Received: 14 February 2022 Revised: 2 August 2022 Accepted: 3 August 2022

DOI: 10.1111/jcpe.13717

ORIGINAL ARTICLE

Effect of periodontal treatment on glycated haemoglobin

and metabolic syndrome parameters: A randomized
clinical trial

Fernanda C. Milanesi1 | Bruna F. Greggianin1 | Gabriela O. dos Santos1 |

Mirian P. Toniazzo1 | Patricia Weidlich2 | Fernando Gerchman3 |
Rui V. Oppermann2

1
Post-graduate Program in Dentistry:
Periodontology, Federal University of Rio Abstract
Grande do Sul, Porto Alegre, Brazil
Aim: To assess the effect of periodontal treatment on HbA1c and diagnostic parame-
2
Department of Periodontology, Federal
University of Rio Grande do Sul, Porto Alegre,
ters of patients with metabolic syndrome (MetS).
Brazil Materials and Methods: One hundred and fifty-eight patients with MetS and moder-
3
Department of Internal Medicine, Hospital de
ate and severe periodontitis were included. They were randomized into a test group
Clínicas de Porto Alegre, Federal University of
Rio Grande do Sul, Porto Alegre, Brazil (n = 79), which received non-surgical periodontal treatment, and a control group
(n = 79), which received no treatment. Medical treatment was delivered to both
Correspondence
Patricia Weidlich, Department of groups. Clinical periodontal, anthropometric and serological parameters were
Periodontology, Federal University of Rio
assessed at baseline, 3 and 6 months. The main outcome was glycated haemoglobin
Grande do Sul, Rua Ramiro Barcelos, 2492/
sala 106, Bom Fim, Zip code: 90035-003, (HbA1c) levels, and the secondary outcomes were changes in the MetS parameters,
Porto Alegre, RS, Brazil.
C-reactive protein (CRP) and HOMA indexes.
Email: patricia.weidlich@ufrgs.br
Results: Significant reductions in all periodontal parameters were observed in the test
Funding information group, compared with the control group, at 3 and 6 months (p < .001). HbA1c levels,
Conselho Nacional de Desenvolvimento
Cientfico e Tecnolgico, Grant/Award Number: MetS parameters, CRP and HOMA indexes showed no significant differences
403298/2012-1; Fundo de Incentivo Pesquisa between the test group and the control group at 3 and 6 months.
do Hospital de Clnicas de Porto Alegre
Conclusions: Periodontal treatment led to a substantial reduction in periodontal
inflammation, although there was no significant effect on the parameters used for
MetS diagnosis in patients with early diagnosed and well-controlled MetS.

KEYWORDS
metabolic syndrome, periodontitis, randomized controlled trial

Clinical Relevance
Scientific rationale for study: Metabolic syndrome (MetS) and periodontitis are associated in
observational and longitudinal studies. Information concerning the adjunct effect of periodontal
treatment on MetS parameters in patients with regular medical care is scarce.
Principal findings: Effective periodontal treatment can be achieved in patients with MetS and
periodontitis. Successful periodontal treatment did not produce significant changes in the MetS
parameters in a group of patients with regular medical care.
Practical implications: Periodontal treatment did not change the disease parameters in patients
with early diagnosed MetS.

Bruna F. Greggianin and Fernanda C. Milanesi contributed equally to this study (co-first authors).

J Clin Periodontol. 2023;50:11–21. wileyonlinelibrary.com/journal/jcpe © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 11

12
1 | I N T RO DU CT I O N
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities
that include elevated blood pressure, dysglycemia, atherogenic dyslipi-
demia and abdominal obesity. With today's increasing prevalence of
obesity and diabetes, it is estimated that MetS affects about a quarter
of the world population (Alberti et al., 2006; Saklayen, 2018). It repre-
sents a pro-inflammatory and pro-thrombotic state (Grundy, 2016),
which increases the risk of cardiovascular disease two-fold, and that
of type 2 diabetes five-fold (Eckel et al., 2005; Alberti et al., 2006).
The factors that seem to link these conditions are insulin resistance
and obesity, because both are independently related to all metabolic
conditions (Jepsen et al., 2020). It is also likely that the conditions pro-
moting a low-grade systemic inflammation also influence obesity, dia-
betes and cardiovascular disease development and their control.
Periodontitis is a chronic, multifactorial, microbially associated
and host-mediated inflammatory disease. It is the result of dysbiotic
ecological changes in the usual microbiome, which lead to loss of peri-
odontal attachment (Tonetti et al., 2018). This process triggers a
destructive inflammatory response with a systemic impact, leading to
the release of systemic inflammatory markers and establishing a low-
grade inflammatory state (Gomes-Filho et al., 2011; Pink et al., 2015).
In addition, the periodontal treatment has a positive systemic impact
on reducing the inflammatory burden and diminishing the risk of
developing other inflammatory conditions (Schenkein & Loos, 2013;
Preshaw et al., 2020).
Since the end of the first decade of the 2000s, observational
studies have researched the association between MetS and periodon-
titis. Cross-sectional studies found an association between both dis-
eases, with odds ratios ranging from 1.47 (95% CI 1.05–2.06) to 2.31
(95% CI 1.13–4.73) (D'Aiuto et al., 2008; Gomes-Filho et al., 2016;
Musskopf et al., 2017; Zuk et al., 2017; Campos et al., 2019). Longitu-
dinal studies showed that the presence of MetS increases the risk of
developing periodontitis (Kaye et al., 2016; Tegelberg et al., 2019),
and the presence of periodontitis can increase the risk of developing
MetS over the years (Morita et al., 2010). A meta-analysis revealed a
positive association between MetS and periodontitis. The risk
reported was of 2.09 (95% CI 1.28–3.44) considering only the studies
with a well-defined diagnosis for both conditions (Nibali et al., 2013).
A more recent meta-analysis also found that individuals with MetS are
38% more likely to present periodontitis compared with those without
MetS (Daudt et al., 2018).
Few randomized clinical trials (RCTs) explored the effects of peri-
odontal treatment on MetS, or a possible causal relation between
MetS and periodontitis. When the effect of periodontal treatment
was evaluated in MetS patients with or without concomitant medical
assistance, a reduction was found in C-reactive protein (CRP), total
leukocyte counts and triglyceride levels (Acharya et al., 2010), and a
reduction in CRP, interleukin-6 (IL-6), triglyceride and glycated hae-
moglobin (HbA1c) levels (Torumtay et al., 2016) in MetS patients.
Reductions in CRP and fibrinogen levels were also reported in another
study that delivered non-surgical periodontal treatment with
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MILANESI ET AL.
 pez et al., 2012). The most recent clini-
antibiotics to MetS patients (Lo
cal trial demonstrated that effective periodontal treatment led to a
significant reduction of CRP in patients with MetS after 6 months
(Montero et al., 2020).
Among the clinical trials reported above, the additional effect of
periodontal treatment on MetS treatment, especially in terms of gly-
caemic control, deserves further clarification. The hypothesis of this
study was that periodontal treatment has a positive impact on HbA1C
and MetS parameters in relation to patients who did not receive peri-
odontal treatment. The aim of the study was to evaluate the effect of
periodontal treatment on HbA1c and diagnostic parameters of
patients with MetS.
2 | M A T E R I A L S A N D M ET H O D S
2.1 | Sample characteristics and recruitment
The participants of this randomized controlled clinical trial were
recruited from dental clinics of the School of Dentistry of the Federal
University of Rio Grande do Sul (UFRGS), Brazil, and from local public
healthcare facilities serving all patients looking for dental care,
between May 2015 and January 2017. The periodontal examinations
and treatment were carried out at the UFRGS School of Dentistry.
The Clinical Research Center of the University Hospital (Hospital de
Clínicas de Porto Alegre) scheduled the medical appointments, col-
lected the blood samples and performed the analyses. Three hundred
and five participants were screened for the study, 158 were included
and 147 did not meet the inclusion criteria.
The participants who met the following criteria were included:
being 18 years old or older; having 10 or more teeth; not receiving
periodontal treatment in the last 6 months; presenting moderate or
severe periodontitis as per the Eke criteria (Eke et al., 2012); and
meeting the MetS criteria as per the International Federation of
Diabetes (Alberti et al., 2009). Converting the inclusion criteria to the
current stage and grade definition of periodontitis (Papapanou
et al., 2018), the participants included had the diagnosis of stages III
and IV and grades B and C. Patients were not included if they had
used antibiotics for the previous 3 months, or chronic systemic corti-
costeroids, if they were pregnant or lactating, and if they had to take
antibiotic prophylaxis for periodontal treatment. Participants initially
included were excluded from the study, if they initiated therapy with
antibiotics or anti-inflammatory. Participants in both groups were
excluded if the progression of clinical attachment loss (CAL) ≥2 mm
was detected. In these cases, the participants were scheduled to
receive periodontal treatment immediately.
The study protocol was approved by both the Ethical Committee
of the University Hospital (Hospital de Clinicas de Porto Alegre) and
UFRGS. Informed consent was obtained from all individual partici-
pants included in the study. This study was registered at www.
clinicaltrials.gov, under number NCT02012842, and followed the
CONSORT guidelines.

MILANESI ET AL.
2.2 | MetS and anthropometric measurements
Medical appointments with a University Hospital physician were
made for all the participants included before randomization and medi-
cine prescription. The appointment included a medical interview to
record the sociodemographic variables, such as age, colour of skin,
smoking status, years of schooling, socio-economic level, medication
intake and physical examination, consisting of measuring systolic and
diastolic blood pressure (DBP), waist circumference, weight and
height, and collecting a blood sample. All these procedures were
repeated at 3- and 6-month visits. Waist circumference was measured
at the navel with a tape measure. Weight was measured using a cali-
brated scale, and height was measured using a stadiometer. Blood
pressure was assessed with an automatic device (Omni 612, Omnimed,
Belo Horizonte, Brazil), by recording the average of two measure-
ments. The patient rested for at least 5 min before measuring blood
pressure, seated with the arm supported at the heart level.
MetS was diagnosed when participants met at least three of the
following five criteria: waist circumference of ≥90 cm for men and
≥80 cm for women; triglycerides ≥150 mg/dl or drug treatment for
elevated triglycerides; high-density lipoprotein cholesterol (HDL-C)
≤40 mg/dl for men and ≤50 mg/dl for women, or drug treatment
for HDL-C; fasting blood glucose ≥100 mg/dl or drug treatment for
elevated fasting blood glucose; systolic blood pressure (SBP)
≥130 mmHg and/or DBP ≥85 mmHg or antihypertensive drug
treatment for SBP and DBP control (Alberti et al., 2009).
The blood sample for testing MetS diagnosis parameters (triglyc-
erides, HDL-C and fasting blood glucose) and the insulin levels, CRP
and HbA1c, were all collected at the University Hospital in the morn-
ing, after 12 h of fasting. Counselling was given for diet and exercises,
medicine prescription or adjustments were made, and medical
appointments were repeated at the 3- and 6-month visits.
2.3 | Periodontal examination
All periodontal examinations were carried out by two periodontists
(B.F.G. and M.P.T.), previously calibrated with a gold standard examiner
(P.W.). The baseline periodontal examination was performed before
randomization. The pre-experimental, inter-examiner values were 0.85
for probing depth and 0.81 for attachment loss, assessed using the
weighted kappa index (± 1 mm), in full-mouth examinations. During the
study, the inter-examiner weighted kappa values were 0.93 for periodon-
tal probing depth (PPD), and 0.87 and 0.82 for CAL, respectively.
The periodontal measurements were repeated at six sites per
tooth, for all existing teeth, excluding the third molars, with a North
Carolina Probe 15 (Neumar, São Paulo, Brazil). The parameters col-
lected were visible plaque index (VPI) (Silness & Löe, 1964); gingival
bleeding index (GBI) (Ainamo & Bay, 1975); presence of plaque reten-
tive factors, such as calculus, caries cavities and overhanging restora-
tions; bleeding on probing (BOP); PPD; and CAL. All periodontal
measurements were performed at baseline, and at the 3- and
6-month visits for both the test and control groups.
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13
2.4 | Interventions
The test groups were randomized and received non-surgical periodon-
tal treatment in four weekly sessions, consisting of scaling and
root planing by manual and ultrasonic instruments (Neumar, São
Paulo, Brazil/Cavitron, Dentsply, NY), and personalized oral
hygiene instructions. At this time, cavity seals, endodontic treat-
ment and tooth extractions were performed when necessary. The
periodontal treatment was carried out by two periodontists at the
UFRGS School of Dentistry (F.C.M. and G.O.S.). Bi-weekly mainte-
nance appointments were scheduled up to 3 months in advance,
and monthly appointments, up to the 6-month visit. They con-
sisted of professional supra- and subgingival plaque control,
patient motivation and re-enforcement of daily oral hygiene
procedures.
The control group did not receive any treatment or maintenance
appointments during the 6 months of the study. Periodontal treat-
ment was performed at the end of the 6-month period for the control
group.
2.5 | Outcomes
The primary outcome was changes in HbA1c blood concentration
from the baseline to 3 and 6 months. The secondary outcomes
included changes in the MetS parameters (triglycerides, HDL-C, fast-
ing blood glucose, SBP and DBP, and waist circumference), CRP and
HOMA indexes.
2.6 | Sample size calculation and randomization
The sample size calculation was based on a reduction difference of
0.4% (±0.18) in HbA1c levels between the test and control groups
(Teeuw et al., 2010). The calculated sample was 64 individuals per
group, and 79 participants were included in each group, considering
an attrition rate of 20%.
A researcher not involved in this study was responsible for ran-
domization. The randomized list was generated by a website (www.
randomization.com) for a party not involved in the study. The alloca-
tion sequence was saved in opaque, sealed and sequentially num-
bered paper envelopes. Randomization was performed after the
baseline periodontal and MetS examinations. The periodontal exam-
iners and the physician were blinded to the group allocation during
the entire study.
2.7 | Data collection
Sociodemographic data, behavioural habits and medical history were
collected by a trained interviewer using REDCap (Research Eletronic
Data Capture) software for data collection and storage (Harris
et al., 2009).

14
2.8 | Data analysis
Data analysis was performed using SPSS statistical software (SPSS
version 20, IBM, USA) and R software 3.5.1 (R Core Team, 2019). All
the variables were tested for normality using the Kolmogorov–
Smirnov test. Sociodemographic variables, smoking, body mass index
(BMI) and MetS diagnosis parameters were categorized and analysed
using the chi-squared test. Hyperglycaemia, hypertension, triglycer-
ides, waist circumference and HDL-C variables were categorized fol-
lowing the criteria established by the International Federation of
Diabetes (Alberti et al., 2009).
The BMI was calculated by dividing weight by height squared, and
was classified as normal (≤24.9 kg/m2), overweight (25–29.9 kg/m2) and
obese (≥30 kg/m2). Self-reported skin colour was reported using
the criteria proposed by the Brazilian Institute of Geography and
Statistics, and the data were categorized into White, Black and
others. Socio-economic status was assessed using the Brazilian Cri-
teria for Economic Classification, and participants' class was cate-
gorized as low, corresponding to the E and D class, medium,
corresponding to the B2, C1 and C2 classes, and high, correspond-
ing to the A1, A2 and B1 classes (available at www.abep.org/
criterio-brasil).
The periodontal outcomes (VPI, GBI, plaque-retentive factors
(PRF), BOP, PPD and CAL) and the MetS diagnosis parameters
Assessed for eligibility (n = 305)
Enrolment
Randomized (n = 158)
Allocation
Allocated to control group (n = 79)
Follow-Up
Lost to follow-up (n = 6):
i At 3 months:
Died (n = 1)
Did not take 3-month exam (n = 2)
i At 6 months:
Discontinued intervention due to CAL
progression ≥2mm (n = 1)
Did not take the final exam (n = 2)
Analysis
Intention-to-treat Analysis (n = 79)
Per Protocol Analysis (n = 73)
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MILANESI ET AL.
(continuous variables) were expressed as mean and standard errors.
Periodontal probing depth and CAL were also expressed as preva-
lence of teeth with PPD of ≥4 and ≥6 mm, and CAL of ≥3 and ≥5 mm
(Holtfreter et al., 2015). The PISA index (Periodontal Inflamed Surface
Area) was calculated using the template available at www.
parsprototo.info website (Nesse et al., 2008).
Generalized estimation equation (GEE) models were used
(Software R, version 3.5.1) to make comparisons between periodontal
and metabolic changes within and between groups, and considered
the interaction between time of examination and allocation group
(test or control). Adjustments were made for medicine intake.
Box–Cox transformations were made to achieve normality for the
metabolic variables. Poisson distribution was considered for the num-
ber of teeth, because this was a count variable. Gamma distribution
was used for the continuous values of PPD and CAL. Binomial distri-
bution was used for the periodontal variables, which were evaluated
by sites (VPI, GBI, PRF and BOP) or by teeth (PPD and CAL above
thresholds). The p-values were adjusted by the Tukey method to make
comparisons within groups. Analysis was performed according to an
intention-to-treat strategy. Missing data were completed by repeating
the values recorded for all variables in the last patient visit (last obser-
vation carried forward). Per protocol analysis was also performed, and
included all the patients who completed the study. The individual was
used as the unit of analysis.
Excluded (n = 147)
i Did not fulfill periodontal criteria (n = 77)
i Did not present MetS (n = 51)
i Could not attend weekly dental visits (n = 9)
i Antibiotics usage in last 3 months (n = 7)
i Antibiotic prophylaxis required for periodontal
treatment (n = 3)
Allocated to test group (n = 79)
Lost to follow-up (n = 1)
i At 6 months:
Did not take the final exam (n = 1)
Intention-to-treat Analysis (n = 79)
Per Protocol Analysis (n = 78) FIGURE 1 Flow chart of the
study
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MILANESI ET AL. 15

3 | RESULTS TABLE 1 Characteristics of the sample at baseline (n/%)

Control (n = 79) Test (n = 79) pa

A total of 305 patients were screened, and 147 did not meet the Gender
inclusion criteria, leaving 158 patients included. During the study, Male 41 (51.9) 36 (45.6) .42
seven patients were excluded. In the control group, one patient died, Female 38 (48.1) 43 (54.4)
one patient had CAL progression and four patients did not show up Age (years)
for the 6-month follow-up visit. In the test group, one patient did not ≤44 13 (16.5) 5 (6.3) .11
show up for the 6-month follow-up visit. At the end, 151 patients 45–64 57 (72.2) 61 (77.2)
completed the study (Figure 1). ≥65 9 (11.4) 13 (16.5)
At baseline, the groups did not show any statistically significant Years of schooling
differences regarding sociodemographic characteristics, smoking habit ≤8 32 (40.5) 36 (45.6) .25
or diagnostic criteria for MetS (Table 1). In relation to medicine intake 9–11 25 (31.6) 16 (20.3)
during the study, no differences were found between the groups >11 22 (27.8) 27 (34.2)
(Table S1). Socio-economic level
Low 3 (3.8) 7 (8.9) .34
Medium 59 (74.7) 59 (74.7)
3.1 | Periodontal parameters High 17 (21.5) 13 (16.5)

Skin colour
There were no statistically significant differences between groups at White 60 (75.9) 54 (68.4) .56
baseline for all periodontal parameters and for the number of teeth Black 8 (10.1) 11 (13.9)
(Table 2). In the intra-group analysis, the test group showed statisti- Other 11 (13.9) 14 (17.7)
cally significant differences for all the parameters at the 3- and Smoking status
6-month visits. The control group also showed statistically significant Never smoker 26 (32.9) 28 (35.4) .94
reductions in some periodontal parameters, although their magnitude Current smoker 17 (21.5) 16 (20.3)
was lower compared with that observed in the test group. Former smoker 36 (45.6) 35 (44.3)
The inter-group analysis showed that all periodontal parameters MetS parameterb
had statistically significant reductions in the test group in comparison Hypertension
to the control group, except for the number of teeth and CAL, after No 8 (10.1) 4 (5.1) .23
3 months of follow-up. At the 6-month visit, significant differences Yes 71 (89.9) 75 (94.9)
were observed for the test group as compared with the control group HDL-cholesterol
in all parameters including a statistically significant improvement in No 26 (32.9) 34 (43.0) .19
CAL. The test group showed a significant reduction between baseline Yes 53 (67.1) 45 (57.0)
and 6-month values in VPI (75.6% vs. 7.7%; p < .001) and GBI (75% Triglycerides
vs. 13.6%; p < .001). The same was true for BOP (66.2% vs. 13.6%; No 31 (39.2) 37 (46.8) .33
p < .001). When the percentage of sites with PPD ≥6 mm (74.8% Yes 48 (60.8) 42 (53.2)
vs. 20.2%; p < .001) was considered, a significant reduction was Hyperglycaemia
observed favouring the test group as compared with the control No 24 (30.4) 24 (30.4) 1
group. Yes 55 (69.6) 55 (69.6)
The PISA index analysis showed statistically significant differ- Waist circumference
ences in both the intra- and inter-groups (Table 2). The test group No 7 (8.9) 6 (7.6) 0.77
showed a significantly higher reduction in the PISA index, compared Yes 72 (91.1) 73 (92.4)
with the control group from baseline to 6 months (77.3% vs. 21%; BMI (kg/m2)
p < .001). The per protocol analysis showed no differences from the Normal 9 (11.4) 7 (8.9) 0.27
intention-to-treat analysis regarding all the comparisons. Overweight 30 (38) 22 (27.8)
Obese 40 (50.6) 50 (63.3)
Diabetesc
3.2 | Metabolic parameters Normal 28 (35.4) 29 (36.7) 0.87
Pre-diabetes 19 (24.1) 21 (26.6)
Table 3 shows the values for HbA1c, MetS diagnostic markers, CRP Diabetes 32 (40.5) 29 (36.7)
and HOMA indexes. All the measurements were similar for the inter-
Abbreviations: BMI, body mass index; MetS, metabolic syndrome.
group comparison at baseline. No statistically significant changes were a
Intergroup t-test or Chi-squared test.
b
observed in either the control or test group throughout the study, According to the International Federation of Diabetes, 2009.
c
Diabetes diagnosis (International Federation of Diabetes Atlas 10th edition, 2021).
even in the adjusted model for medication intake (Table 4). In the
 16

TABLE 2 Periodontal parameters at baseline, and 3 and 6 months of follow-up intervention (mean ± SE)

Baseline 3 months 6 months

Control (n = 79) Test (n = 79) p* Control (n = 79) Test (n = 79) p* Control (n = 79) Test (n = 79) p*
d a d
Number of teeth 19.74 (±5.24) 20.32 (±4.97) .50 19.52 (±5.37) 19.74 (±5.35) .81 19.38 (±5.40) 19.63 (±5.37) .80
VPI (mean % of sites) 45.5 (±27.37) 44.3 (±25.59) .77 41.1 (±25.24) 10.7 (±11.64)d <.0001 42.0 (±26.04) 10.8 (±9.0)d <.0001
GBI (mean % of sites) 21.2 (±17.68) 18.8 (±15.90) .35 17.8 (±15.73)a 5.0 (±5.51)d <.0001 18.3 (±19.02) 4.7 (±4.79)d <.0001
PRF (mean % of sites) 28.6 (±19.19) 26.7 (±21.24) .55 25.4 (±15.64)a 4.6 (±5.51)d <.0001 25.9 (±18.93) 4.5 (±6.57)d <.0001
b d b d
BOP (mean % of sites) 58.7 (±25.24) 58.0 (±24.44) .86 51.9 (±24.61) 22.4 (±13.50) <.0001 50.7 (±26.39) 19.6 (±10.22) <.0001
Mean PPD (mm) 2.95 (±0.79) 3.02 (±0.71) .59 2.80 (±0.71)b 2.33 (±0.35)d <.0001 2.79 (±0.79)b 2.27 (±0.35)d <.0001
a d b d
Proportion of teeth PPD ≥4 mm (%) 57.7 (±27.55) 60.4 (±25.77) .52 51.9 (±28.61) 30.8 (± 23.90) <.0001 48.5 (±28.53) 25.6 (±23.28) <.0001
Proportion of teeth PPD ≥6 mm (%) 18.8 (±20.88) 21.9 (±24.88) .39 14.7 (±19.82)b 5.7 (±8.88)d .0001 15.0 (±21.24)a 3.5 (±6.04)d <.0001
b d b d
Mean CAL (mm) 4.04 (±1.51) 3.96 (±1.42) .74 3.89 (±1.51) 3.49 (±1.24) .07 3.84 (±1.51) 3.39 (±1.24) .04
Proportion of teeth CAL ≥3 mm (%) 89.9 (±15.64) 89.1 (±17.68) .76 89.0 (±16.17) 83.2 (±22.39)c .05 88.3 (±18.93) 78.7 (±26.66)d .009
a d a d
Proportion of teeth CAL ≥5 mm (%) 53.6 (±30.57) 54.1 (±28.17) .91 50.3 (±29.95) 46.5 (±29.68) .42 49.3 (±29.41) 43.0 (±30.75) .18
PISA (mm2) 757.10 (±55.66) 831.17 (±65.21) .54 642.60 (±54.00)b 231.83 (±22. 07)d <.001 598.410 (±48.03)b 188.44 (±14.26)d <.001

Note: Asterisk indicates inter-group comparison with GEE (generalized estimated equations).
Abbreviations: BOP, bleeding on probing; CAL, clinical attachment loss; GBI, gingival bleeding index; PPD, periodontal probing depth; PRF, plaque retentive factors; VPI, visible plaque index.
a
p < .05.
b
p < .001 for intra-group comparison with baseline for control group.
c
p < .05.
d
p < .001 for intra-group comparison with baseline for test group.
MILANESI ET AL.

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 TABLE 3 Results of metabolic syndrome and other parameters at baseline and 3 and 6 months of follow-up (mean ± SE)

Baseline 3 months 6 months

c d c d
Control (n = 79) Test (n = 79) p p Control (n = 79) Test (n = 79) p p Control (n = 79) Test (n = 79) pc pd
MILANESI ET AL.

MetS parameter
Waist circumference (cm) 101.42 (±16.72) 102.56 (±13.47) 0.90 - 101.05 (±13.27) 102.69 (±15.37) 0.51 - 100.12 (±13.24) 100.66 (±13.42) 0.81 -
a
p - - < 0.01 0.99 0.0001 0.01
SBP (mmHg) 138.27 (±16.71) 139.86 (±18.74) 0.64 0.80 139.59 (±19.11) 136.93 (±20.13) 0.36 0.22 138.74 (±19.94) 137.15 (±20.15) 0.56 0.39
a
p - - 0.92 0.29 1.00 0.37
pb - - 0.90 0.25 0.99 0.38
DBP (mmHg) 82.73 (±12.02) 81.45 (±10.71) 0.58 0.44 83.01 (±12.22) 84.16 (±14.94) 0.60 0.76 84.40 (±15.66) 83.01 (±12.23) 0.58 0.42
pa - - 0.99 0.15 0.66 0.59
pb - - 0.99 0.17 0.68 0.64
HDL-cholesterol (mg/dl) 41.97 (±10.28) 45.10 (±14.20) 0.22 0.30 43.56 (±11.42) 45.31 (±13.69) 0.53 0.67 44.94 (±16.44) 45.75 (±15.17) 0.78 0.90
a
p - - 0.19 0.91 0.14 0.97
pb - - 0.23 0.97 0.17 0.99
Fasting blood glucose 136.93 (±60.69) 137.37 (±67.08) 0.95 0.65 126.22 (±52.70) 122.48 (±50.44) 0.74 0.83 127.12 (±55.11) 120.08 (±46.49) 0.40 0.49
(mg/dl)
pa - - 0.03 0.01 0.26 0.89
b
p - - 0.08 0.004 0.33 0.01
Triglyceride (mg/dl) 179.41 (±88.24) 238.16 (±491.29) 0.85 0.86 175.39 (±109.74) 168.44 (±87.49) 0.79 0.71 191.59 (±134.49) 196.36 (±114.56) 0.54 0.52
a
p - - 0.36 0.38 0.89 0.44
pb - - 0.42 0.51 0.75 0.23
Other parameters
HbA1c (%) 7.15 (±2.35) 7.20 (±2.26) 0.22 0.29 6.91 (±1.93) 6.92 (±1.95) 0.53 0.66 6.79 (±1.91) 6.82 (±1.63) 0.77 0.90
a
p - - 0.19 0.91 0.13 0.96
pb - - 0.22 0.97 0.17 0.99
C-reactive protein 5.27 (±5.68) 5.79 (±7.14) 0.29 0.38 5.34 (±5.96) 7.13 (±13.86) 0.48 0.61 5.89 (±6.21) 7.67 (±10.10) 0.39 0.47
pa - - 0.49 0.23 0.92 0.73
pb - - 0.65 0.33 0.99 0.92
HOMA 2—insulin resistance 2.11 (±1.25) 2.17 (±1.54) 0.93 0.94 1.99 (±1.44) 2.05 (±1.38) 0.68 0.71 2.12 (±2.09) 2.03 (±1.41) 0.87 0.83
a
p 0.04 0.49 0.21 0.23
pb 0.06 0.49 0.32 0.24
HOMA 2—β cell function 105.35 (±134.24) 95.61 (±63.91) 0.86 0.88 107.50 (±131.27) 104.07 (±63.87) 0.55 0.57 104.39 (±129.81) 101.14 (±63.69) 0.51 0.54
pa 0.69 0.13 0.70 0.19
pb 0.62 0.12 0.63 0.18
17

(Continues)

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18 MILANESI ET AL.

TABLE 4 Medication intake by patients at baseline (n/%)

0.85
pd
Control (n = 79) Test (n = 79) p

Abbreviations: DBP, diastolic blood pressure; HbA1c, glycated haemoglobin; HDL-cholesterol, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; MetS, metabolic syndrome; SBP,
Sulfonylurea
0.89
pc

No 65 (82.3) 71 (89.9) .16

Yes 14 (17.7) 8 (10.1)
72.90 (±49.80)
Test (n = 79)

Metformin
No 49 (62.0) 51 (64.6) .74
0.25
0.25

Yes 30 (38.0) 28 (35.4)

Insulin
No 67 (84.8) 69 (87.3) .64
Control (n = 79)
69.90 (±41.83)

Yes 12 (15.2) 10 (12.7)

6 months

Thiazidic
0.18
0.28

No 55 (69.6) 50 (63.3) .40

Yes 24 (30.4) 29 (36.7)
0.73

Β-blockers
d
p

No 60 (75.9) 53 (67.1) .21

0.71

Yes 19 (24.1) 26 (32.9)

c
p

Calcium channels blockers

71.04 (±48.69)

No 65 (82.3) 65 (82.3) .99

Test (n = 79)

Yes 14 (17.7) 14 (17.7)

0.45
0.45

Angiotensin-converting enzyme inhibitor

No 48 (60.8) 46 (58.2) .74
Yes 31 (39.2) 33 (41.8)
Control (n = 79)
74.56 (±57.76)

Angiotensin blockera
3 months

No 59 (74.7) 66 (83.5) .17

0.03
0.05

Yes 20 (25.3) 13 (16.5)

Levothyroxine
No 72 (91.1) 76 (96.2) .19
0.92
d
p

Yes 7 (8.9) 3 (3.8)

0.90

Statin
c
p

No 43 (54.4) 39 (49.4) .52

Generalized estimation equation (GEE) intra-group comparison with baseline.

Yes 36 (45.6) 40 (50.6)

64.96 (±38.38)

GEE intra-group comparison with baseline adjusted for medicine intake.

Test (n = 79)

Fibrate
No 79 (100) 76 (96.2) .08
Yes 0 (0) 3 (3.8)
Acetylsalicylic acid
No 61 (77.2) 54 (68.4) .21
Control (n = 79)
63.18 (±35.36)

Yes 18 (22.8) 25 (31.6)

GEE inter-group adjusted for medicine intake.
Baseline

Furosemide
No 75 (94.9) 69 (87.3) .09
Yes 4 (5.1) 10 (12.7)
HOMA 2—insulin sensitivity

Note: Chi-square test.

a
Angiotensin II receptor blockers.
(Continued)

systolic blood pressure.

intra-group analysis, statistically significant differences were found for

GEE inter-group.

waist circumference at 3 months in the control group, and 6 months

TABLE 3

in both groups, compared with the baseline values. Statistically signifi-

pb
pa

cant differences were also found for fasting blood glucose at 3 months
for both groups and at 6 months for the test group. The inter-group
b

d
a

c

MILANESI ET AL.
TABLE 5 Number of MetS parameters at baseline, 3- and 6-month visits, for control and test groups (n/%)
Baseline 3 months
MetS criteria Control (n = 79) Test (n = 79) p a
Control (n = 79)
1 0 0 0
2 0 0 5 (6.3)
3 32 (40.5) 29 (36.7) 29 (36.7)
4 28 (35.4) 32 (40.5) 27 (34.2)
5 19 (24.1) 18 (22.8) 1 18 (22.8)
pb 1 0.84
a
intergroup comparison with McNemar test.
b
intragroup comparison (baseline-3m; baseline-6m) with Bonferroni correction.
analysis showed no statistically significant differences for HbA1c,
MetS parameters, CRP and HOMA indexes at the 3- and 6-month
visits.
The subgroup analysis for patients with or without diabetes
showed no statistically significant differences in the inter-group analy-
sis among the values for baseline, 3 and 6 months. The same was true
for the intra-group analysis, except for the significantly higher levels
of triglycerides in the test group at 6 months, compared with the
baseline (Tables S1 and S2).
Subgroup analysis was also performed to evaluate the influence
of the periodontal treatment on MetS diagnostic parameters and
HbA1c in patients with the higher levels of periodontal inflammation
at baseline from the control and the test groups (Table S3). There
were no differences in regard to blood pressure, waist circumference,
fasting blood glucose, triglycerides, HDL-C or HbA1c levels at the 3-
and 6-month visits between the control and the test groups.
The changes in the number of MetS components during the study
are shown in Table 5. The percentage of participants who reverted
out from MetS at the 3-month visit was 6.3 and 10.2 for the control
and the test group, respectively. After 6 months, 19% of individuals in
the control group and 16.4% of individuals in the test group reverted
from MetS, without differences both in the intra-group and inter-
group analyses.
The per protocol analysis showed no differences from the
intention-to-treat analysis regarding all comparisons.
4 | DISCUSSION
The present RCT evaluated the effect of non-surgical periodontal
treatment on MetS diagnostic parameters of patients with MetS and
periodontitis. Effective periodontal treatment at 6 months of follow-
up was not associated with significant differences in the HbA1c levels
or the MetS diagnostic parameters of those receiving periodontal
treatment, compared with those not receiving it.
The periodontal treatment provided to the test group was
effective in reducing periodontal inflammation, plaque levels and
probing depths. Plaque and marginal bleeding scores indicated peri-
odontal health (Chapple et al., 2018), and both probing pocket
depths and BOP were drastically reduced. These results indicated
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19
6 months
Test (n = 79) pa
Control (n = 79) Test (n = 79) pa
1 (1.3) 2 (2.5) 2 (2.5)
7 (8.9) 13 (16.5) 11 (13.9)
28 (35.3) 19 (24.1) 23 (29.1)
24 (30.4) 23 (29.1) 23 (29.1)
19 (24.1) 1 22 (27.8) 20 (25.4) 1
0.16 0.34
that periodontitis was successfully managed in the test group (Sanz
et al., 2015; Tonetti et al., 2018; Loos & Needleman, 2020). The
results of this study also indicated a 77% reduction in the PISA index in
the test group, corroborating the results of another clinical trial with
MetS patients (Bizzarro et al., 2017). Altogether, the results achieved by
the periodontal treatment used in this study showed that the exposure
was adequately managed in the test group.
Systemic markers for MetS were not affected by periodontal treat-
ment. Although periodontitis may increase the systemic inflammatory
burden as a minor contributing factor (Gomes-Filho et al., 2011; Pink
et al., 2015), systemic conditions and diseases such as hyperglycaemia,
hypercholesterolemia, overweight/obesity, hypertension and MetS unde-
niably contribute directly to increasing the systemic inflammatory
response (Alberti et al., 2009). The results of this study corroborate those
of one RCT that demonstrated the absence of the effect of periodontal
treatment on MetS diagnostic parameters, but decreased fibrino-
gen levels for periodontally treated patients, and decreased CRP
levels for both the test and the control groups at 9- and 12-month
 pez et al., 2012). Another clinical trial showed
post-treatment (Lo
that periodontal treatment reduced IL-1β, TNF-α and HbA1c levels,
and blood pressure in the test group at the 3-month visit, and CRP
levels at the 6-month visit (Montero et al., 2020). The two afore-
mentioned studies provided non-surgical periodontal treatment
with the adjunct use of antimicrobials, which can in part explain the
results of the significant reduction in systemic inflammation and
atherosclerotic risk biomarkers.
Insulin resistance is related to the development of hyperglycae-
mia and alterations in HbA1c levels and was used as a marker to cal-
culate the sample size. The present study found no significant
changes in HbA1c levels for either group. The baseline levels of
HbA1c indicated overall good glycaemic control. After 6 months,
HbA1c levels were 6.8% for both the control and the test groups, and
hyperglycaemia was properly managed in both groups. The IDF
threshold HbA1c for diabetes diagnosis is 6.5% (International Diabe-
tes Federation, 2019). However, an HbA1c level of about 7% is con-
sidered the therapeutic goal for treating diabetes patients (Sociedade
Brasileira de Diabetes, 2019). The relatively low baseline values could
have influenced the ability of the periodontal treatment to produce
significant changes in HbA1c, as reported recently in a systematic
review (Chen et al., 2021). Most of the patients in the study were

20
adults and were diagnosed with MetS when they entered it. Considering
the epidemiology of this condition, it can be postulated that early diagno-
sis of MetS and immediate delivery of medical treatment can be at least
partly responsible for the reduction in systemic MetS markers in both
treated and untreated patients with periodontitis.
The limitations of the study include the fact that MetS was
addressed based on the insulin resistance pathway, in individuals with
early diagnosed MetS. It is known that MetS is a cluster of different
medical conditions leading to increased cardiovascular risk if it is not
treated. The results of this study should not be extrapolated to indi-
viduals with long-term and untreated MetS. We also could not rule
out the interference of the Hawthorne effect. The strength of the
study comprises the consistent reduction in clinical inflammatory
parameters demonstrated in the test group, which remained stable
over time. This expected outcome was essential for comparisons
between the test and control groups. The results of this investigation
warrant further studies on the relationship between PE and MetS.
Future studies should also focus on the role of periodontal treatment
in central obesity as it is a prerequisite risk factor for MetS.
Based on the results, it can be concluded that the periodontal treat-
ment was effective in reducing the periodontitis-related inflammatory
burden; however, it promoted no changes in HbA1c levels and MetS
parameters in patients with early diagnosed and well-controlled MetS.
AUTHOR CONTRIBUTIONS
All the authors were responsible for drafting the manuscript, revising
it critically and approving the final version to be published. All authors
were also responsible for the accuracy and integrity of the study. Fer-
nanda C. Milanesi and Bruna F. Greggianin made substantial contribu-
tions to the acquisition, analysis and interpretation of data. Gabriela
O. dos Santos and Mirian P. Toniazzo made substantial contributions
to the analysis and interpretation of data. Fernando Gerchman, Rui
V. Oppermann and Patricia Weidlich made substantial contributions
to the conception, design, analysis and interpretation of data.
ACKNOWLEDGEMEN TS
We would like to thank all the patients who agreed to participate in
this study, Dr Vanessa Bielefeldt Leotti for her statistical analysis sup-
port and scientific initiation students André Altíssimo dos Santos,
Kelly Carvalho, Natália Dier and Tuane Regina Grechi.
CONF LICT OF IN TE RE ST
The authors declare no potential conflict of interest.
DATA AVAI LAB ILITY S TATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Fernanda C. Milanesi https://orcid.org/0000-0001-7541-3246
Bruna F. Greggianin https://orcid.org/0000-0001-6944-3238
Gabriela O. dos Santos https://orcid.org/0000-0001-5364-5855
Mirian P. Toniazzo https://orcid.org/0000-0003-3852-3117
Patricia Weidlich https://orcid.org/0000-0003-2013-8229
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MILANESI ET AL.
Fernando Gerchman https://orcid.org/0000-0001-5873-9498
Rui V. Oppermann https://orcid.org/0000-0002-4490-6088
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SUPPORTING INF ORMATION
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How to cite this article: Milanesi, F. C., Greggianin, B. F.,
dos Santos, G. O., Toniazzo, M. P., Weidlich, P., Gerchman, F.,
& Oppermann, R. V. (2023). Effect of periodontal treatment on
glycated haemoglobin and metabolic syndrome parameters: A
randomized clinical trial. Journal of Clinical Periodontology,
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