Over all, this meta-analysis of 10 intervention studies found a non-significant 0.38% reduction in actual value of HbA1c, and 0.71% among 5 studies conducted among patients with type 2 diabetes. However, inflammation is implicated in the pathogenesis of type 2 diabetes; thus, including subjects with type 1 diabetes, where the pathogenesis is presumed to be an autoimmune process (Ludwig and Ebbeling, 2001
), might have attenuated the effects of periodontal treatment on glycemic control. Thus, restricting the summary results among type 2 diabetic patients may be more pertinent. When each study has a very small sample size, a meta-analysis may offer a better estimate of periodontal treatment than any individual study.
Some studies might have considered their mean as a population mean and used standard errors of the means rather than standard deviation (Grossi et al., 1997
; Stewart et al., 2001
). Thus, their standard deviations were much smaller than those reported in other studies (standard deviations in parentheses): [Miller '92
(1.85), Seppala '94
(1.77), Aldridge '95
(2.00), Westfelt '96
(2.00), Grossi '97
(0.6), Christgau '98
(1.6), Stewart '01
(0.6), Iwamoto '01
(1.72), Rodrigues '03
(1.75)]. To avoid erroneously amplifying the impact of these studies on the final summary of this meta-analysis, we imputed the average standard deviation of all the studies included in this
Some studies were criticized for dispensing doxycycline systemically, and thus for potential bias due to the reduction of systemic CRP and other systemic pro-inflammatory mediators. Our results suggest, however, that doxycycline 10 mg, topically delivered in periodontal pockets (Iwamoto et al., 2001
), was more efficacious (10.5% decrease from pre-treatment level) than systemic administration of doxycycline 100 mg/day (4.7% decrease from pre-treatment levels) in reducing HbA1c (Grossi et al., 1997
). In addition, we expected that local administration would have less serious and less frequent adverse events. These facts were not known prior to our systematic review and meta-analysis, and future investigators may wish to consult our recommendations in their respective studies.
Sixty percent of our samples studied predominantly type 1 DM patients who might not have displayed any noticeable changes in HbA1c, due to etiology and tighter control of insulin and HbA1c. Thus, restricting the summary results to type 2 diabetic patients who were not on an insulin regimen (we do not have this information) might elicit the true effects of periodontal treatment.
Studies with parallel comparison groups tended to show evidence of unbalanced randomization (Grossi et al., 1997
; Rodrigues et al., 2003
). Clearly, the control group had better glycemic control at baseline, which was significant (Rodrigues et al., 2003
). In this case, adjusting for the baseline differences may be appropriate to differentiate the treatment effects from the effects due to baseline characteristics.
Recommendations for future studies are as follows:
- Type 1 diabetes is presumed to originate from an autoimmune process (Ludwig and Ebbeling, 2001), and is usually controlled by the administration of insulin. Glucose levels in these patients are very tightly monitored and adjusted frequently to prevent hypoglycemic crisis. Thus, any obvious change in HbA1c might not be evident, although it is possible that insulin requirements might have been lower. Further, type 1 diabetic patients in general may be too young to develop moderate to severe periodontitis. Thus, future study participants should be limited to type 2 diabetic patients on oral hypoglycemic agents or diet regimen only.
- Since both diabetes and periodontal disease are multifactorial, other confounding factors for TNF-α and CRP—such as smoking, BMI, and diet, as well as baseline characteristics affecting glycemic control—should be adjusted, especially when there are signs of unbalanced randomization. The exception to this principle may apply in cases where 'self' was considered as the control, and the duration of the study was reasonably short (8–12 wks). In this case, BMI change might be negligible, and if diet and smoking status did not change, no adjustment may be justified.
- Our post hoc calculation of sample size revealed that we needed at least 246 participants to observe a 10% reduction in HbA1c (0.7% in actual value of HbA1c) with 90% power. A 10% reduction in mean HbA1c is so minute that a large sample size is needed for any significance to be observed. Therefore, 90% power should be used in sample size calculation.
- HbA1c reflects the mean glucose level 2–3 mos prior to the measurement of HbA1c. Thus, duration should be at least 2 mos if any relevant changes in HbA1c are to be observed.
- Comparing the effect of periodontal therapy in diabetic patients and healthy controls incorporates bias due to effect-modification. Diabetes has been associated with heightened immune response (Firatli, 1997; Beck et al., 1998). Thus, the intervention should be rendered only to diabetic patients with the same type, similar duration after diagnosis, and similar baseline glycemic control.
- The intervention should result in a clear improvement in periodontal health. Ineffective interventions may not be different from non-intervention. Also, amoxicillin administration, when causative agents are predominantly Gram-negative organisms, may elicit less efficacious results (Rodrigues et al., 2003). Local doxycycline treatment targeted to periodontal tissue appeared to be most effective in reducing blood HbA1c levels (Iwamoto et al., 2001). We postulated that local delivery of doxycycline would be associated with fewer adverse events. Our assumption was confirmed when we contacted the investigators of the study where doxycycline was delivered locally. They observed no adverse events among 13 patients in a month-long trial (personal communication via e-mail with Drs. Nishimura/Iwamoto). However, since this observation was drawn from a single study, further corroboration by future studies is necessary before we can make clear recommendations. Although sample size was larger (N = 140), the VA dental diabetes study documented adverse events with systemic doxycycline administration in 19% of the participants, and 16.4% (86% of all adverse events) showed mild to severe gastro-intestinal irritation (Jones et al., 2005).
Periodontal therapy with antibiotics appeared to decrease HbA1c levels by statistically non-significant 0.71% among patients with type 2 diabetes. Although this percent improvement in glycemic control may be of value to some patients, the evidence currently available was not strong enough for us to reject the null hypothesis, "periodontal treatment does not affect glycemic control in patients with diabetes". Further studies with a larger sample size among appropriate target populations and utilizing effective treatments are needed to discern whether there is a significant clinical benefit of periodontal therapy on blood sugar control in persons with type 2 diabetes.