Adjuvants with non-surgical therapy in type 2 diabetes

Research Topic:

Background + Aims

Type 2 diabetes mellitus (T2DM) is a metabolic condition characterised by elevated blood sugar levels due to insufficient insulin function. Effective glycaemic control is crucial for minimising the risk of both microvascular and macrovascular complications. Research indicates that even a 1% reduction in HbA1c levels can significantly lower the incidence of related health issues.
Periodontitis, a severe gum disease, affects approximately 11% of the general population and a striking 68% of those with diabetes. While subgingival debridement is the standard treatment, adding antimicrobial therapies can enhance clinical outcomes. Studies have shown that the use of systemic antimicrobials, particularly combinations of amoxicillin with metronidazole and azithromycin, can lead to notable improvements in periodontal health.
The relationship between T2DM and periodontitis is reciprocal, with periodontal treatment demonstrating potential benefits for glycaemic control. Recent analyses have shown reductions in HbA1c levels following periodontal therapy; however, the most effective treatment modalities remain uncertain. Network meta-analysis offers a promising approach to compare various treatment regimens, but current evidence on the optimal combined therapies lacks comprehensive periodontal outcome data.
This Bayesian network meta-analysis of randomised controlled trials aims to assess the effect of adjunctive interventions on periodontal treatment (subgingival debridement) in both periodontal and HbA1c outcomes in adult individuals with type 2 diabetes.

Materials + Methods

A systematic review was conducted up to February 2023 to evaluate the effectiveness of subgingival debridement (subgingival non-surgical periodontal therapy) combined with local or systemic adjuvant therapies versus subgingival debridement alone in patients with T2DM. Studies were screened by two reviewers independently.
Eligible studies included adult participants (≥18 years) diagnosed with both T2DM and periodontitis, adhering to case definitions outlined in the relevant literature. To qualify for inclusion, studies needed to report at least one of these parameters in parallel randomised controlled trials (RCTs) and a minimum follow-up duration of three months
The interventions consisted of subgingival debridement paired with various adjuvant treatments, such as systemic or local antibiotics, lasers, and host modulation therapies, compared against no periodontal treatment, supragingival scaling, or subgingival debridement alone.
The outcomes assessed were:
- Primary outcomes – Changes in absolute HbA1c (%) levels and full-mouth probing pocket depth (PPD) measured 3 to 6 months post-treatment.
- Secondary outcomes – Clinical attachment level (CAL), bleeding on probing (BOP).
The assessment of risk of bias was conducted using Cochrane’s risk of bias tool for randomised controlled trials (RCTs). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was employed to evaluate the strength of the evidence. Sensitivity analyses were performed to examine the influence of risk of bias and discrepancies in baseline levels on the results by excluding trials that had a high or some concerns regarding bias, as well as those with baseline values outside the 15th and 85th percentiles.

Results

A systematic review included 65 two-arm and 7 three-arm randomised controlled trials (RCTs), with 15% of participants being smokers. Each study had a follow-up period of 3 to 6 months and was conducted in universities or hospitals across Asia, Europe, and South America.
Network Meta-Analysis (NMA) evaluated various interventions and yielded different treatment comparisons for key outcomes: 28 for HbA1c, 30 for PPD, 28 for CAL, and 19 for BOP.
The analysis indicated that systemic metronidazole (MD 1.4%) and alpha-lipoic acid (ALA) (MD 2.4%) significantly improved HbA1c levels compared to subgingival debridement (SD) alone. Additionally, SD outperformed no scaling (MD 0.51%).
The use of systemic ampicillin plus tinidazole (MD 1.2 mm), metronidazole (MD 0.89 mm), local tetracycline (MD 0.92 mm), and diode laser therapy (MD 0.58 mm) with SD resulted in greater reductions in PPD than SD alone. Again, SD was superior to no scaling (MD 0.55 mm).
Systemic doxycycline (MD 0.51 mm) and local tetracycline (MD 2.2 mm) significantly improved CAL when used with SD compared to SD alone, with SD also outperforming no scaling (MD 0.46 mm).
The systemic use of azithromycin (MD 22%) significantly reduced BOP compared to SD alone, with SD also showing improvement over no scaling (MD 22%).
SUCRA rankings indicated that systemic metronidazole and ALA provided the best results in reducing both HbA1c and PPD levels when used alongside SD.
Funnel plots suggested publication bias, particularly for PPD and CAL outcomes. Sensitivity analyses showed that certain treatments lost significance when excluding studies with high bias risk, indicating that unequal baseline values influenced results. Overall, the risk of bias was low in less than 20% of RCTs, leading to a low or very low certainty of evidence across all comparisons.

Limitations

Many of the interventions assessed were based on a limited number of studies, most of which exhibited significant limitations, including a high risk of bias and small sample sizes. As a result, the evidence derived from these studies is considered to have very low certainty. This is particularly relevant for the effects of metronidazole (MTZ) and alpha-lipoic acid (ALA) observed in the analysis, as these findings were largely derived from a single study with notable outcomes, suggesting the possibility of a ‘small study effect.’ This means that the actual effect may differ significantly from the estimated effect, which restricts the ability to make definitive clinical practice recommendations.
To confirm and validate our findings, larger RCTs with effective periodontal treatment protocols and extended follow-up periods should be conducted.

Conclusion

The adjunctive use of metronidazole (MTZ) or alpha-lipoic acid (ALA) has been identified as the most effective strategy for achieving significant reductions in clinically relevant HbA1c levels and PPD.
The combination of SD with systemic MTZ or ALA demonstrated notable improvements over SD alone
- MTZ contributed to a 1.4% reduction in HbA1c and a probing depth decrease of 0.89 mm.
- ALA showed a 2.4% reduction in HbA1c and a 0.92 mm decrease in probing depth.
The combination of SD with MTZ or ALA led to an absolute reduction in HbA1c of 1.8% and 2.9%, respectively, when compared to no treatment.
Other adjunct treatments also provided benefits for periodontal outcomes but did not significantly affect glycaemic control.
These findings align with previous meta-analyses indicating that SD alone is superior to either no treatment or limited periodontal interventions. However, due to the limited number of studies and the low certainty of the available evidence, clinical recommendations cannot be made until further confirmatory evidence is available.

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