Journal of Current Biomedical Reports jcbior.com Volume 2, Number 1, 2021 eISSN: 2717-1906 1 Original research The effect of non-surgical periodontal therapy on glycemic control and C1-reactive protein levels among type 2 diabetic patients with periodontitis: A clinical trial Mohammad Moshtaghi Moghaddam1, Arman Keymoradzadeh2, Rashed Ghorbandoust1,* 1Department of Periodontics, Dental School, Guilan University of Medical Sciences, Rasht, Iran 2Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran Abstract It suggests that non-surgical periodontal therapy without systemic antibiotic therapy may not achieve a significant improvement in glycemic control and systemic inflammation in diabetic patients. However, it is important to highlight that the decision of whether or not to use antibiotics to treat periodontitis. Thus this study aimed to evaluate over 3 months the consequence of non-surgical periodontal treatment without systemic antibiotic therapy on serum levels of HbA1c and C-reactive protein (CRP). Forty-two participants with type 2 diabetes mellitus (DM) and moderate periodontal disease were randomized into intervention (IG) and control (CG) groups. The IG received non-surgical periodontal therapy in the form of full-mouth scaling and root planing. Participants were followed up for 3 months. The CG received non-surgical periodontal therapy after 3 months. Clinical parameters, including plaque index (PI), gingival bleeding index (GBI), probing pocket depth (PPD), clinical attachment level (CAL), and HbA1c and CRP levels, of all patients were recorded at baseline and after 3 months. A p-value less than 0.05 considered significant. At the end of 3 months, IG showed improvement in all the clinical parameters compared to CG. There were no significant differences in HbA1c and CRP after 3 months when compared to the baseline level in both groups. Clinical parameters were significantly improved by the employment of non-surgical periodontal treatment without systemic antibiotic therapy, but HbA1C and CRP levels were not significantly affected. Keywords: Antibiotics, Diabetes, Non-surgical periodontal treatment, Periodontal Disease 1. Introduction Diabetes is a chronic disease that affects 8.5% of the world's population. It is estimated that by 2040, the number of people with the disease will increase to 642 million worldwide. Based on the epidemiological studies it is estimated that in the year 2030 nearly 9.2 million Iranians likely to have diabetes [1]. It has been described that periodontal disease is the sixth complication of diabetic patients after * Corresponding author: Rashed Ghorbandoust, MD Department of Periodontics, Dental School, Guilan University of Medical Sciences, Rasht, Iran Tel/Fax: +98 911 8069141 Email: rashed.ghd@gmail.com https://orcid.org/0000-0003-0540-3768 Received: December, 12, 2020 Accepted: February, 09, 2021 diabetic nephropathy, neuropathy, retinopathy, vascular disease, and delayed healing [2]. Periodontitis is a chronic inflammatory disease that causes progressive damage of periodontium and leading to tooth loss. It is associated with an undesirable impression on the patient's quality of life [3]. The production of pro-inflammatory mediators such as and C-1 reactive protein (CRP) in patients with periodontitis is increased. All these mediators can https://jcbior.com/ Moshtaghi Moghaddam et al. 2 cause insulin resistance and also alter the lipid and glucose metabolism [4]. Glycosylated haemoglobin (HbA1c) forms by irreversible binding of glucose to haemoglobin. HbA1c levels represent glycaemic control over the previous 1-3 months [5]. Thus, periodontal disease can affect HbA1c and CRP levels in diabetic patients [4]. One of the most common therapy that used for the treatment of periodontitis is scaling and root planing. Although scaling and root planing improves the periodontal status in the majority of patients, it is usually insufficient to alter the bacterial profile followed by periodontal status [6]. The aim of systemic periodontal antibiotic therapy is to killing subgingival pathogens that remain after conventional mechanical periodontal therapy to support mechanical periodontal therapy and the host defense system [7]. It suggests that in patients with a long history of diabetes, the conventional periodontal therapy alone cannot achieve a significant improvement in glycemic control and systemic inflammation [7-9]. However, it is important to highlight that improper administration of antibiotics can lead to side effects of various intensities, and their indiscriminate use might lead to the tolerance to the antibiotics [10]. Therefore, the need to use or not to use these agents by dentists can be a challenge. Thus, this study aimed to evaluate the consequence of non-surgical periodontal therapy without systemic antibiotic treatment on serum levels of HbA1c and CRP over 3 months. 2. Materials and Methods 2.1 Study population This study received ethics approval by Guilan University of Medical Sciences (Approval code: IR.GUMS.REC.1398.307). Also, the clinical trial protocol was registered (IRCT registration number: IRCT20190721044287N1) and available online. The study population consisted of 42 participants with type 2 DM (HbA1c ≥ 7%). Inclusion criteria included the following: 1) Patients with chronic periodontitis who received no periodontal treatment in the past 6 months; 2) Receiving periodontal and antibiotic treatments during the last 6 months; 3) Patients with at least 14 teeth in the mouth and a pocket depth (PD) ≥ 5 mm in at least four areas and 4 ≥ clinical attachment level (CAL) ≥ 3 mm in at least four areas; 4) Diabetes diagnosed by a physician for the past 6 months; 5) Patients with unchanged diabetic medication for the past 3 months. Exclusion criteria included: 1) Patients with advanced diabetic problems (macrovascular and microvascular); 2) Chronic pulmonary disease; 3) Kidney and liver diseases; 4) Malignancies; 5) Heart disease (coronary artery disease); 6) Transplanted patients; 7) History of infection and trauma; 8) Alcoholic and smoker patients; 9) Pregnant women; 10) Patients with severe periodontitis. 2.2 Groups In this study, using a computer program, participants were randomized into two groups of 21 each: the intervention group (IG) and the control group (CG). All the patients received health education using toothbrush and toothpaste with a modified bass method twice a day, and dental floss and chlorhexidine mouthwash (0.12%) twice a day. The IG received non- surgical periodontal therapy in the form of full-mouth scaling and root planing in two sessions, 1 week apart, with the use of slim instruments, under local anesthesia. Participants were followed up for 3 months. The CG received non-surgical periodontal therapy after 3 months. 2.3 Follow up During 3 months of follow up, patients with the following criteria were excluded from the study: 1) Patients with diabetic diet changes during the study period; 2) Patients with problems requiring emergency treatment; 3) Patients who changed their diets or medications or used antibiotics during the study. 2.4 Data collection Clinical parameters, including plaque index (PI), gingival index (GI), gingival bleeding index (GBI), probing pocket depth (PPD), CAL were examined at baseline and after 3 months. Patients’ blood samples were obtained from the Razi Laboratory at 8.5-11 A.M. to assess their HbA1c and CRP levels at baseline and after 3 months. 2.5 Statistical analysis Data was compiled and analyzed through SPSS version 24. Quantitative variables like HbA1c and CRP were presented as mean ± SD. The Pearson test was used to test the correlation of the periodontal parameters with HbA1C and CRP levels, and the Moshtaghi Moghaddam et al. 3 correlation of serum level of HbA1C with CRP level. Differences among all variables from baseline to the 3- month visit were analyzed using the Wilcoxon Mann- Whitney U test because it was not normally distributed. The linear regression test was used to evaluate the effect of age and gender on the HbA1C and CRP levels. A p-value <0.05 considered significant. 3. Results HbA1c and CRP levels in the CG and IG at baseline and after 3 months are shown in Table 1 and Table 2, respectively. Table 3 showed HbA1c and CRP levels changes between baseline and after 3 months. Based on the results of the present study, the two groups did not differ significantly in the HbA1C (Table 1) and CRP (Table 2) levels at baseline. Also, the results indicated that age and gender did not significantly affect the HbA1C and CRP levels at baseline. The results indicated that all periodontal parameters measured (PI, GI, GBI, PPD, and CAL) showed improvement after 3 months of non-surgical periodontal treatment in the IG compared to the CG (Table 4). Based on the result of the present study, the relation between HbA1C (Table 5) and CRP (Table 6) 1with periodontal parameter changes was not statistically significant. T a b le 1 . H b A 1 c le v e l in th e c o n tr o l g ro u p (C G ) a n d in te rv e n ti o n g ro u p ( IG ) a t b a se li n e a n d a ft e r 3 m o n th s G r o u p S u b g r o u p N u m b e r M e a n S D B a se li n e C G > 9 H b A 1 c 1 5 8 .0 7 0 .4 6 ≤ 9 H b A 1 c 6 9 .7 6 0 .5 4 IG > 9 H b A 1 c 1 5 7 .8 5 0 .6 4 ≤ 9 H b A 1 c 6 1 0 .3 5 1 .1 5 A ft e r 3 m o n th s C G > 9 H b A 1 c 1 5 7 .9 1 0 .7 8 ≤ 9 H b A 1 c 6 9 .6 0 .3 5 IG > 9 H b A 1 c 1 5 7 .9 2 0 .8 0 ≤ 9 H b A 1 c 6 1 0 .0 6 1 1 .9 0 T a b le 3 . H b A 1 c a n d C R P l e v e ls c h a n g e s b e tw e e n b a se li n e a n d a ft e r 3 m o n th s in c o n tr o l g ro u p ( C G ) a n d i n te rv e n ti o n g ro u p ( IG ) P a r a m e te r G r o u p S u b g r o u p N u m b e r M e a n S D H b A 1 C C G > 9 H b a 1 c 1 5 -0 .1 3 0 .5 4 ≤ 9 H b A 1 c 6 -0 .2 3 0 .4 7 IG > 9 H b a 1 c 1 5 0 .1 7 0 .5 7 ≤ 9 H b A 1 c 6 -0 .5 5 0 .5 6 C R P C G - 2 1 0 .0 0 4 0 .6 7 IG - 2 1 -0 .6 0 0 .7 0 T a b le 2 . C R P l e v e l in t h e c o n tr o l g ro u p ( C G ) a n d in te rv e n ti o n g ro u p ( IG ) a t b a se li n e a n d a ft e r 3 m o n th s G r o u p N u m b e r M e a n S D B a se li n e C G 2 1 3 .6 0 2 .3 6 IG 2 1 3 .0 4 2 .1 0 A ft e r 3 m o n th s C G 2 1 3 .6 1 2 .3 8 IG 2 1 2 .4 3 2 .0 9 Moshtaghi Moghaddam et al. 4 Discussion Based on the result of the present study, non- surgical periodontal therapy without systemic antibiotic therapy could improve the periodontal status of patients with type 2 DM. Similar to the result of the present study, Vaghani et al. showed scaling, and root planing is associated with significant reductions in the GI, Oral Health Index (OHI-S), PPD, and CAL levels of patients with periodontitis [4]. These findings are similar to a study done by Obeid et al., which showed the effectiveness of scaling and root planing in improving the periodontal status of patients with periodontitis [11]. Based on the results of the present study, non- surgical periodontal therapy without systemic antibiotic therapy did not affect the serum level of HbA1C. Similarly, a study done by Aldridge et al. reported a significant improvement in periodontal parameters after scaling and root planing without systemic antibiotic therapy but did not found any improvement in HbA1c levels in 22 patients with type 1 diabetes and severe periodontitis [9]. Grossi et al. Table 4. Differences of periodontal parameters in intervention group (IG) compared to control group (CG) after 3 months Periodontal parameter Group Statistic P value CG (Mean Difference ± SD) IG (Mean Difference ± SD) PI 16.89 ± -4.95 8.16 ± -40.62 4.70 <0.001 GI 0.12 ± 0.08 0.28 ± -0.88 5.61 <0.001 PD 0.15 ± 0.07 0.55 ± - 1.10 5.60 <0.001 CAL 0.15 ± 0.03 0.31 ± - 0.50 5.24 <0.001 GBI 8.41 ± 0.19 19.01 ± -46.24 5.04 <0.001 Plaque index (PI), Gingival index (GI), Pocket depth (PD), Clinical attachment level (CAL), Gingival bleeding index (GBI) Table 5. Relationships between periodontal parameters and HbA1c serum level changes in the control group (CG) and intervention group (IG) after 3 months Group Subgroup PI GI PD CAL GBI CG >9 HbA1c r = 0.06 p = 0.820 r = -0.26 p = 0.342 r = 0.04 p = 0.869 r = -0.23 p = 0.39 r = 0.23 p = 0.410 ≤9 HbA1c r = 0.47 p = 0.340 r = -0.25 p = 0.633 r = 0.24 p = 0.641 r = -0.61 p = 0.191 r = 0.69 p = 0.125 IG >9HbA1c r = - 0.36 p = 0.182 r = -0.23 p = 0.409 r = 0.05 p = 0.851 r = -0.27 p = 0.329 r = -0.06 p = 0.831 ≤9 HbA1c r = -0.50 p = 0.313 r = 0.51 p = 0.313 r = 0.01 p = 0.984 r = -0.58 p = 0.222 r = -0.19 p = 0.718 Plaque index (PI), Gingival index (GI), Pocket depth (PD), Clinical attachment level (CAL), Gingival bleeding index (GBI) Table 6. Relationships between periodontal parameters and CRP serum level changes in the control group (CG) and intervention group (IG) after 3 months Group PI GI PD CAL GBI CG r = -0.20 p = 0.383 r = - 0.32 p = 0.158 r = 0.10 p = 0.679 r = - 0.04 p = 0.876 r = 0.007 p = 0.976 IG r = -0.23 p = 0.318 r = - 0.24 p = 0.299 r = -0.20 p = 0.381 r = -0.20 p = 0.393 r = 0.36 p = 0.109 Plaque index (PI), Gingival index (GI), Pocket depth (PD), Clinical attachment level (CAL), Gingival bleeding index (GBI) Moshtaghi Moghaddam et al. 5 indicated that that topical antimicrobial and systemic doxycycline along with mechanical therapy (100 mg/day for 14 days) resulted in a significant gain in attachment level and a reduction of almost 1% in the levels of HbAlc at 3 months after treatment [12]. Another study conducted by Singh et al. showed that non-surgical periodontal treatment followed by systemic doxycycline is associated with improved glycaemic control in type 2 diabetic patients [10]. This may be due to their antimicrobial effects. Based on the results of the present study, non- surgical periodontal therapy without systemic antibiotic therapy did not affect the serum level of CRP. Similarly, in a study, non-surgical periodontal therapy without systemic antibiotic therapy did not affect the serum level of high‐sensitivity C‐reactive protein (hsCRP) in Sixty participants with type 2 DM and moderate to severe periodontal disease [8]. Also, Katagiri et al. evaluated the effects of periodontal treatment simultaneously on both A1c and CRP levels in DM [13]. In that study of 49 participants, scaling and root planing plus topical treatment with minocycline ointment showed no effect on hsCRP levels after 6 months. It seems that the clinical beneficial results achieved with non-surgical periodontal treatment in the short-term are frequently not maintained in the long term, particularly in more advanced cases [6] or in those associated with risk factors, such as smoking [14] and diabetic patients [15], because of tolerance to the treatment observed in the case of smokers, or due to the higher prevalence of severe periodontitis observed in patients with diabetes mellitus [5, 15]. For this reason, it has been suggested that the administration of systemic antibiotics can be used together with scaling and root planing. The limitations of the study were the small sample size. Also, serum levels of pro-inflammatory mediators such as TNF-α, IL-1 β, IL-6 were not measured. In conclusion, there is a need for more randomized controlled clinical trials with larger sample sizes, long- term follow-ups, and strict adjustments for confounding factors, such as age, gender, body mass index (BMI), race/ethnicity, and smoking status to confirm the findings of this study Despite the improvement of clinical parameters after three months of non-surgical treatment due to no change in important serological markers associated with inflammatory disease and there is a possibility of disease progression and re-alteration of clinical parameters, it is suggested that antibiotic therapy should be used as adjunctive therapy. Acknowledgments This work was supported by the Guilan University of Medical Sciences. Author Contributions All authors contributed equally in conceptualization, methodology, software, validation, formal analysis, investigation, resources, data collection, writing original draft, visualization, supervision, and project administration. Conflicts of Interest The authors declare no potential conflicts of interest. Ethical declarations This study received ethics approval by Guilan University of Medical Sciences (Approval code: IR.GUMS.REC.1398.307). Also, the clinical trial protocol was registered (IRCT registration number: IRCT20190721044287N1) and available online. Financial Support Self-funding. References 1. Mirzaei M, Rahmaninan M, Mirzaei M, Nadjarzadeh A. Epidemiology of diabetes mellitus, pre-diabetes, undiagnosed and uncontrolled diabetes in Central Iran: results from Yazd health study. BMC Public Health. 2020; 20(1):166. 2. Thorstensson H, Hugoson A. Periodontal disease experience in adult long‐duration insulin‐dependent diabetics. J Clin Periodontol. 1993; 20(5):352-8. 3. Buset SL, Walter C, Friedmann A, Weiger R, Borgnakke WS, Zitzmann NU. Are periodontal diseases really silent? A systematic review of their effect on quality of life. J Clin Periodontol. 2016; 43(4):333-44. 4. Vaghani H, Mehta R, Desai K, Duseja S, Mehta T. Effect of Non- surgical Periodontal Therapy on Glycosylated Haemoglobin Levels in Diabetics and Non-diabetic Healthy Controls with Periodontitis. Adv Hum Biol. 2016; 6(2):95-98. 5. Wolff RE, Wolff LF, Michalowicz BS. A Pilot Study of Glycosylated Hemoglobin Levels in Periodontitis Cases and Healthy Controls. J Periodontol. 2009; 80(7):1057-61. 6. Fritoli A, Gonçalves C, Faveri M, Pérezchaparro PJ, Fermiano D, Feres M. The effect of systemic antibiotics administered during the active phase of non-surgical periodontal therapy or after the healing phase: A systematic review. J Appl Oral Sci. 2015; 23(3):249-54. https://doi.org/10.1186/s12889-020-8267-y https://doi.org/10.1186/s12889-020-8267-y https://doi.org/10.1186/s12889-020-8267-y https://doi.org/10.1186/s12889-020-8267-y https://pubmed.ncbi.nlm.nih.gov/8501275/ https://pubmed.ncbi.nlm.nih.gov/8501275/ https://pubmed.ncbi.nlm.nih.gov/8501275/ https://pubmed.ncbi.nlm.nih.gov/26810308/ https://pubmed.ncbi.nlm.nih.gov/26810308/ https://pubmed.ncbi.nlm.nih.gov/26810308/ https://pubmed.ncbi.nlm.nih.gov/26810308/ https://pubmed.ncbi.nlm.nih.gov/19563284/ https://pubmed.ncbi.nlm.nih.gov/19563284/ https://pubmed.ncbi.nlm.nih.gov/19563284/ https://pubmed.ncbi.nlm.nih.gov/26221918/ https://pubmed.ncbi.nlm.nih.gov/26221918/ https://pubmed.ncbi.nlm.nih.gov/26221918/ https://pubmed.ncbi.nlm.nih.gov/26221918/ https://pubmed.ncbi.nlm.nih.gov/26221918/ Moshtaghi Moghaddam et al. 6 7. Van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotic therapy in periodontics. Periodontol 2000. 1996; 10(1):45-78. 8. Koromantzos PA, Makrilakis K, Dereka X, Offenbacher S, Katsilambros N, Vrotsos IA, et al. Effect of Non-Surgical Periodontal Therapy on C-Reactive Protein, Oxidative Stress, and Matrix Metalloproteinase (MMP)-9 and MMP-2 Levels in Patients With Type 2 Diabetes: A Randomized Controlled Study. J Periodontol. 2012; 83(1):3-10. 9. Aldridge JP, Lester V, Watts TLP, Collins A, Viberti G and Wilson RF. Single-blind studies of the effects of improved periodontal health on metabolic control in type 1 diabetes mellitus. J Clin Periodontol. 1995; 22(4):271-5. 10. Singh S, Kumar V, Kumar S, Subbappa A. The effect of periodontal therapy on the improvement of glycemic control in patients with type 2 diabetes mellitus: a randomized controlled clinical trial. Int J Diabetes Dev Ctries. 2008; 28(2):38-44. 11. Obeid PR, D’Hoore W, Bercy P. Comparative clinical responses related to the use of various periodontal instrumentation. J Clin Periodontol. 2004; 31(3):193-9. 12. Grossi SG, Skrepcinski FB, DeCaro T, Robertson DC, Ho AW, Dunford RG, et al. Treatment of Periodontal Disease in Diabetics Reduces Glycated Hemoglobin. J Periodontol. 1997; 68(8):713-9. 13. Katagiri S, Nitta H, Nagasawa T, Uchimura I, Izumiyama H, Inagaki K, et al. Multi-center intervention study on glycohemoglobin (HbA1c) and serum, high-sensitivity CRP (hs- CRP) after local anti-infectious periodontal treatment in type 2 diabetic patients with periodontal disease. Diabetes Res Clin Pract. 2009; 83(3):308-15. 14. Silva MP, Feres M, Oliveira Sirotto TA, Silva Soares GM, Velloso Mendes JA, Faveri M, et al. Clinical and microbiological benefits of metronidazole alone or with amoxicillin as adjuncts in the treatment of chronic periodontitis: A randomized placebo- controlled clinical trial. J Clin Periodontol. 2011; 38(9):828-37. 15. Miranda TS, Feres M, Perez-Chaparro PJ, Faveri M, Figueiredo LC, Tamashiro NS, et al. Metronidazole and amoxicillin as adjuncts to scaling and root planing for the treatment of type 2 diabetic subjects with periodontitis: 1-year outcomes of a randomized placebo-controlled clinical trial. J Clin Periodontol. 2014; 41(9):890-9. https://pubmed.ncbi.nlm.nih.gov/9567937/ https://pubmed.ncbi.nlm.nih.gov/9567937/ https://pubmed.ncbi.nlm.nih.gov/21627458/ https://pubmed.ncbi.nlm.nih.gov/21627458/ https://pubmed.ncbi.nlm.nih.gov/21627458/ https://pubmed.ncbi.nlm.nih.gov/21627458/ https://pubmed.ncbi.nlm.nih.gov/21627458/ https://pubmed.ncbi.nlm.nih.gov/21627458/ https://pubmed.ncbi.nlm.nih.gov/7622632/ https://pubmed.ncbi.nlm.nih.gov/7622632/ https://pubmed.ncbi.nlm.nih.gov/7622632/ https://pubmed.ncbi.nlm.nih.gov/7622632/ https://pubmed.ncbi.nlm.nih.gov/19902046/ https://pubmed.ncbi.nlm.nih.gov/19902046/ https://pubmed.ncbi.nlm.nih.gov/19902046/ https://pubmed.ncbi.nlm.nih.gov/19902046/ https://pubmed.ncbi.nlm.nih.gov/15016023/ https://pubmed.ncbi.nlm.nih.gov/15016023/ https://pubmed.ncbi.nlm.nih.gov/15016023/ https://pubmed.ncbi.nlm.nih.gov/9287060/ https://pubmed.ncbi.nlm.nih.gov/9287060/ https://pubmed.ncbi.nlm.nih.gov/9287060/ https://pubmed.ncbi.nlm.nih.gov/19168253/ https://pubmed.ncbi.nlm.nih.gov/19168253/ https://pubmed.ncbi.nlm.nih.gov/19168253/ https://pubmed.ncbi.nlm.nih.gov/19168253/ https://pubmed.ncbi.nlm.nih.gov/19168253/ https://pubmed.ncbi.nlm.nih.gov/19168253/ https://pubmed.ncbi.nlm.nih.gov/21762197/ https://pubmed.ncbi.nlm.nih.gov/21762197/ https://pubmed.ncbi.nlm.nih.gov/21762197/ https://pubmed.ncbi.nlm.nih.gov/21762197/ https://pubmed.ncbi.nlm.nih.gov/21762197/ https://pubmed.ncbi.nlm.nih.gov/24930639/ https://pubmed.ncbi.nlm.nih.gov/24930639/ https://pubmed.ncbi.nlm.nih.gov/24930639/ https://pubmed.ncbi.nlm.nih.gov/24930639/ https://pubmed.ncbi.nlm.nih.gov/24930639/ https://pubmed.ncbi.nlm.nih.gov/24930639/