Periodontal disease: associations with diabetes, glycemic control and complications
There are no financial relationships that may pose a conflict of interest.
George W Taylor, School of Dentistry and School of Public Health, University of Michigan, 1011 N. University, Ann Arbor, MI 48109, USA. Tel: 734 764 1737, Fax: 734 936 1597, E-mail: firstname.lastname@example.org
Objective: This report reviews the evidence for adverse effects of diabetes on periodontal health and periodontal disease on glycemic control and complications of diabetes.
Design: MEDLINE search of the English language literature identified primary research reports published on (a) relationships between diabetes and periodontal diseases since 2000 and (b) effects of periodontal infection on glycemic control and diabetes complications since 1960.
Results: Observational studies provided consistent evidence of greater prevalence, severity, extent, or progression of at least one manifestation of periodontal disease in 13/17 reports reviewed. Treatment and longitudinal observational studies provided evidence to support periodontal infection having an adverse effect on glycemic control, although not all investigations reported an improvement in glycemic control after periodontal treatment. Additionally, evidence from three observational studies supported periodontal disease increasing the risk for diabetes complications and no published reports refuted the findings.
Conclusion: The evidence reviewed supports diabetes having an adverse effect on periodontal health and periodontal infection having an adverse effect on glycemic control and incidence of diabetes complications. Further rigorous study is necessary to establish unequivocally that treating periodontal infections can contribute to glycemic control management and to the reduction of the burden of diabetes complications.
Diabetes mellitus and periodontal disease are two common chronic diseases that have long been considered to be biologically linked. Diabetes is an important chronic disease globally as reflected in the World Health Organization (WHO) declaring the rate of increase in diabetes prevalence is an epidemic. The WHO estimated there were 30 million people who had diabetes worldwide in 1985. This number increased to 135 million by 1995, and reached 217 million in 2005. By 2030 WHO predicts this number to increase to at least 366 million (Smyth and Heron, 2006). This growth in diabetes prevalence, driven principally by increasing prevalence of type 2 diabetes, is occurring in both developing and developed countries. The two countries with the largest predicted increases are India and China and the US ranked third (Smyth and Heron, 2006).
Susceptible individuals with diabetes and those with chronically poor metabolic control can experience microvascular and macrovascular complications leading to a significant burden for the individual and society. This burden includes direct costs of medical care and indirect costs, such as lost productivity, which result from diabetes-related morbidity and premature mortality (Harris, 1995; Hogan et al, 2003). Health care spending for people with diabetes is more than double what spending would be without diabetes, and direct and indirect expenditures attributable to diabetes in 2002 in the US were conservatively estimated at $132 billion, with slightly more spent on chronic complications attributable to diabetes than on diabetes care itself (Hogan et al, 2003). The International Diabetes Federation estimated that diabetes accounts for 5–10% of the total healthcare budget in many countries (Smyth and Heron, 2006).
Gingivitis and periodontitis are the most common periodontal diseases. For example, in the US approximately 50% of the population in all age groups exhibit reversible gingival inflammation (Albandar and Kingman, 1999). Moderate or severe periodontitis, with destruction of periodontal attachment tissues is much less common than gingivitis yet still a common chronic disease, affecting approximately 5–15% of any population (Albandar et al, 1999; Burt, 2005).
Current evidence regarding the biologic link between diabetes and periodontal disease supports diabetes and persisting hyperglycemia leading to an exaggerated immuno-inflammatory response to the periodontal pathogenic bacterial challenge (Southerland et al, 2006; Nishimura et al, 2007), resulting in more rapid and severe periodontal tissue destruction. In the metabolic dysregulation of diabetes, persisting hyperglycemia causes non-enzymatic glycation and oxidation of proteins and lipids, and the subsequent formation of advanced glycation endproducts (AGEs), which accumulate in the plasma and tissues (Brownlee, 1994; Schmidt et al, 1996b; Ramasamy et al, 2005). Hyperglycemia and resultant AGE formation are considered to be a major causal factor in the pathogenesis of diabetes complications (Brownlee, 1994; Vlassara, 1994). In subjects with diabetes who also have periodontitis, AGEs with accompanying markers for increased oxidant stress have been demonstrated in human gingiva (Schmidt et al, 1996a). Cell surface binding sites or receptors for AGE (RAGE) have been identified on the cell surfaces of several cell types exhibiting a heightened inflammatory response and involved with the pathogenesis of complications of diabetes. These cell types include mononuclear phagocytes, endothelial cells, fibroblasts, smooth muscle cells, lymphocytes, podocytes, and neurons (Brett et al, 1993; Ramasamy et al, 2005). The receptor for AGEs, RAGE, is the principal signal transducer for the AGE ligand (Schmidt et al, 2000).
The underlying postulate associated with these findings is that enhanced oxidant stress in the gingival tissues could contribute to more frequent and more severe periodontal tissue destruction in individuals with diabetes. For example, it has been hypothesized that the AGE-RAGE interaction induces an oxidant stress that may contribute to chronic monocytic upregulation, activation of NF-κB, and subsequent expression of mRNA and secretion of proinflammatory cytokines (such as TNF-α, IL-1β, and IL-6) by monocytic phagocytes involved in periodontal tissue inflammation and destruction (Baeuerle, 1991; Schreck et al, 1991; Moughal et al, 1992; Collins, 1993; Schmidt et al, 1994, 1996a; Takahashi et al, 1994; Yan et al, 1994). These mediators are recognized as effectors in periodontal tissue inflammation and destruction (Salvi et al, 1998). Blockade of RAGE has been shown to diminish Porphyromonas gingivalis-triggered alveolar bone loss in the periodontium and limit the enhanced inflammatory response in peripheral wounds, accelerating wound closure and facilitating angiogenesis (Lalla et al, 2000; Goova et al, 2001). Additionally, AGE interaction with endothelial cell RAGE has been shown to enhance endothelial cell vascular hyperpermeability and expression of vascular cell adhesion molecule-1, an adherence molecule capable of attracting mononuclear cells to the vascular wall (Schmidt et al, 1995; Wautier et al, 1996; Lalla et al, 1998b). Hence, AGE-RAGE interaction has been proposed to result in pertubation of cellular properties, exaggerated and sustained inflammatory response, impaired wound healing, and more severe diabetes-associated periodontal disease (Lalla et al, 1998a).
The specific ways in which diabetes-enhanced inflammation and apoptosis may specifically impact on periodontal tissues of was recently thoroughly reviewed (Graves et al, 2006). In their review, Graves and colleagues describe that diabetes has been reported to adversely affect bone repair by decreasing expression of genes that induce osteoblast differentiation, and diminishing growth factor and extracellular matrix production (Bouillon, 1991; Kawaguchi et al, 1994; Lu et al, 2003). One proposed mechanism for these adverse effects is through the contribution of AGEs to decreased extracellular matrix production and inhibition of osteoblast differentiation (McCarthy et al, 2001; Cortizo et al, 2003; Santana et al, 2003). AGEs may also delay wound-healing by inducing apoptosis of extracellular-matrix-producing cells. This enhanced apoptosis would reduce the number of osteoblastic and fibroblastic cells available for the repair of resorbed alveolar bone (Graves et al, 2006). In addition to promoting apoptosis, AGEs could affect oral tissue healing by reducing expression of collagen and promoting inflammation. The mechanisms suggested for AGE-enhanced apoptosis include the direct activation of caspase activity, and indirect pathways that increase oxidative stress or the expression of pro-apoptotic genes that regulate apoptosis (Graves et al, 2006).
Diabetes mellitus and its effects on periodontal disease
Evidence establishing the link between diabetes mellitus and adverse effects on periodontal health have been extensively reviewed (Taylor, 2001; Mealey et al, 2006). In a narrative review of the English language literature published between 1960 and 2000 Taylor (2001) reported that 44 of 48 observational studies provided supportive evidence of diabetes adversely affecting periodontal health provided (37 of the 41 cross-sectional and seven of the seven cohort studies).
The review conducted for this current report extends that 2001 review to include reports published into 2007. The search used MEDLINE as well as reviewed reference lists of relevant papers obtained from the search to identify primary research reports on investigations of relationships between diabetes/diabetes control and periodontal diseases/periodontal treatment. While the literature review is extensive in conducting the MEDLINE search, it is not exhaustive in that no other databases were searched. This review does not provide a formal assessment of the quality of the reports. The reports identified are displayed in table-form and the corresponding description is organized according to the following groupings of studies: (1) The effects of having diabetes on periodontal diseases in studies that include a non-diabetes comparison group (Table 1) and (2) Effect of the degree of glycemic control, usually measured by level of glycosylated hemoglobin, on periodontal status in studies that included assessment of degree of glycemic control while evaluating periodontal status in participants with diabetes (Table 2).
Table 1. Effects of diabetes on periodontal diseases in studies including a non-diabetes control group; ordered by diabetes type and subject age
|Tervonen et al (2000)||Finland||Cross-sectional||1||a. 35|
|a. 29.7 (mean)|
b. 29.0 (mean)
|XRBL: 1e||Glycemic control|
Duration of diabetes
Diabetes severity based on presence of complications
|Endean et al (2004)||Australia||Cross-sectional||2||a. 58|
|Ppd: 1p, 1s||None|
|Mattout et al (2006)||France||Cross-sectional||2||a. 71|
a. 54.5 (mean)
b. 49.0 (mean)
|Ging: 1p, 1s|
Ppd: 0p, 0s
Lpa: 1p, 1s
|Fasting blood glucose|
|Campus et al (2005)||Italy||Cross-sectional||2||a. 71|
Ppd: 1e, 1s
|Orbak et al (2002)||Turkey||Cross-sectional||2||a. 40|
|a1. 46 (mean)|
a2. 43 (mean)
b. 41 (mean)
|Ging: 1e, 1p, 1s||Glycemic control|
|Tsai et al (2002)||USA||Cross-sectional||2||a. 502|
|Lpa & Ppd: 1p||Glycemic control|
|Lu and Yang (2004)||Taiwan||Cross-sectional||2||a. 72|
|a. 54.3 (mean)|
b. 54.9 (mean)
|Ging: 1p, 1e, 1s|
Lpa: 1p, 1e, 1s
Duration of diabetes
|Chuang et al (2005)||Taiwan||Cross-sectional||2||a. 43|
a. 60.2 (mean)
b. 56.1 (mean)
|Ppd: 0s||Glycemic control|
|Sandberg et al (2000)||Sweden||Cross-sectional||2||a. 102|
|a. 64.8 (mean)|
b. 64.9 (mean)
Duration of diabetes
|Zielinski et al (2002)||USA||Cross-sectional||2||a. 32|
a. 71 (mean)
b. 74 (mean)
|Ppd: 0e, 0p, 0s||Glycemic control|
Duration of diabetes
|Borges-Yáñez et al (2006)||Mexico||Cross-sectional||2||a. 247|
a. 73.4 (mean)
|Lpa: 0p||Fasting blood glucose|
|Lalla et al (2007)||USA||Cross-sectional||1, 2||a. 350|
|Ging: 1e, 1p, 1s|
Ppd: 1e, 1p, 1s
Lpa: 1e, 1p, 1s
|Duration of diabetes|
|Arrieta-Blanco et al (2003)||Spain||Cross-sectional||1, 2||a. 70|
Ppd: 0s, 0e
Lpa: 1e, 1s
|Glycemic control Duration of diabetes|
|Ogunbodede et al (2005)||Nigeria||Cross-sectional||1, 2||a. 65|
|Ppd: 0p||Duration of diabetes|
|Xiong et al (2006)||USA||Cross-sectional||1, 2, GDM||a. 81|
|Ppd or Lpa: 1p||None|
|Novak et al (2006)||USA||Cross-sectional||2, GDM||a. 113|
|Ging & ppd & lpa: 1p, 1s||Glycemic control|
Duration of diabetes
|Mittas et al (2006)||Greece||Cross-sectional||GDM||a. 64|
|a. 31.1 (mean)|
b. 26.5 (mean)
The reports included in Table 1 were restricted to studies which compared periodontal health in subjects with and without diabetes. This subject has attracted increasing attention with greater numbers of publications in consecutive decades, ranging from six in the 1960s, eight in the 1970s, and 12 in the 1980s to 20 in the 1990s. This review identified 17 reports published in the current decade starting in the year 2000. Table 1 presents a summary of the evidence on the relationship between diabetes and periodontal disease. Studies were broadly classified and ordered by type of diabetes and age of subjects (Table 1). In contrast to seven reports of prospective studies published prior to 2000, all of the studies identified for this review are cross-sectional and thus limited in their ability to provide evidence for causal inferences. There was one study of type 1 diabetes and it reported more extensive radiographic bone loss in participants with type 1 diabetes (Tervonen et al, 2000).
Regarding the relationship between type 2 diabetes and periodontitis the review identified 10 reports. One report comprised 15–45+ year olds (Endean et al, 2004), and nine (Sandberg et al, 2000; Orbak et al, 2002; Tsai et al, 2002; Zielinski et al, 2002; Lu and Yang, 2004; Campus et al, 2005; Chuang et al, 2005; Borges-Yáñez et al, 2006; Mattout et al, 2006) included only adults. Seven of these 10 studies reported significantly poorer periodontal health in subjects with type 2 diabetes, whereas no significant difference was discerned in a study of mostly older Taiwanese dialysis patients with and without ‘insulin-dependent (type II) diabetes’ (Chuang et al, 2005) as well as in a study of U. S. university clinic patients 60+ years of age with good medical and dental care comparing well-controlled (mean HbA1c = 7.3% with 70% having HbA1c > 7.5%) subjects with diabetes to subjects without diabetes (Zielinski et al, 2002); whereas in a study of Mexicans 60+ years of age there was a marginally significantly greater prevalence (P = 0.09) of periodontitis in the group with diabetes (61.5%) than in the group without diabetes (49.5%) (Borges-Yáñez et al, 2006).
Several reports consist of analyses in which subjects with type 1 and type 2 diabetes were not distinguished. All of the studies in this subset were cross-sectional. One study included children only (Lalla et al, 2007), and all other studies included adult subjects, although one also included children or adolescents (Arrieta-Blanco et al, 2003). Two of these three studies reported greater prevalence, extent, or severity of periodontal disease for at least one measure or index of periodontal disease (Arrieta-Blanco et al, 2003; Lalla et al, 2007). One report did not find significant differences in periodontal disease between subjects with and without diabetes (Ogunbodede et al, 2005).
Two studies report on analyses on National Health and Nutrition Examination Survey III data from over 4000 women with a history of gestational diabetes (GDM) in the US. One report included ages 15–44 (Xiong et al, 2006) the other ages 20–59 (Novak et al, 2006). Both reports concluded there is a strong relationship between GDM and periodontal disease. Xiong et al (2006) found periodontitis in 45% of pregnant women with GDM vs 13% in the group without diabetes, with an adjusted odds ratio of 9.11. In non-pregnant women, 40% of women with type 1 or 2 diabetes, 25% of those with a history of GDM, and 14% of women without diabetes had periodontal disease. The odds ratio for those with type 1 and 2 diabetes was 2.76 (Xiong et al, 2006).Novak et al (2006) found the prevalence of periodontal disease to be higher in women with a history of GDM and concluded that women with at history of GDM may be at greater risk for developing more severe periodontal disease. A smaller Greek study of 34–36 weeks pregnant women also concluded gingival inflammation was more prevalent in the women with GDM (Mittas et al, 2006), but also found more plaque in that group.
As with other complications of diabetes, current evidence also supports poorer glycemic control contributing to poorer periodontal health. Primary research reports in the literature published since 2000 investigating relationships between glycemic control level and periodontal disease have included studies with subjects with type 1 diabetes exclusively (one study), type 2 diabetes exclusively (seven studies), or a combination of individuals with either type 1 or type 2 diabetes (three studies) (Table 2). Only seven of the 12 reports published regard the association between degree of glycemic control and periodontal disease specifically in type 2 diabetes (Sandberg et al, 2000; Tsai et al, 2002; Lu and Yang, 2004; Campus et al, 2005; Chuang et al, 2005; Jansson et al, 2006; Peck et al, 2006). Five of the latter found poorer glycemic control to be a significant factor associated with poorer periodontal health, the association was borderline significant in one study of dialysis patients (Chuang et al, 2005) and no difference was found in the remaining study (Sandberg et al, 2000). Among the studies providing information on differences in periodontal health classified by glycemic control status, most have been cross-sectional, with eight of 12 publications reporting more prevalent or more severe periodontal disease in those with poorer glycemic control (Tervonen et al, 2000; Tsai et al, 2002; Guzman et al, 2003; Lu and Yang, 2004; Negishi et al, 2004; Campus et al, 2005; Jansson et al, 2006; Peck et al, 2006) and four reporting no differences (Sandberg et al, 2000; Arrieta-Blanco et al, 2003; Karikoski and Murtomaa, 2003; Chuang et al, 2005). There was one follow-up study identified (evidence level II-2) that was published since 2000 (Karikoski and Murtomaa, 2003).
The preponderance of studies included in this review of reports published since 2000 on the adverse effects of diabetes on periodontal health are cross-sectional and describe findings of convenience samples, principally from outpatients in hospitals and clinics. While limitations on causal inference must be considered, these reports continue to support previous consistent evidence of greater prevalence, severity or extent of at least one manifestation of periodontal disease in the large majority of studies. The reports reviewed also provide additional evidence to support a ‘dose-response’ relationship, i.e., as glycemic control worsens, the adverse effects of diabetes on periodontal health become greater. Further, focused study of the relationship between gestational diabetes and periodontal health is emerging in body of literature.
Finally, the findings and conclusions from this review are consistent with two published meta-analyses that have provided quantitative summaries of the adverse effects of diabetes on periodontal health (Papapanou, 1996; Khader et al, 2006).
Periodontal disease: its effects on glycemic control and complications of diabetes mellitus
In addition to the substantial evidence demonstrating diabetes as a risk factor for poor periodontal health, there is a growing body of evidence supporting periodontal infection adversely affecting glycemic control in diabetes and contributing to increased risk for the pathogenesis of diabetes complications. Because of the high vascularity of the inflamed periodontium, this inflamed tissue may serve as an endocrine-like source for TNF-α and other inflammatory mediators (Offenbacher et al, 1996; Grossi and Genco, 1998). Because of the predominance of Gram-negative anaerobic bacteria in periodontal infection, the ulcerated pocket epithelium is thought to constitute a chronic source of systemic challenge from bacteria, bacterial products and locally produced inflammatory mediators. TNF-α, IL6, and IL1, all mediators important in periodontal inflammation, have been shown to have important effects on glucose and lipid metabolism, particularly following an acute infectious challenge or trauma (Feingold et al, 1989; Ling et al, 1995; Grossi and Genco, 1998). TNF-α has been reported to interfere with lipid metabolism and to be an insulin antagonist (Grunfeld et al, 1990; Feingold and Grunfeld, 1992). IL6 and IL1 have also been reported to antagonize insulin action (Ling et al, 1995; Michie, 1996; Pickup et al, 1997).
More direct, empirical evidence regarding the effects of periodontal infection on glycemic control of diabetes comes from treatment studies using non-surgical periodontal therapy and observational studies (Table 3). The treatment studies are a heterogeneous set of reports that include randomized clinical trials (RCTs) and non-RCTs. The RCTs used control groups that were either non-treated controls (Aldridge et al, 1995; Kiran et al, 2005), positive controls (Grossi et al, 1997; Rodrigues et al, 2003; Skaleric et al, 2004), or controls advised to continue with their usual source of dental care (Jones et al, 2007). Of the seven RCTs, four reported a beneficial effect for periodontal therapy (Grossi et al, 1997; Rodrigues et al, 2003; Skaleric et al, 2004; Kiran et al, 2005).
Table 3. Effects of periodontal disease and its treatment on glycemic control: clinical and epidemiological evidence, ordered by evidence level
|Aldridge et al (1995): Study 1||RCT||1||a. 16 (16–40)|
b. 15 (16–40)
|2 months||a. Oral hygiene instruction, scaling, adjustment of restoration margins, and reinforcement after 1 month.|
b. No treatment
|Glycated hemoglobin Fructosamine||Periodontal treatment had no effect on change in glycated hemoglobin||I|
|Aldridge et al (1995): Study 2||RCT||1||a. 12 (20–60)|
b. 10 (20–60)
|2 months||a. Oral hygiene instruction, scaling and root planing, extractions, root canal therapy|
b. No treatment
|Glycated hemoglobin||Periodontal treatment had no effect on change in glycated hemoglobin||I|
|Skaleric et al (2004)||RCT||1||All: 26–58 (41.8 = mean)|
a. 10 (42.0 = mean)
b. 10 (41.6 = mean)
|24 weeks||a. Scaling and root planing + minocycline microshperes (Arestin®) in pockets ≥ 5 mm at baseline and at 12 weeks|
b. Scaling and root planning
|Glycated hemoglobin||Decreased glycated hemo globin in test and control groups;|
Adjunct local Arestin® treatment is significantly more effective than scaling and root planning only
|Grossi et al (1996, 1997)||RCT||2||a. 89 (25–65)|
b. 24 (25–65)
|12 months||a. Either systemic doxycycline or placebo and ultrasonic bactericidal curettage with irrigation using either H2O, chlorhexidine, or povidone-iodine |
b. Ultrasonic bacterial curettage with H2O irrigation and placebo
|Glycated hemoglobin||The three groups receiving doxycycline and ultra sonic bacterial curettage showed significant reductions (P ≤ 0.05) in mean glycated hemo globin at 3 months||I|
|Kiran et al (2005)||RCT||2||a. 22 (31–79) (56 = mean)|
b. 22 (31–79)
(53 = mean)
|3 months||a. Scaling and root planing|
Oral hygiene instruction
b. No treatment
Fasting plasma glucose
2-h post-prandial glucose
|Decreased glycated hemoglobin and 2-h post-prandial glucose levels in treatment group only||I|
|Rodrigues et al (2003)||RCT||2||a. 15 (unknown)|
b. 15 (unknown)
|3 months||a. Initial full-mouth scaling and root planingSystemic amoxicillin/clavulanic acid 875 mg Oral hygiene instruction at baseline Control/re-instruction and prophylaxis every two weeksb. Same as a, except no medication||Glycated hemoglobin Fasting plasma glucose||Periodontal therapy was associated with improved glycemic control expressed as glycated hemoglobin and fasting plasma glucose, (but only significant improvement in glycated hemoglobin in b)||I|
|Jones et al (2007)||RCT||2*,c||a. 82 (59 = mean)|
b. 83 (60 = mean)
|4 months||a. Early Tx: scaling/root planing; 100 mg doxycycline daily for 14 days; two daily 30 cc chlorhexidine rinses for 4 months.|
b. Usual care: usual dental and medical care
|‘The results….suggest that the addition of periodontal therapy to current medical therapy may have promise in regard to improvement of glycemic control’.|
No significant differences between early treatment and usual care groups
|Talbert et al (2006)||Treatment study, non-RCT||2||a. 25 (16–64)|
|3 months||a. Scaling and root planing|
b. No control group
|Periodontal treatment did not decrease HbA1c levels||II-2|
|Smith et al (1996)||Treatment study, non-RCT||1||a. 18 (26–57)|
|2 months||a. Scaling and root planning with ultrasonic and curettes; oral hygiene instruction|
b. No control group
|Glycated hemoglobin||Found no statistically or clinically significant change in glycated hemoglobin||II-1|
|Westfelt et al (1996)||Treatment study, non-RCT||1, 2||a. 20 (45–65)|
b. 20 (45–65)e
|5 years||a. Baseline oral hygiene instruction, scaling and root planing followed by periodic prophys, OHI, localized subgingival plaque removal, and surgery at sites with bleeding on probing and PPD > 5 mm|
b. Same as group a
|Glycated hemoglobin||‘The mean value of HbA1c between BL-24 months was not signif different from that between 24–60 months’||II-1|
|Christgau et al (1998)||Treatment study, non-RCT||1, 2||a. 20 (30–66)|
b. 20 (30–66)e
|2 months||a. Scaling/root planing; subgingival irrigation with chlorhexidine; OHI; and extractions|
b. Same as group a
|Glycated hemoglobin||No effect on glycated hemoglobin||II-1|
|Taylor et al (1996)||Historical prospective cohort||2||a, b. No tx or control subjects|
49 (sev. periodis)
56 (less sev.
|2–4 years||Not applicable||Glycated hemoglobin||Those with severe periodontitis were ∼6 times more likely to have poor glycemic control at follow-up||II-2|
|Collin et al (1998)||Retrospective cohort||2||a, b. No subjects received treatment|
25 with diabetes (ages 58–76)
40 without diabetes
|2–3 years||Not applicable||Glycated hemoglobin||Among subjects with type 2 diabetes the HbA1c level significantly increased in those with advanced periodontitis, but not in those without advanced periodontitis||II-2|
|Schara et al (2006)||Treatment study, non-RCT||1||a. 10 (26–55) (38.6 = mean)|
|12 months||a. At baseline: Full-mouth disinfection; At 6 months: ultrasonic debridement; scaling & root planing; crown polishing; chlorhexidine gel, rinse, and irrigation followed by 14 days of chlorhexidine rinsing|
b. No control group
|Glycated hemoglobin||Reduction in HbA1c 3 months after each treatment, but not at 6 months post-treatment. [Baseline mean HbA1c = 10.5% (range 8.4–16.4%)]||III|
|Seppala et al (1993, 1994)||Treatment study, non-RCT||1||a. 38-1y; 22-2y 26 PIDD-1y (48 ± 6)d 12 CIDD-1y (43 ± 5) 16 PIDD-2y 6 CIDD-2y|
|1–2 years||a. Scaling and root planing, periodontal surgery, and extractions|
b. No control group
|Glycated hemoglobin blood glucose||Reported an improvement of the HBA1 levels of the PIDD and CIDD subjects (P = 0.068, t-test)||III|
|Miller et al (1992)||Treatment study, non-RCT||1||a. 10 (Unknown)|
|8 weeks||a. Scaling and root planing, systemic doxycycline|
b. No control group
|Glycated hemoglobin Glycated albumin||Found decrease in glycated hemoglobin and glycated albumin in patients with improvement in gingival inflammation (P < 0.01);|
Patients with no improvement in gingival inflammation had either no change or increase in glycated hemoglobin post treatment
|Wolf (1997)||Treatment study, non-RCT||1, 2||a. 117 (16–60)|
|8–12 months||a. Scaling and home care instr.; periodontal surgery; extractions; endodontic treatment; restorations; denture replacement or repair|
b. No control group
|Blood glucose, 24-h urinary glucose|
|Compared 23 subjects with improved oral infect. with 23 who had no improvem aft tx for oral infec. and inflam. The subj. with improved oral inflam. and infect. tended to demonstrate diab. ctrl. improvement (P < 0.1). However, Wolf states in discussion, ‘tx of periodontal inflam. and periapical lesions… does little to improve the control of diabetes’.||III|
|Iwamoto et al (2001)||Treatment study, non-RCT||2||a. 13 (19–65)|
|1 month||a. Local minocycline in every perio-dontal pocket and mechanical debridement once a week for a month|
b. No control group
|Glycated hemoglobin||Anti-infectious treatment is effective in improving metabolic control||III|
|Faria-Almeida et al (2006)||Treatment study, non-RCT||2||All: 35–70|
a. 10 (Unknown)
b. 10 (Unknown)5
|6 months||a. Scaling and root planing|
b. Same as group a
|Glycated hemoglobin||Significant reductions in HbA1c values from baseline to 3- and 6-months follow-up, respectively||III|
|Stewart et al (2001)||Treatment study, non-RCT||2||a. 36 (DM+) (62 = mean)|
b. 36 (DM+) (67 = mean)
|18 months||a. Scaling, sub-gingival curettage, and root planing Oral hygiene instruction|
b. No intervention
Changes in medications/ dosages
|Periodontal therapy was associated with improved glycemic control||III|
|Promsudthi et al (2005)||Treatment study, non-RCT||2||a. 27 (55–80)|
b. 25 (55–73)
|3 months||a. Mechanical perio treatment and systemic doxycycline 100 mg daily for 15 days|
b. No intervention
Fasting plasma glucose
|Test group: the reductions in the levels of fasting plasma glucose and HbA1c did not reach significance; ‘no association between periodontal treatment with adjunctive antimicrobial treatment and changes in HbA1c levels’||III|
|Williams and Mahan (1960)||Descriptive clinical study||9||a. 9 (20–32)|
|3–7 months||a. Extractions, scaling and curettage, gingivectomy, systemic antibiotics|
b. No control group
Diabetes control (not operationally defined)
|7/9 subjects had ‘significant’ reduction in insulin requirements||III|
An important source of variation in the RCTs is the use of adjunctive antibiotics with the non-surgical periodontal therapy. Among the RCTs, four included adjunctive antibiotics used systemically (Grossi et al, 1997; Rodrigues et al, 2003; Jones et al, 2007) or delivered locally (Skaleric et al, 2004). Three of these four RCTs using antibiotics showed beneficial effects on glycemic control (Grossi et al, 1997; Rodrigues et al, 2003; Skaleric et al, 2004). However, it is important to note the significant improvement for one study was in the positive control group that did not receive the systemic antibiotic (Rodrigues et al, 2003) and one of the four RCTs reporting a beneficial effect did not use antibiotics (Kiran et al, 2005). Hence, to date there is no clear-cut evidence to support a requirement for the use of antibiotics in combination with non-surgical periodontal treatment in order to observe an improvement in glycemic control associated with periodontal therapy.
Among the set of thirteen periodontal treatment studies that were not RCTs, eight reported a beneficial effect on glycemic control (Williams and Mahan, 1960; Wolf, 1977; Miller et al, 1992; Seppala et al, 1993; Seppala and Ainamo, 1994; Iwamoto et al, 2001; Faria-Almeida et al, 2006; Schara et al, 2006) and five did not (Smith et al, 1996; Westfelt et al, 1996; Christgau et al, 1998; Promsudthi et al, 2005; Talbert et al, 2006). Only two of these studies had control or comparison groups (Stewart et al, 2001; Promsudthi et al, 2005). Like the RCTs there was marked variation in the use of adjunctive antibiotics, with three of the five studies that used systemic antibiotics reporting a beneficial effect on glycemic control (Williams and Mahan, 1960; Miller et al, 1992; Iwamoto et al, 2001).
As shown in Table 3, there is marked heterogeneity in the studies’ designs, conduct, length of follow-up, types of participants, and periodontal treatment protocols. The details of the variation in this body of literature have been extensively described in several detailed reviews (Grossi and Genco, 1998; Taylor, 1999; Janket et al, 2005).
Additional evidence to support the effect of severe periodontitis on increased risk for poorer glycemic control comes from two longitudinal observational studies. A longitudinal epidemiological study of the Pima Indians in Arizona, USA (Taylor et al, 1996) found subjects with type 2 diabetes in good to moderate control and with severe periodontitis at baseline were approximately six times more likely to have poor glycemic control at approximately 2-years follow-up than those without severe periodontitis at baseline. In another observational study of 25 adults with type 2 diabetes, aged 58–77 years, Collin et al (1998) also reported an association between advanced periodontal disease and impaired metabolic control.
It is well recognized that poor glycemic control is a major determinant for the development of the chronic complications of diabetes. Results from the landmark Diabetes Control and Complications Trial (type 1 diabetes) and the UK Prospective Diabetes Study (type 2 diabetes) demonstrated that attaining and maintaining good glycemic control could reduce the risk for and slow the progression of microvascular complications in patients with type 1 and type 2 diabetes (Anonymous, 1993, 1998a,b) (Diabetes Control and Complications Trial Research Group, 1993). Additionally, the UKPDS observed a 16% reduction (P = 0.052) in the risk of combined fatal or nonfatal myocardial infarction and sudden death. Further epidemiological analysis from the UKPDS showed a continuous association between the risk of cardiovascular complications and glycemia; every percentage point decrease in HbAlc (e.g., 9–8%), was associated with 25% reduction in diabetes-related deaths, 7% reduction in all-cause mortality, and 18% reduction in combined fatal and nonfatal myocardial infarction (Genuth et al, 2003).
There is emerging evidence from observational studies regarding the association between periodontal disease and the risk for diabetes complications. Thorstensson et al (1996) studied 39 case-control pairs of individuals with type 1 and type 2 diabetes for 6 years median follow-up time in Jönköping, Sweden. In each pair the cases had severe alveolar bone loss and controls had gingivitis or minor alveolar bone loss. They found that cases were significantly more likely to have prevalent proteinuria, and cardiovascular complications including stroke, transient ischemic attacks, angina, myocardial infarction, and intermittent claudication than controls at their follow-up medical assessments.
Two recent reports from the on-going longitudinal study of diabetes and its complications in the Gila River Indian Community in Arizona, USA, conducted by the National Institute of Diabetes and Digestive and Kidney Diseases, address nephropathy and cardiovascular disease. Saremi et al (2005) studied a cohort of 628 individuals for a median follow-up time of 11 years. Individuals with severe periodontal disease had 3.2 times greater risk for cardio-renal mortality (i.e., ischemic heart disease and diabetic nephropathy combined) than those with no, mild, or moderate periodontal disease. This estimate of significantly greater risk persisted while controlling for several major risk factors of cardio-renal mortality including: age, sex, diabetes duration, HbA1c, body mass index (BMI), hypertension, blood glucose, cholesterol, electrocardiographic abnormalities, macroalbuminuria, and smoking.
In the second report Shultis et al (2007) investigated the effect of periodontitis on risk for development overt nephropathy (macroalbuminuria) and end-stage renal disease (ESRD) in a group of 529 Gila River Indian Community adults with type 2 diabetes. Their proportional hazards models analyses, adjusted for age, sex, diabetes duration, body mass index, and smoking, indicated periodontitis and edentulism were significantly associated with the risk of overt nephropathy and ESRD. The incidence of macroalbuminura was 2.0, 2.1, and 2.6 times greater in individuals with moderate or severe periodontitis or in those who were edentulous, respectively, than those with none/mild periodontitis. The incidence of ESRD was also 2.3, 3.5, and 4.9 times greater for individuals with moderate or severe periodontitis or for those who were edentulous, respectively, than those with none/mild periodontitis.
The clinical and epidemiological evidence reviewed provides support for the concept that periodontal infection contributes to poorer glycemic control and the risk for diabetes complications in people with diabetes mellitus. However, further rigorous, controlled trials in diverse populations are warranted to firmly establish that treating periodontal infections can be influential in contributing to glycemic control management and possibly to the reduction of the burden of complications of diabetes mellitus.
Summary and conclusion
The evidence reviewed in this report supports previous conclusions that diabetes is associated with increased occurrence and progression of periodontitis and periodontal infection is associated with poorer glycemic control in people with diabetes. There is also evidence emerging that gestational diabetes may adversely affect periodontal health. Additionally, evidence is emerging to suggest that periodontal disease is associated with increased risk for diabetes complications. While treating periodontal infection in people with diabetes is clearly an important component in maintaining oral health, it may also have an important role in establishing and maintaining glycemic control and possibly in delaying the onset or progression of diabetes complications. Further rigorous, systematic study in diverse populations is warranted to support existing evidence that treating periodontal infections can be influential in contributing to glycemic control management and possibly to the reduction of the burden of complications of diabetes mellitus.
Drs. Taylor and Borgnakke both searched the literature for reports for possible inclusion in this manuscript. Both authors reviewed reports, conferred on which articles to include, and completed article assessment forms, designed by Dr. Taylor, to summarize the content of relevance to this literature review for each included report. Dr. Taylor designed the format for the tables and both authors contributed contents in the tables. Both authors drafted sections of the manuscript and contributed in responding to reviewers' comments, participated in final review of the proofs, and approved the proofs for publication.