolosi LN, Lewin PG, Gonzalez N, Jara L, Rubio Mdel C. Association between oral health and acute coronary syndrome in elderly people. Acta Odontol Latinoam. 2011;24(3):229-234. 45. Fukui N, Shimazaki Y, Shinagawa T, Yamashita Y. Periodontal status and metabolic syndrome in middleaged Japanese. J Periodontol. 2012;83(11):1363-1371. e15. Holmlund A, Lind L. Number of teeth is related to atherosclerotic plaque in the carotid arteries in an elderly population. J Periodontol. 2012;83(3):287-291. e16. Cinar AB, Oktay I, Schou L. Relationship between oral health, diabetes management and sleep apnea. Clin Oral Investig. 2013;17(3):967-974. e17. Furuta M, Shimazaki Y, Takeshita T, et al. Gender differences in the association between metabolic syndrome and periodontal disease: the Hisayama study. J Clin Periodontol. 2013;40(8):743-752. e18. Tu Y, D’aiuto F, Lin H, Chen Y, Chien K. Relationship between metabolic syndrome and diagnoses of periodontal diseases among participants in a large Taiwanese cohort. J Clin Periodontol. 2013;40(11):994-1000. e19. Del Brutto OH, Mera RM, Del Brutto VJ, Zambrano M, Montenegro JE, Castillo PR. Edentulism associates with poor cardiovascular health: results from the Atahualpa Project. Int J Cardiol. 2014;176(3):1013-1014.

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e20. LaMonte MJ, Williams AM, Genco RJ, et al. Association between metabolic syndrome and periodontal disease measures in postmenopausal women: the Buffalo OsteoPerio study. J Periodontol. 2014;85(11):14891501. e21. Lee KS, Kim EK, Kim JW, et al. The relationship between metabolic conditions and prevalence of periodontal disease in rural Korean elderly. Arch Gerontol Geriatr. 2014;58(1):125-129. e22. Lim SG, Han K, Kim H, et al. Association between insulin resistance and periodontitis in Korean adults. J Clin Periodontol. 2014;41(2):121-130. e23. Meisel P, Holtfreter B, Volzke H, Kocher T. Sex differences of tooth loss and obesity on systemic markers of inflammation. J Dent Res. 2014;93(8):774779. 46. Thanakun S, Watanabe H, Thaweboon S, Izumi Y. Association of untreated metabolic syndrome with moderate to severe periodontitis in Thai population. J Periodontol. 2014;85(11):1502-1514. e24. Minagawa K, Iwasaki M, Ogawa H, Yoshihara A, Miyazaki H. Relationship between metabolic syndrome and periodontitis in 80-year-old Japanese subjects. J Periodontal Res. 2015;50(2):173-179. 47. Ojima M, Amano A, Kurata S. Relationship between decayed teeth and metabolic syndrome: data from 4716 middle-aged male Japanese employees. J Epidemiol. 2015;25(3):204-211. e25. Kawashita Y, Kitamura M, Ando Y, Saito T. Relationship between metabolic syndrome and number of teeth in Japan. JDR Clin Trans Res. 2017;2(1):87-92. 13. Lamster IB, Pagan M. Periodontal disease and the metabolic syndrome. Int Dent J. 2017;67(2):67-77. e26. Song IS, Han K, Ryu JJ, Choi YJ, Park JB. Coffee intake as a risk indicator for tooth loss in Korean adults. Sci Rep. 2018;8:2392. e27. Han K, Park JB. Evaluation of the association between sleep duration and tooth loss among Korean adults: data from the Korean National Health and Nutrition Examination Survey (KNHANES 2012-2014). BMJ Open. 2018;8(5):e018383.

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eTable 1. Risk of bias assessment according to the Newcastle-Ottawa Scale.* STUDY Holmlund and Colleagues,28 2007 Hyvärinen and Colleagues, Kang,

24

SELECTION†

COMPARABILITY†

OUTCOME†

Cross-sectional

2

2

1

Cross-sectional

2

2

2

Cross-sectional

2

2

2

STUDY DESIGN

27

2015

2015

Kang and Yul,

39

Cross-sectional

2

2

2

Tsai and Colleagues,23 2015

2015

Cross-sectional

2

2

2

Zhu and Hollis,29 2015

Cross-sectional

3

2

2

Furuta and Colleagues, 2016

Cohort

3

2

3

Kaye and Colleagues,10 2016

Cohort

3

2

3

Cross-sectional

3

2

2

Cross-sectional

2

2

2

9

Kim and Colleagues, Ma and Colleagues,

25

26

2016 2017

Musskopf, and Colleagues,

48

2017

Shin,30 2017

Cross-sectional

2

2

2

Cross-sectional

3

2

2

* Source: Wells and colleagues.38 † Scale of cohort studies ranges between 0 and 9 stars: maximum of 4 stars for selection, 2 for comparability, and 3 for outcome. Scale of cross-sectional studies ranges between 0 and 7 stars: maximum of 3 stars for selection, 2 for comparability, and 2 for outcome. The number of stars is indicated by the numbers in the table.

eTable 2. GRADE* summary-of-findings table.† OUTCOME

NO. OF PARTICIPANTS (NO. OF STUDIES)

CERTAINTY OF THE EVIDENCE (GRADE)

RELATIVE EFFECT (95% CI)‡

ANTICIPATED ABSOLUTE EFFECTS Risk With No MetS§

Very Low{,#

Mean Number of Teeth

6,855 (5 observational studies)

Lack of Functional Dentition

26,869 (4 observational studies) Very Low{,#

Not applicable Odds ratio, 2.37 (1.89 to 2.96)

Not applicable 122 per 1,000

Risk Difference With MetS Standardized mean difference 2.77 fewer (4.56-0.98 fewer) 126 more per 1,000 (86-170 more)

* GRADE: Grading of Recommendations Assessment, Development and Evaluation. The GRADE Working Group41 grades of evidence are high certainty: very confident that the true effect lies close to that of the estimate of the effect; moderate certainty: moderately confident in the effect estimate, the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; low certainty: confidence in the effect estimate is limited, the true effect may be substantially different from the estimate of the effect; very low certainty: very little confidence in the effect estimate, the true effect is likely to be substantially different from the estimate of effect. † Prepared using software (GRADEpro, McMaster University). ‡ CI: Confidence interval. The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). § MetS: Metabolic syndrome. { Selection bias. # High heterogeneity.

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