Abstract
Objective
To assess the effects of adjunctive use of systemic antibiotics in nonsurgical periodontal treatment compared to nonsurgical periodontal treatment alone, on mean glycated hemoglobin (HbA1c) reductions in patients with diabetes.
Data
Two independent reviewers screened six electronic databases, registers of clinical trials, meeting abstracts and four major dental journals for controlled clinical trials with at least 3-month follow-up.
Sources
After duplicates removal, electronic and hand searches yielded 2136 records; 32 full-text articles were independently read by two reviewers. To evaluate the additional effect of antibiotic usage, pooled weighted mean differences and 95% confidence intervals were calculated using fixed and random effects models.
Study selection
Twelve studies met the inclusion criteria, nine of which provided data that allowed their inclusion in meta-analyses. The meta-analyses showed no significant effect favouring scaling and root planing (SRP) plus antibiotic for reductions in mean HbA1c (−0.11% [−0.35, 0.13]; 6 studies), and an estimated prediction interval varying from −0.45 to 0.23. There was also no significant effect favouring the adjunctive usage of sub-antimicrobial doxycycline in HbA1c mean reduction (−0.19% [−1.04, 0.67]; 2 studies).
Conclusion
Adjunctive use of systemic antibiotic provides no statistically significant benefit in terms of HbA1c improvement in periodontal treatment of patients with diabetes.
Clinical significance
Adjunctive use of systemic antibiotics associated with nonsurgical periodontal treatment provides no additional benefit in terms of HbA1c of diabetic patients. Clinicians should weigh the trade-off between risks and benefits provided by the use of systemic antibiotics before prescribing them for periodontal disease treatment.
1
Introduction
Periodontitis and diabetes are two interrelated chronic diseases; diabetes might lead to enhanced periodontal destruction due to a dysregulated inflammatory response and an impairment of the resolution of inflammation and repair, whereas periodontitis might negatively affect the glycemic control and contribute to the development of complications in diabetic patients . In addition, periodontal treatment might positively influence the glycemic control in this group of patients . A meta-analysis has found that periodontal treatment improved glycemic control in patients with diabetes, with a mean percentage 3–4 month reduction in glycated hemoglobin (HbA1c) of 0.29% (0.10–0.48%) . The risk of any outcome related to diabetes is reduced by 21% by each 1% reduction in mean HbA1c .
The use of systemic antibiotics as an adjunctive measure to standard periodontal treatment, i.e. scaling and root planing, has been employed for a long time aiming to reduce the number of pathogenic bacteria in the periodontal environment . Indeed, meta-analyses have shown that the adjunctive use of systemic antibiotics provide some clinical benefit, such as probing depth reduction, over scaling and root planing alone in otherwise healthy patients with periodontitis . In diabetic patients, adjunctive antibiotics provide small but statistically significant benefits in terms of reductions in mean probing depth and mean percentage of bleeding on probing .
Since diabetic patients exhibit impaired wound healing and are at higher risk for periodontitis, a periodontal treatment approach specifically targeted at these patients, which incorporates antimicrobial therapy and pharmacological modulation of the host response, was proposed. This approach aimed to eliminate periodontal infection, reduce associated inflammation and improve the metabolic control . However, the evidence regarding the effects of systemic antibiotics adjunctive to mechanical periodontal treatment on HbA1c levels in diabetic patients is conflicting , and a thorough synthesis of all available studies on the topic is needed to clarify whether the use of antibiotics could provide benefits in terms of glycemic control in these patients. This study aimed to assess the effects of adjunctive use of systemic antibiotics in nonsurgical periodontal treatment, compared to nonsurgical periodontal treatment alone, on metabolic control in patients with diabetes.
2
Material and methods
This is a systematic review of controlled clinical trials that assessed changes in glycated hemoglobin (HbA1c) levels in diabetic patients with periodontitis after scaling and root planing (SRP) combined with systemic antibiotics or sub-antimicrobial doxycycline (SDD) in comparison to SRP alone, with or without a placebo. Studies where participants had chronic and aggressive periodontitis were considered for inclusion with no age restriction, but studies involving gestational diabetes were not eligible . Studies were also excluded when systemic antibiotics were used only in periodontal supportive therapy or as co-interventions such as slow-release devices or subgingival irrigation with antimicrobials. Only trials with a follow-up of at least three months were considered for inclusion.
The following databases were searched from their earliest records through September 2016: MEDLINE via PubMed, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, BBO (Brazilian Dental Library), and the Brazilian database of theses and dissertations ( Banco de Teses CAPES ). The strategy was developed for MEDLINE using controlled vocabulary, with words derived from “Medical Subject Headings” (MeSH) associated with free terms relevant to the topic in question; the asterisk symbol (*) was used for truncation ( Table 1 ). This strategy was adapted for the other databases without any idiom restrictions.
| #1 periodontal disease* (MeSH term); or periodontal index* (MeSH term); or aggressive periodontitis (MeSH term); or chronic periodontiti* (MeSH term); or alveolar bone loss* (MeSH term); or periodontal attachment loss (MeSH term); or periodontal pocket* (MeSH term); or furcation defect* (MeSH term); or tooth loss (MeSH term); or tooth mobilit* (MeSH term); or periodont* (All fields); attachment loss (All fields); or bone loss* (All fields) |
| #2 dental scaling (MeSH term); or subgingival curettage* (MeSH term); or root planing* (MeSH term); or periodontal debridement* (MeSH term); or periodontal treatment (All fields); or periodontal therapy (All fields); or (scaling and root planing) (All fields); or nonsurgical periodontal treatment (All fields); or non-surgical periodontal treatment (All fields); or non surgical periodontal treatment (All fields); or full-mouth debridement (All fields); or tooth scaling (All fields); or teeth scaling (All fields); or subgingival scaling (All fields) |
| #3 diabetes mellitus (MeSH term); or diabetes mellitus, type 1 (MeSH term); or diabetes mellitus, type 2 (MeSH term); hemoglobin a, glycosylated (MeSH term); or hyperglycemia* (MeSH term); or glucose (MeSH term); or glucose intolerance* (MeSH term); or blood glucose (MeSH term); or insulin resistance (MeSH term); diabet*(All fields); or mellitus (All fields); or diabetic patient (All fields); or type 1 diabetes (All fields); or type 2 diabetes (All fields); or DM (All fields); or DM1 (All fields); or DM2 (All fields) |
| #4 antibiotic prophylaxis (MeSH term); or amoxicillin (MeSH term); or metronidazole (MeSH term); or azithromycin (MeSH term); or tetracycline (MeSH term); or tetracyclines (MeSH term); or doxycycline (MeSH term); or erythromycin (MeSH term); antibiot* (All fields); or sub-antimicrobial doxycycline (All fields); or anti-infective agent* (All fields); or antiinfective agent* (All fields); or anti infective agent* (All fields); or anti-bacterial agent*; or antibacterial agent*; or anti bacterial agent*; or anti-microb*(All fields); or antimicrob*(All fields); or systemic treatment (All fields); or systemic therapy (All fields); or systemic (All fields); or adjunctive therapy (All fields); or adjunctive (All fields) |
| #1 and #2 and #3 and #4 |
The following registers of ongoing trials were also scrutinized: ClinicalTrials.gov, Current Controlled Trials, EU Clinical Trials Register, Australian New Zealand Clinical Trials Registry, and Registro Brasileiro de Ensaios Clínicos (ReBEC). The following journals were handsearched: Journal of Dental Research (since 2004), Journal of Periodontal Research (since 2004), Journal of Clinical Periodontology (since 2003) and Journal of Periodontology (since 2003). Journals included in the Cochrane Master List of Journals Being Searched were examined from the last update onward. In addition, abstracts from the International Association for Dental Research (2001–2015) and the European Federation of Periodontology meetings (EuroPerio 4–7) were examined.
Two independent reviewers (RLJ and CMMLS) read the titles and the available abstracts of all records identified. The full-text article was obtained whenever a study seemed to meet the inclusion criteria, but complete information was lacking. By using a pre-defined data extraction form, the reviewers independently extracted the data on characteristics of the study population, length of follow-up, interventions and outcomes. Attempts were made to contact authors in order to obtain relevant missing data. Disagreements were solved by discussion with two other reviewers (BHO and APPS).
The Cochrane Collaboration tool for assessing risk of bias was used in the included studies . The following domains were evaluated as having low, high or unclear risk of bias: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, losses to follow-up (low risk of bias when losses were non-differential and less than 20%), diagnosis reliability (low risk of bias when good, according to Altman ), and comparability between groups at baseline .
Meta-analyses of the differences in three-month means were performed. Heterogeneity of studies was assessed by Chi-square (χ 2 ) test for heterogeneity and Higgins index (I 2 ). A random-effects model was used, despite the absence of statistical heterogeneity, when meta-analysis included more than four studies performed by researchers operating independently because it was unlikely that these studies were functionally equivalent and therefore were estimating the same effect. When fewer than four studies were included, the fixed-effect model was used, since under the random-effects model the estimate of the between-studies variance has poor precision when the number of studies is very small . All analyses were carried out in Stata ® 13 (StataCorp LP, College Station, Tex., USA).
2
Material and methods
This is a systematic review of controlled clinical trials that assessed changes in glycated hemoglobin (HbA1c) levels in diabetic patients with periodontitis after scaling and root planing (SRP) combined with systemic antibiotics or sub-antimicrobial doxycycline (SDD) in comparison to SRP alone, with or without a placebo. Studies where participants had chronic and aggressive periodontitis were considered for inclusion with no age restriction, but studies involving gestational diabetes were not eligible . Studies were also excluded when systemic antibiotics were used only in periodontal supportive therapy or as co-interventions such as slow-release devices or subgingival irrigation with antimicrobials. Only trials with a follow-up of at least three months were considered for inclusion.
The following databases were searched from their earliest records through September 2016: MEDLINE via PubMed, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, BBO (Brazilian Dental Library), and the Brazilian database of theses and dissertations ( Banco de Teses CAPES ). The strategy was developed for MEDLINE using controlled vocabulary, with words derived from “Medical Subject Headings” (MeSH) associated with free terms relevant to the topic in question; the asterisk symbol (*) was used for truncation ( Table 1 ). This strategy was adapted for the other databases without any idiom restrictions.
| #1 periodontal disease* (MeSH term); or periodontal index* (MeSH term); or aggressive periodontitis (MeSH term); or chronic periodontiti* (MeSH term); or alveolar bone loss* (MeSH term); or periodontal attachment loss (MeSH term); or periodontal pocket* (MeSH term); or furcation defect* (MeSH term); or tooth loss (MeSH term); or tooth mobilit* (MeSH term); or periodont* (All fields); attachment loss (All fields); or bone loss* (All fields) |
| #2 dental scaling (MeSH term); or subgingival curettage* (MeSH term); or root planing* (MeSH term); or periodontal debridement* (MeSH term); or periodontal treatment (All fields); or periodontal therapy (All fields); or (scaling and root planing) (All fields); or nonsurgical periodontal treatment (All fields); or non-surgical periodontal treatment (All fields); or non surgical periodontal treatment (All fields); or full-mouth debridement (All fields); or tooth scaling (All fields); or teeth scaling (All fields); or subgingival scaling (All fields) |
| #3 diabetes mellitus (MeSH term); or diabetes mellitus, type 1 (MeSH term); or diabetes mellitus, type 2 (MeSH term); hemoglobin a, glycosylated (MeSH term); or hyperglycemia* (MeSH term); or glucose (MeSH term); or glucose intolerance* (MeSH term); or blood glucose (MeSH term); or insulin resistance (MeSH term); diabet*(All fields); or mellitus (All fields); or diabetic patient (All fields); or type 1 diabetes (All fields); or type 2 diabetes (All fields); or DM (All fields); or DM1 (All fields); or DM2 (All fields) |
| #4 antibiotic prophylaxis (MeSH term); or amoxicillin (MeSH term); or metronidazole (MeSH term); or azithromycin (MeSH term); or tetracycline (MeSH term); or tetracyclines (MeSH term); or doxycycline (MeSH term); or erythromycin (MeSH term); antibiot* (All fields); or sub-antimicrobial doxycycline (All fields); or anti-infective agent* (All fields); or antiinfective agent* (All fields); or anti infective agent* (All fields); or anti-bacterial agent*; or antibacterial agent*; or anti bacterial agent*; or anti-microb*(All fields); or antimicrob*(All fields); or systemic treatment (All fields); or systemic therapy (All fields); or systemic (All fields); or adjunctive therapy (All fields); or adjunctive (All fields) |
| #1 and #2 and #3 and #4 |
The following registers of ongoing trials were also scrutinized: ClinicalTrials.gov, Current Controlled Trials, EU Clinical Trials Register, Australian New Zealand Clinical Trials Registry, and Registro Brasileiro de Ensaios Clínicos (ReBEC). The following journals were handsearched: Journal of Dental Research (since 2004), Journal of Periodontal Research (since 2004), Journal of Clinical Periodontology (since 2003) and Journal of Periodontology (since 2003). Journals included in the Cochrane Master List of Journals Being Searched were examined from the last update onward. In addition, abstracts from the International Association for Dental Research (2001–2015) and the European Federation of Periodontology meetings (EuroPerio 4–7) were examined.
Two independent reviewers (RLJ and CMMLS) read the titles and the available abstracts of all records identified. The full-text article was obtained whenever a study seemed to meet the inclusion criteria, but complete information was lacking. By using a pre-defined data extraction form, the reviewers independently extracted the data on characteristics of the study population, length of follow-up, interventions and outcomes. Attempts were made to contact authors in order to obtain relevant missing data. Disagreements were solved by discussion with two other reviewers (BHO and APPS).
The Cochrane Collaboration tool for assessing risk of bias was used in the included studies . The following domains were evaluated as having low, high or unclear risk of bias: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, losses to follow-up (low risk of bias when losses were non-differential and less than 20%), diagnosis reliability (low risk of bias when good, according to Altman ), and comparability between groups at baseline .
Meta-analyses of the differences in three-month means were performed. Heterogeneity of studies was assessed by Chi-square (χ 2 ) test for heterogeneity and Higgins index (I 2 ). A random-effects model was used, despite the absence of statistical heterogeneity, when meta-analysis included more than four studies performed by researchers operating independently because it was unlikely that these studies were functionally equivalent and therefore were estimating the same effect. When fewer than four studies were included, the fixed-effect model was used, since under the random-effects model the estimate of the between-studies variance has poor precision when the number of studies is very small . All analyses were carried out in Stata ® 13 (StataCorp LP, College Station, Tex., USA).
3
Results
The electronic search retrieved 2311 records. One additional record was found after hand searching IADR meeting abstracts. After excluding duplicates, there were 2136 records, 2104 of which did not meet the inclusion criteria; 33 were selected for full reading, but one full-text could not be obtained. Thus, 32 papers were read and assessed for eligibility. Twelve studies met the inclusion criteria and nine were included in the meta-analyses. It was not possible to obtain HbA1c levels data from three studies, as they were presented in charts in two papers , and as a dichotomous variable in one trial , even after contacting the authors. Fig. 1 describes the studies identified, screened, assessed for eligibility, excluded and included in the review. The list of 18 excluded studies and the reasons for their exclusion are presented in the S1 Appendix.
