Systemic benefits of periodontal therapy in patients with obesity and periodontitis: a systematic review

Abstract This systematic review aimed to answer the focused question: “What are the benefits of subgingival periodontal therapy on blood hematological and biochemical index, biomarkers of inflammation and oxidative stress, quality of life, and periodontal pathogen counts in patients with obesity and periodontitis?”. A systematic literature search was performed in six databases: PubMed, Embase, LILACS, Web of Science, Cochrane and SCOPUS and other sources, and a manual search was conducted as well. Inclusion criteria were randomized and non-randomized clinical trials, and before-and-after studies on patients with obesity subjected to periodontal therapy. The results were synthesized qualitatively. Risk of bias within studies was assessed using RoB 2 and ROBINS-I tools. The certainty of evidence was evaluated following the GRADE approach. Three randomized controlled trials and 15 before-and-after studies were included. Randomized controlled trials were considered to have a low risk of bias, as compared to before-and-after studies assessed as having low, serious, and critical risks of bias. Non-surgical periodontal therapy plus azithromycin, chlorhexidine, and cetylpyridinium chloride reduced blood pressure and decreased serum levels of HbA1c, hsCRP, IL-1β, and TNF-α. Salivary resistin level also decreased in patients with obesity and periodontitis after therapy and chlorhexidine mouth rinse. Before-and-after data suggest an improvement in total cholesterol, LDL, triglycerides, insulin resistance, C3, GCF levels of TNF-α, chemerin, vaspin, omentin-1, visfatin, 8-OHdG, and periodontal pathogen counts after therapy.


Introduction
Obesity is known as body mass index (BMI) ≥ 30.0 kg/m 2 , indicating excessive accumulation of fat, which can impair health.2][3] Adipose tissue is a metabolically active endocrine organ 4 responsible for the increase in serum levels of adipokines in obesity.It is associated with dysregulation of the immunoinflammatory response and endocrine function, hormonal and metabolic disorders, increased susceptibility to infections, hyperinflammatory state, and impaired wound healing.Both obesity and periodontal disease are low-intensity, long-lasting chronic inflammatory diseases, regarded as chronic non-communicable diseases, which share a multifactorial relationship and comorbidities. 5,6 he i nterac t ion b e t we e n bac ter i a l load and host response links periodontitis to DM, cardiovascular 7,8 and kidney diseases, 9 preterm birth, and low birth weight newborn babies. 10Although its pathophysiological mechanism is unknown, studies have suggested that obesity may be a risk factor for periodontitis, 11,12 as first proposed by Perlstein & Bissada. 13Some studies propose that the high levels of circulating proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) in patients with obesity may increase periodontal destruction. 14,15Systematic reviews have evaluated the effect of obesity on non-surgical periodontal therapy (NSPT) 16 and on periodontal and immunological parameters in patients with obesity, compared to those without obesity. 2,17,18Even though periodontal therapy (PT) is associated with reduced periodontal and systemic inflammation in patients with periodontitis and non-communicable diseases with a chronic inflammatory course, 19 one question remains: Is there evidence that subgingival PT offers systemic benefits for patients with obesity?Accordingly, this review aims to answer the focused question: "What are the benefits of periodontal therapy on blood hematological and biochemical index, biomarkers of inflammation and oxidative stress, quality of life, and periodontal pathogen counts in patients with obesity and periodontitis?"

Protocol and registration
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 20 .The qualitative synthesis of results followed the SWiM reporting guideline. 21isk of bias within studies were assessed using "Revised Cochrane risk-of-bias tool for randomized trials" (RoB 2), and non-randomized studies of intervention "Risk Of Bias In Non-randomized Studies -of Interventions" (ROBINS-I) tool for (uncontrolled) before-and-after studies.The certainty of evidence was evaluated following the GRADE approach, 22,23 adapting all the judgments to qualify the evidence in a narrative way.24 The review protocol was registered in the PROSPERO (CRD42021241653).

Search strategy
PubMed, EMBASE, LILACS, Web of Science, Cochrane and SCOPUS databases were systematically searched using the following heading terms: (obesity AND (periodontal diseases OR periodontitis)) AND (root planing OR periodontal therapy OR periodontal treatment OR scaling and root planing).Furthermore, other sources were searched: Google Schoolar, OpenGrey, ClinicalTrials.govand ReBEC.

Focused question
Based on the PICO principle-Population: patients with obesity and periodontitis, regardless of age, sex and race; Intervention: periodontal therapy with subgingival approach; Control: no periodontal treatment or supragingival periodontal treatment (without subgingival approach); Outcomes: blood hematological and biochemical index, biomarkers of inflammation and oxidative stress on serum, saliva and g i ng ival crevicular f luid (GCF), quality of life, periodontopathogen counts and adverse effects.

Study selection criteria
• Inclusion criteria: i-randomized controlled trials (RCTs), non-randomized controlled clinical trials (CCTs) and before-and-after (prepost) data (BAS) from groups of patients with obesity and periodontitis from clinical trials: ii-studies that evaluated the systemic effect (on serum, saliva and/or gingival crevicular fluid [GCF]) of therapeutic interventions for periodontitis in patients with obesity, with at least a 3-month follow-up; and iii-outcomes of interest.• Exclusion criteria: i-pilot studies; ii-no description of the periodontitis diagnostic criteria used; iii-participants with congenital syndrome (e.g., Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, Stickler syndrome, osteogenesis imperfecta, Papillon-Lefevre syndrome, among others.);iv-unavailability of full paper copy; v-trials in which no confirmation or diagnostic criteria for obesity and/or periodontitis were reported and could not be retrieved after contacting the original authors; and vitrials in which outcomes of interest were not available for analysis and the original values could not be retrieved after contacting the original authors.
• No data or language restrictions were applied.

Data items and synthesis
Data were independently extracted by two reviewers (blinded process) using a standardized sh e e t, a s r e com me nde d b y t h e Co c h ra n e Collaboration's handbook for systematic review.From the selected articles the following data were extracted: author, country and year; participant's demographic profile; smoking; alcohol consumption; systemic conditions/diseases, periodontal diagnosis; obesity diagnosis; periods of data collection; characteristics of periodontal inter vention; comparison groups; blood hematological and biochemical index; biomarkers of inflammation and oxidative stress; quality of life; study duration (follow-up); periodontal pathogens count and     adverse effects.The synthesis of qualitative results followed the SWiM reporting guideline 21 .

Risk of bias within studies
The evaluation of quality and risk of bias in clinical studies was performed by two authors independently, using specific risk of bias and methodological quality assessment tools for randomized controlled trials-Figure 4A and 4B.

Certainty of evidence assessment
The certainty of evidence was evaluated following the GRADE approach 22,23 , adapting all the judgments to qualify the evidence in a narrative way 24 .Thus, the evidence quality index is defined in four categories: high, moderate, low, and very low applied to each of the evaluated outcomes 22,23 .

Study selection
A total of 763 records were retrieved from the following databases: PubMed (n = 86), Web of Science (n = 101), Cochrane Library (n = 31), Embase (n = 193), Scopus (n = 341), and LILACS (n = 10).After removing 390 duplicates, 345 reports were excluded according to the eligibility criteria, and 28 were selected for full-text reading.Four reports were excluded because of the study design, 25,26,27,28 five because the obesity group included non-obesity, 29,30,31,32,33 and one because periodontitis diagnostic criteria were not reported 34 (Fig. 1).No records were included from the other sources because of subject or duplicity.
A total of 634 patients with obesity and periodontitis were considered for analysis, among whom 187 were from RCTs and 447 from BAS.The diagnostic criteria for obesity and periodontitis varied between studies, as reported in Table 1 and Figures 2 and 3.The distribution of smokers in the control group (CG) and intervention group (IG) did not differ between the three RCTs. 4,35,36Akram et al. 4 controlled statistical analyses for the assessment of smoking and Montero et al. 36 reported adjusted p-values for this variable.

Results of individual studies
Individual descriptive data from included studies are presented in Table 2 for RCT outcomes, and Table 3 for BAS outcomes.

RCT studies
The clinical approach performed in RCT studies were NSPT plus antibiotic therapy, 36 and NSPT in the IG and no-PT in the CG 4,35 .Two studies 4,35 used 0.12% chlorhexidine, and one 36 study used 0.12% chlorhexidine and 0.05% cetylpyridinium chloride twice daily for 14 days post-therapy.

Adipokines
In the study by Akram et al., 4 the mean resistin level differed between the CG and IG (14.25 ± 4.58 ng/mL and 12.26 ± 1.24 ng/mL, respectively; p < 0.05).There was a significant reduction in resistin after NSPT (p < 0.05) in the IG but not in the CG (mean difference 0.65 ± 1.24 ng/mL and 0.78 ± 4.08 ng/mL, respectively) -logistic regression analysis revealed that change in salivary resistin level was not significantly associated with improvement in probing depth (PD) or clinical attachment level (CAL), even after smoking control (p > 0.05).According to the authors, resistin level did not differ between the CG and IG at the 12-week follow-up.

Quality of life
Basher et al. 35 reported a decrease in Oral Health Impact Profile-14 (OHIP-14) PI and OHIP-14 EI

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and an increase in OHIP-14 SS over time in both groups (p < 0.05).The mean OHIP-14 EI at 12 weeks post-NSPT decreased in both CG and IG at 0.65 (1.02%) and 0.47 (0.91%), respectively.Only "bad breath" (functional limitation domain) and "food impaction" (psychological discomfort domain) were significantly reduced (p < 0.05). 35According to the authors, quality of life did not differ between the CG and IG.
Subset analysis -non-surgical periodontal therapy plus antibiotic therapy Montero et al. 36 performed a study associating NSPT with antibiotic therapy.The test group (IG) received an intensive periodontal treatment with two sessions of non-surgical subgingival instrumentation and administration of azithromycin 500 mg q.d. for three days, administered during the last NSPT session.The control group (CG) received minimal periodontal treatment, which consisted of two sessions of supragingival plaque and calculus mechanical removal and administration of placebo medication for 3 days.Both groups received an antiseptic mouth rinse containing 0.12% chlorhexidine and 0.05% cetylpyridinium chloride and oral hygiene instructions.

Hematological and biochemical index
Three months after NSPT, glycated hemoglobin (HbA1c) decreased in the IG compared with CG -difference adjusted for covariates, 0.3% (95%CI: 0.1-0.6;p = 0.013).The proportion of patients with HbA1c ≥ 7% decreased significantly in the IG, from 31.25% at baseline to 18.8% at 3 months of follow-up (p = 0.028), with no changes in the CG (post-hoc analyses); no differences between the two groups were observed six months after NSPT.The multilevel linear regression determined that the variance in HbA1c was only predicted by being in the IG (p = 0.013) and by the baseline HbA1c percentage (p < 0.001), without any significant additional effect in the model for age, sex, BMI, or smoking status.In addition, no differences between the CG and the IG were observed for white blood cell count, fibrinogen, and α-1 antitrypsin at any time point after therapy. 36he authors 36 reported a decrease in the mean highsensitive C-reactive protein (hsCRP) concentration after three and six months in the IG, but not in the CG.The difference between groups, adjusted for age, sex, smoking, baseline BMI, and hsCRP was 1.4 mg/L (95%CI: 0.5-2.2;p = 0.001) at three months and 1.2 mg/L (95%CI: 0.4-2.0;p = 0.004) at 6 months of follow-up.The odds ratio for IG versus CG from an hsCRP value ≥ 3 to < 3mg/L was 5.4 (95%CI: 1.0-31.6;p = 0.040).68.8% of patients in the IG experienced a reduction in hsCRP levels within 6 months of follow-up, while this percentage was 29% in the CG (p < 0.001).The NSPT led to a 30.8% reduction in hsCRP from baseline and a difference of 1.2 mg/L at 6 months of follow-up compared to the CG.Improvements in periodontal health, despite actively following strict cardiovascular risk reduction protocols, significantly improved hsCRP levels and cardiovascular risk.In the multilevel linear regression, baseline hsCRP levels (p < 0.001) and smoking (p = 0.014) significantly and independently predicted the variance of hsCRP decline over six months in the IG.

Cytokines
Montero et al. 36 also reported a significant decrease in IL-1β and TNF-α at 3 months of follow-up in the IG compared with the CG.However, no differences between the groups were observed for these biomarkers at 6 months of follow-up, or for IL-6 and IL-8 at any time point after therapy.

Microbiological evaluation
The authors 36 reported counts of anaerobic bacteria and high proportions and counts of Porphyromonas gingivalis (Pg) in all patients at baseline.The NSPT significantly reduced both the counts of anaerobic bacteria and Pg, and this microbiological impact was associated with significant reductions in hsCRP.

BAS studies Hematological and biochemical index
T he r e wa s sig n i f ic a nt i mproveme nt i n anthropometric and metabolic parameters and C3 (immunity) 12 weeks after NSPT in the obesity diet group (p < 0.05). 46Altay et al. 37 reported a significant reduction in serum levels of HOMA-IR score and Martínez-Herrera et al. 46 reported a significant decrease in RBP4 three months after NSPT.
Al Zahrani et al. 11 reported a mean difference in hsCRP of 0.19 ± 0.32 (p = 0.015).According to Zuza et al., 44 patients with obesity and periodontitis who received basic PT exhibited significant reduction in the serological levels of total cholesterol, low-density lipoprotein, triglycerides, and hsCRP 90 days after NSPT.In contrast, Altay et al., 37 Taşdemir et al., 43 and Martínez-Herrera et al. 46,47 reported a non-significant reduction in hsCRP after NSPT.

Cytokines
Altay et al., 37 Taşdemir et al., 43 and Martínez-Herrera et al. 46,47 reported a decrease in serum TNF-a levels after NSPT.Balli et al. 41 reported the same result for GCF.According to Gonçalves et al., 39 concentrations of TNF-a and leptin increased in shallow and deep sites of patients with obesity at 6and 12 months of follow-up compared to baseline (p < 0.05).There were no statistically significant A B changes in the GCF levels of IL-6 and resistin, and in the serum levels of any adipokines at any time point after therapy.In contrast, Çetiner et al. 45 did not observe a significant decrease in TNF-α in the GCF after NSPT.Furthermore, serum PTX-3 levels were not significantly reduced after NSPT. 43even studies evaluated the concentration of IL-6 in serum 37,43,45,46,47 and in the GCF. 38,39,40Only two studies (2:5 ratio, 28.57%) reported significant reductions in serum and GCF IL-6 37,40 (respectively).

Adipokines
Altay et al. 37 reported a reduction in serum leptin levels after NSPT, but Gonçalves et al. 38 reported no changes in serum leptin levels three and six months after NSPT.Periodontal therapy reduced the GCF levels of chemerin, vaspin, omentin-1, and visfatin in the GCF 40,41,45 and increased leptin levels in the shallow and deep sites 12 months after therapy, compared to baseline 39 (p < 0.05).There were no statistically significant changes in the serum and GCF levels of resistin and adiponectin at any time point after NSPT. 38,39,49idative stress Levels of 8-OHdG in plasma, saliva, and GCF significantly decreased after NSPT (p < 0.01). 42

Microbiological evaluation
Within nine months, Pg and Aggregatibacter actinomycetemcomitans (Aa) significantly decreased. 48mall counts of Tannerella forsythia (Tf) were observed only at 3 months of follow-up; however, reductions in Tf count were not maintained at 9 months of follow-up.NSPT also reduced Treponema denticola (Td) count (p < 0.05).In contrast, Md Tahir et al. 49 reported no significant changes in mean Pg and Tf counts at 12 weeks of follow-up.According to the authors, the mean Prevotella intermedia (Pi) count decreased by almost half 12 weeks after NSPT.

Quality of life
OHRQoL (oral health-related quality of life) increased and OIDP (oral impact on daily performance) decreased six months after NSPT (p < 0.05).Regarding OIDP, pain, discomfort, and functional limitation significantly improved at 6 months of follow-up.The prevalence of oral impacts on activities of daily living, such as eating and enjoying food and cleaning teeth, significantly decreased six months after NSPT. 50

Risk of bias in studies
All RCTs included in this review were considered to have a low risk of bias 4,35,36 (Figure 4A).Nine BAS studies were classified as low risk of bias. 11,38,39,40,41,42,43,44,45onfounding and missing data domains accounted for the low methodological quality of the BAS studies [serious risk of bias 37,46,47,50 and critical risk of bias 48,49 (Figure 4B)].

Certainty of evidence
Regardless of the variation in the approach of the applied intervention, outcome assessed, type of sample, and evaluation time, the overall certainty of the evidence ranged from moderate (evidence from RCT) to low or very low (evidence from BAS studies).Evidence from RCT was seriously affected by the imprecision item due to the small number of individuals included in the syntheses.It is important to mention that some aspects such as the precision of the estimates and consistency of the results could not be evaluated because a meta-analysis was not performed and the syntheses for all outcomes always included a single RCT, respectively.On the other hand, evidence from BAS studies was seriously or very seriously affected by the risk of bias item, seriously affected by the inconsistency item in most of the syntheses that included more than one study, and seriously affected by the imprecision item due to the insufficient number of participants evaluated.

Discussion
Recognizing the limited number of studies on the subject and analyzing the results of this study with caution, the available data support at least moderate evidence on the benefits of NSPT for cardiometabolic, inflammatory, and microbiological parameters in patients with obesity and periodontitis, based on RCT studies.As expected, the certainty of evidence from BAS studies was limited by the study design.Pre-post analysis showed local, systemic, and quality of life improvement after subgingival instrumentation of periodontal pockets, corroborating the findings of RCT studies.
Periodontitis, as an inflammatory disease, is linked to non-communicable chronic diseases, such as obesity.A possible mechanism that contributes to this relationship may be the low-grade systemic inflammation caused by periodontitis, which is common in many chronic conditions.In contrast, systemic diseases also affect periodontitis. 52SPT can significantly reduce several biochemical markers of obesity and provide periodontal clinical improvements, but these are smaller than in nonobese individuals. 53he significant reduction in SBP and DBP three months after effective PT 36 corroborated the metaanalysis by Muñoz Aguilera et al. 54 Law et al. 55 associated PT with 10-mmHg reduction in SBP or a 5-mmHg reduction in DBP, and 25% to 30% reduction of cardiovascular events.This can be considered a significant benefit, especially due to suboptimal adherence to pharmacotherapy for hypertension. 56,57,58,59The serum levels of total cholesterol, LDL, and triglycerides also improved after NSPT, compared to baseline. 44Periodontal therapy was effective in reducing HbA1c and blood pressure at 3 months of follow-up, suggesting early benefits of periodontitis treatment for metabolic control and vascular function. 36,60,61The lack of repeated periodontal interventions during the study 36 appears to explain the late reversal of HbA1c improvement. 62,63on-surgical periodontal therapy led to a 30.8% decrease in hsCRP from baseline values and showed a difference of 1.2 mg/L at 6 months of follow-up compared with the CG, 36 reducing cardiovascular risk. 64,65On the other hand, the results from the PAVE study suggest that PT is not able to maintain the reduction of serum hsCRP levels at 6 months of follow-up. 66In addition, BAS studies showed significant 11,44 or non-significant 37,43,46,47 reduction in serum hsCRP levels after NSPT.
Most studies address the effects of obesity on the periodontium, 4,12,67,68 but the literature remains scarce on the benefits of periodontitis therapy for patients with obesity.One RCT reported a significant decrease in serum levels of IL-1β and TNF-α at 3 months of follow-up in the IG, and no difference for IL-1β, IL-6, IL-8, and TNF-α six months after PT. 36 The BAS analyses showed a decrease in TNF-α levels in both serum and GCF matrices. 37,41,43,46,47Contrasting results such as no significant change in GCF levels of IL-6, TNF-α, and resistin, and in the serum levels of any adipokines at any time point after therapy, 39,43,45 reinforce the need for more RCTs on the subject.
NSPT improved the circulating levels of proinflammatory cytokines and C3 and insulin resistance, compared to baseline. 37,46According to Akram et al., 69 GCF may be more sensitive than saliva to detect changes in cytokine levels caused by local inflammation.The authors reported a significant reduction in resistin after NSPT in the IG but not in the CG -this result was not correlated with improvement in PD or CAL, probably because only shallow and moderate sites improved and there were higher resistin levels in the CG than in the IG at baseline, thus introducing a risk of bias.Despite the inclusion of smokers is considered an important potential confounding factor, [70][71][72] there was no significant impact on periodontal outcomes in the study by Akram et al. 69 Other studies have associated NSPT with decreased levels of resistin in the saliva, suggesting the need for further studies on this biomarker. 67,73ncreased inflammatory factors, disturbances in glycolipid metabolism, and adipokine overexpression in obesity can be worsened by periodontitis. 74Although serum and GCF concentrations of leptin, adiponectin, and oxidative stress biomarkers remain uncertain and underexplored in the obesity-periodontitis scenario, chemerin, vaspin, omentin-1, and visfatin in GCF improved after NSPT. 40,41,45In the study by Öngöz Dede et al., 42 8-OHdG, a powerful periodontal disease marker, 75 significantly decreased in plasma, saliva, and GCF after NSPT.
7][78][79][80][81][82][83][84] Subcutaneous and visceral adiposity, CRP, and IL-6 also represent a risk for type 2 DM. 85,86eople with obesity have higher rates of periodontal pathogens and an increased risk of progressive attachment loss than normal-weight individuals. 87ean Pg, Tf, and Pi counts can be reduced by 7% to 45% 12 weeks after periodontitis therapy 88,89 and ranged from 18% to 99% after NSPT in patients with DM. 90,91 Periodontal therapy appears to reduce Pg, Pi, Aa, Tf, and Td counts for three months, 48,49 although Md Tahir et al. 49 reported no significant changes in mean Pg and Tf counts at 12 weeks of follow-up.Diagnostic criteria for periodontitis, the full-mouth disinfection protocol, 92,93 and the periodontal maintenance phase [94][95][96] adopted by Peralta et al. 48may explain this divergence.The SRP strategy with and without chlorhexidine should not respond to this difference, 97,98 although the difference between the response to one-stage full-mouth therapy and quadrant-by-quadrant root planing could be expected. 99Montero et al. 36 adopted azithromycin as an adjuvant antibiotic for NSPT and used 0.12% chlorhexidine and 0.05% cetylpyridinium chloride twice daily for 14 days post-therapy.The authors reported a decrease in anaerobic bacteria and Pg counts after PT and associated this result with significant reductions in hsCRP.
In our inclusion criteria, we accepted all types of treatment with a subgingival approach, including adjunctive antimicrobials, photodynamic therapy, laser therapy, and surgical treatment.
The results presented by Monteiro et al 36 , whose study used antibiotics, demonstrated improvement in parameters related to hsPCR, IL-1β, TNF-α, and P. gingivalis count.These results were similar to those found in the BAS studies reported by Zuza et al., 44 Altay et al., 37 Tasdemir et al., 43 Martin-Herrera et al., 46,47 and Md Tahir et al., 49 which did not use antibiotics.Therefore, there was no advantage in these results when compared with the other studies included in this review.Regarding the other parameters evaluated in the study by Monteiro et al., 36 there was no difference between the control and test groups.Adjuvant antibiotic therapy does not seem to have caused significant changes when compared with studies that did not use such therapy.
Interestingly, the immunomodulatory properties of azithromycin for the levels of cytokines and chemokines should be considered confounding factors by the author. 100Macrolides decrease the formation of proinflammatory cytokines, adhesion molecules, reaction to chemoattractants, oxidative burst, and adaptive immunity, and promote the release of antiinflammatory cytokines, neutrophil apoptosis, and neutrophil degranulation. 100,1013][104][105][106][107] Therefore, the cardiovascular effect reported by Montero et al. 36 could be attributed to antibiotics rather than to PT.In addition, although hCRP is a surrogate biomarker for cardiovascular risk, 108,109 its predictive value may be limited. 110ommensal microbiota and complement are both necessary for Pg-induced bone loss, as confirmed in germ-free or C3a-and C5a receptor-deficient mice inoculated with Pg.Regarding the pathogenicity of key species in periodontitis, Pg was able to subvert complement receptor 3 and anaphylatoxin C5a receptor signaling.Even a single low-abundance species can disrupt homeostasis, leading to dysbiosis, inflammatory events, and disease.2][113] The improvement in Pg counts and serum levels of C3 reported in the studies may be correlated.
The slow and progressive nature of chronic periodontitis allows the patient to adapt to clinical symptoms and seek dental care later.Therefore, limited perception of patients to recognize chronic periodontitis as a condition may affect the OHRQoLmultidimensional construct that includes a subjective evaluation of the individual's oral health, functional well-being, emotional well-being, expectations, and satisfaction with care and sense of self. 35,114The effects of PT on quality of life were inconclusive due to the limited number of studies and the subjectivity of the method.
The present systematic review has several limitations, and the results must be interpreted with caution.The included studies used different criteria to define periodontitis and obesity, different periodontal therapy protocols, periodontal maintenance phase, objects of investigation, and low number of included participants.

References
To strengthen the quality of this systematic review, no restrictions were applied to databases, records, and other sources in the screening process.The search and selection of articles, data collection, and synthesis were performed independently by two researchers and a validated quality assessment tool was used.The certainty of evidence was also evaluated following the GRADE approach.Publication bias cannot be excluded, as studies with positive results tend to be more easily published. 115Performing a metaanalysis was considered, but the limitations described above make it difficult.Despite the methodological heterogeneity and scarcity of publications on the subject, some clear pattern was established.
Based on the limitations found during this systematic review, future controlled and well-planned clinical trials are needed to evidence the benefits of periodontal therapy on systemic parameters in patients with obesity and periodontitis.
The benefits reported in this review were achieved with non-surgical periodontal therapy, and only one study used an adjuvant antibiotic, having obtained equivalent results to those of the other studies.
Future well-designed studies are important to elucidate the impact and benefits of periodontal therapy on hematological and biochemical index, biomarkers of inflammation and oxidative stress, quality of life, and periodontal pathogen counts in patients with obesity and periodontitis.

From:
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ 2021;372:n71.doi: 10.1136/bmj.n71.For more information, visit: http://www.prisma-statement.org/Footnote: *, Only Montero et al. (2020) and MdTahir et al. (2020) returned the contact.The other three studies were not excluded, as data available only in graphics were extracted by the WebPlotDigitizer â version 4.4 program; **, the first 100 results of Google Schoolar search results were accessed for the eligibility criteria.

Figure 1 .
Figure 1.PRISMA flow diagram for new systematic reviews which included searches of databases, registers, and other sources of the screening process.
via databases and registers Identification of studies via other methods

Figure 2 .
Figure 2. Descriptive pie chart of diagnostic criteria for obesity reported in the studies.

Figure 4 .
Figure 4. Bias risk analysis dashboard using Cochrane tools: A, "Revised Cochrane risk-of-bias tool for randomized trials" (RoB 2); and B, "Risk Of Bias In Non-randomized Studies -of Interventions" (ROBINS-I) tool for (uncontrolled) before-and-after studies.

Table 1 .
Descriptive data on medical and periodontal condition.

Table 2 .
Primary outcome measures for RCT studies.

Table 3 .
Descriptive data on primary outcomes for BAS.