Diabetes and Periodontitis: The Associations, the Risk, and the Need for Optimal Control

Introduction

The bridge between systemic and oral health has been strengthened over the past decade by multiple publications in medical and dental journals. The oral focus of these publications has been on periodontal diseases, which are the most common dental conditions. The strongest data supporting an oral-systemic association exists for diabetes and periodontitis.

Despite multiple published reports of this association, which date back to the 1920s¹ and 1930s,² many practitioners in the medical and dental fields have been unable to convert these findings into clinical actions. A recent survey of general dentists and periodontists revealed that the dental practitioner's rates of proactive management of diabetic patients (eg, willingness to change/adjust treatment plans) and referring patients for evaluation of suspected diabetes or screening for diabetes with a finger-stick test may actually be quite low.³

There is no doubt that poor control of diabetes increases the risk for developing a number of oral manifestations of the disease, including periodontitis. In addition, an uncontrolled oral infection such as periodontitis increases the risk for poor metabolic control and certain long-term complications of the diabetes, particularly nephropathy⁴ and cardiovascular disease (CVD).⁵ Recent research has shown that improving oral health is important to optimizing metabolic control of diabetes. This association has led to the belief that not only is metabolic control key to the proper management of the diabetic patient, but we can now conclude that the treatment of periodontal diseases should not be considered an option or elective, but instead a necessary and integral part of a patient's overall health care program. Just as the bar has been raised for the proper management by the physician of diabetic patients requiring tighter control (ie, lower hemoglobin A_1c levels), so too must dentists raise the bar for the level of oral care provided to diabetic individuals because periodontal evaluation and therapy appear to be necessary for the physician and patients to achieve their ultimate goal of preventing the long-term complications of diabetes.

The American Medical Association (AMA) and American Dental Association (ADA)

A joint press conference was held in February 2006 between the AMA and the ADA entitled "Oral and Systemic Health: Exploring the Connection" to address the emerging data associating periodontitis to diabetes, heart disease, stroke, respiratory infections, and adverse pregnancy outcomes.⁶ The esteemed speakers from the dental and medical professions who participated in this media briefing emphasized the need for collaborative efforts to achieve optimal overall care for patients. Studies supporting these associations were presented, as well as the results of some pilot intervention studies demonstrating that periodontal therapy can improve metabolic control in diabetes, reduce pre-term birth in high-risk pregnant females, and reduce pneumonia in patients in intensive care units.

However, despite the strong data confirming the association between diabetes and periodontitis, oral health was barely addressed in the Clinical Practice Recommendations of the American Diabetes Association for the Standards of Medical Care in Diabetes.⁷ There was a brief mention in its components of the comprehensive diabetes evaluation (Table 1) under medical history, where current or prior infections include dental infection, yet periodontitis is not listed below as a complication associated with diabetes. It is interesting that an oral examination is suggested as part of the physical examination, but dentists are not listed as one of the referrals to be considered.

Hopefully the joint media briefing between the AMA and the ADA will help to forge an alliance between the medical and dental professions, as well as among all other allied health providers, to incorporate the mounting findings connecting oral and systemic health into the respective management of patients with diabetes. It is also important that the ADA—representing the dental profession—and the American Diabetes Association—which is actively involved in the development and dissemination of diabetes care standards and guidelines—recognize the synergy that can be achieved by working together to inform patients and practitioners of the importance of good oral health to the overall well-being of the diabetic patient.

The Importance of Knowledge Transfer

It is the practitioner's charge to empower their patients with the knowledge necessary to combat their disease. Practitioners should inform their patients about the associations between diabetes and other diseases, such as periodontitis. Interaction with many patients and diabetes support groups reveals that the dissemination of this information to patients is lagging behind the publication of significant supporting studies. Sharing information such as that presented in this publication will enable patients to better assess their risk for developing certain long-term complications of diabetes, as well as motivate them to determine—through appropriate evaluations—what preventive measures can be taken and whether or not they require active therapy and follow-up care.

Diabetes and periodontitis are diseases that cannot currently be cured, but with appropriate therapy, regular follow-up, and a motivated patient, they can be kept under control. Successful management of these diseases requires frequent monitoring of the patient and careful attention to therapeutic responses. A team effort is truly necessary for the proper management of the diabetic patient: the physician, nurse, diabetes educators, dieticians, dentists, hygienists, and a number of other specialists should work collaboratively in the patient's best interest.

Diabetes

Diabetes mellitus is a disease of metabolic dysregulation, primarily carbohydrate metabolism. It is characterized by hyperglycemia or elevated blood glucose levels. Hyperglycemia is due to defects in insulin secretion and/or impaired insulin action. Alterations in lipid and protein metabolism are also hallmarks of the disease. In 2004, 18.2 million Americans (ie, 6.3% of the population) were believed to have diabetes, with 13 million diagnosed and an estimated 5.2 million not diagnosed. From 1980 to 2004, the number of Americans with diabetes more than doubled.⁸ In 2004, about 1.4 million adults between 18 and 79 years of age were diagnosed with diabetes.⁹ The reasons for such an increase include increasing longevity, change in demographics, and genetic predispositions. Rising urbanization and changes in lifestyle also play a role, in addition to an increased prevalence of obesity. In the United States, obesity is known to play a major role, with more than 60% of the adult population considered either overweight or obese.

There are a number of long-term complications that result as chronic hyperglycemia persists and leads to dysfunction and damage of numerous organs. These include complications related to angiopathy, nephropathy, retinopathy, neuropathy, wound healing, and periodontitis. Periodontitis was identified as the sixth long-term complication of diabetes by Dr. Harold Loe, the former director of the National Institute for Dental and Craniofacial Research.¹⁰ Ninety percent to 95% of all cases of diabetes in the United States are type 2. Half of all people with type 2 diabetes are unaware that they even have the disease because it is possible to have mild symptoms that would not lead to a timely diagnosis.

This presents a substantial health care problem considering the long-term complications of the disease. Diabetes is the leading cause of blindness in adults. End-stage renal disease, cardiovascular complications, and nontraumatic amputations are additional complications, and the health care costs are immense: $132 billion annually.¹¹ In 1997, 159,720 deaths were attributed to diabetes and its complications, with cardiovascular complications accounting for the majority (92,557) of the fatalities.¹²

There are an additional 41 million adults aged 40-74 who are considered to be pre-diabetic. There is evidence to suggest that chronic inflammation may play a role in converting these pre-diabetic individuals to diabetics, and there are criteria for testing for diabetes in asymptomatic adult individuals (Table 2).⁷ The presence of significant periodontitis with no evident risk factors (eg, smoking or poor oral hygiene) can sometimes be a sign that systemically the patient may have an underlying disease such as diabetes.

Dentists should be very suspicious of rapidly progressing cases of periodontitis with no apparent risk factors. Risk assessment needs to be conducted on a regularly basis because a patient's risk will change based on environmental and systemic factors. Suspicious cases of periodontitis should be referred from the dentist/hygienist to a physician for evaluation of underlying systemic contributions, such as those seen in diabetics.

Periodontitis

The association between periodontal and systemic health is a two-way street, particularly when it comes to periodontitis and diabetes mellitus. A number of systemic diseases and conditions can increase a patient's susceptibility to periodontitis, with significant data supporting the contribution of diabetes mellitus. Furthermore, poor metabolic control of diabetes may not only make an individual more susceptible to developing periodontitis but can lead to more aggressive periodontitis once it has developed (Figure 1). However, it is generally accepted that adults whose diabetes is well-controlled do not have more destructive periodontitis than non-diabetics. Conversely, periodontal infections may have an impact on systemic health, particularly for diabetes, where untreated periodontitis may impede metabolic control. Periodontitis can impair a diabetic's ability to process and/or utilize insulin, which obviously leads to less optimal diabetic control. To prevent this vicious cycle of events from occurring, it is important for diabetics to be aware of their periodontal status.

Understanding the pathway to periodontitis is important to understanding these associations because it helps healthcare professionals consider the possible mechanisms by which oral and systemic diseases—such as periodontitis and diabetes—are associated. It is the microbial challenge that initiates periodontal disease. The presence of endotoxins, antigens, and other virulence factors stimulate the host immuno-inflammatory response. Neutrophils are recruited to the site of infection to address the pathogenic microbes, which invokes an antibody response. In more resistant individuals, the development of gingivitis is observed, but without the breakdown of the bone and connective tissue that's seen in periodontitis. However, in susceptible individuals, very high levels of proinflammatory mediators, known as cytokines and prostanoids, as well as enzymes such as matrix metalloproteinases, will be secreted into the tissues. These are the factors that lead to connective tissue destruction and bone metabolism changes. In the clinical setting, this presents as the sign of periodontal disease: increases in probing pocket depths, loss of clinical attachment, and radiographic evidence of bone loss. Unfortunately for diabetic patients, their diabetic condition leads to an overproduction of proinflammatory mediators, which in turn can cause more aggressive periodontal disease (Figure 1).

Diabetics may also experience decreased or diminished flow of saliva and increases in sugars in the saliva and the fluid between the teeth and gums, known as gingival crevicular fluid. All of these factors can lead to increased plaque and calculus formation, thereby increasing the chance of not only developing periodontal disease but also a higher risk for caries. Xerostomia or dry mouth can also contribute to the development of candidiasis (eg, burning mouth and tongue). The administration of anti-fungal agents may be necessary for the management of candidiasis. The management of oral burning symptoms can include the maintenance of adequate oral hydration and restrictions on the intake of caffeine and alcohol.

In addition, preventive measures for infection and delayed wound healing need to be taught at all levels because diabetics are at greater risk for infection, and delayed wound healing is a well-known complication of diabetes. Preventive measures include frequent dental visits to assess plaque control, risk assessment profiles to identify risk—particularly preoperatively, as well as postoperative antibiotic therapy, if necessary, and the avoidance of compounding risk factors such as smoking.

The Systemic Impact of Oral Infection and Inflammation in Diabetes

The surface area of the pocket epithelium is estimated to be the equivalent of the surface area of the palm of one or even two hands, depending on the severity of periodontal disease.¹³ In a poorly controlled diabetic patient, the extent of the oral challenge to the patient once identified may be clearly evident (Figure 2). If a patient had an equivalent challenge anywhere else on the body, such as a non-healing ulcer on the leg of a diabetic patient (Figure 3), it certainly would be of concern as it is easily visible. A bacterial infection of the gingival tissues and the ensuing inflammation resulting in periodontitis can complicate the management of diabetes in the same manner as any other unresolved infection in the body, such as a chronic foot ulcer.

Periodontal disease is very often a silent disease, with few obvious signs and symptoms, similar to type 2 diabetes. Periodontitis, if left untreated, often increases in severity, making it a leading cause of adult tooth loss in the United States. Juvenile diabetic patients are just as susceptible to periodontal disease as adult diabetics. Early detection could prevent unnecessary tooth loss.

Individuals with diabetes who have periodontal disease are more prone to develop abscesses or areas around certain teeth that, in addition to being inflamed and infected, may swell and become painful. Periodontitis must be treated regularly through professional care to halt the progress of the disease and prevent tooth loss. Just as a patient works closely with their physician to monitor the status of their diabetes to keep it under control, so too must they work closely with their dentist to monitor their periodontal status, which may have a significant impact on the control of their diabetes.

It is important for dental practitioners to explain the dangers of a hidden oral infection not only to their patients but also to physicians. Many physicians are often unaware of the significant challenge that oral infection and inflammation may present to the entire body. If periodontitis is left untreated, bacteria may eventually enter the bloodstream, attracting platelets and possibly putting patients at greater risk for a number of systemic diseases, including CVD, which is the number one killer of people with diabetes.¹² The systemic exposure to periodontal pathogens is a result of the loss of the epithelial integrity within the periodontal pockets in people with periodontal disease, allowing for bacterial penetration into the tissues and eventually the blood stream, resulting in a bacteremia. Recurrent transient bacteremias can occur every time a person with untreated periodontitis eats.

Oral pathogens have been found throughout the body, even in atheromatous plaques.¹⁴ Endotoxins from these pathogens can also penetrate into the tissues, resulting in endotoxemia. In addition, many of the proinflammatory mediators present in patients with periodontitis can be found not only locally within the gingival crevicular fluid—flowing out of their pockets—but also within the gingival tissues, alveolar bone, and eventually in the blood stream, resulting in systemically elevated levels of interleukins (IL-1 and IL-6), tumor necrosis factor-α (TNF-α), and prostanoids. When there is gingival inflammation, there is much more vascularity in these tissues and, therefore, a greater chance for bacteremia and endotoxemia to occur, and more chances for the inflammatory mediators to enter into the bloodstream. Once all of these factors are introduced into the systemic circulation, they can have a profound effect on the patient, particularly the diabetic patient, leading to insulin resistance and resulting in difficulties in achieving metabolic control of the diabetes.

Periodontitis, C-Reactive Protein (CRP), and Diabetes

The persistent chronic inflammation related to untreated periodontitis ultimately results in elevations of the systemic inflammatory marker CRP that is produced by the liver in response to bacterial challenge and chronic inflammation.^15-19 High sensitivity or hsCRP is one of the best indicators for risk of CVD and, along with cholesterol levels, provides the most accurate risk assessment for future cardiovascular events.²⁰ Regarding CVD risk, a cross-sectional study of 3,873 subjects from the National Health and Nutrition Examination Survey (NHANES) reported odds ratio for CVD of 1.99 (95% CI 1.10-3.59) for subjects without diabetes with high CRP levels.²¹ For those with diabetes and low CRP levels, the reported odds ratio for CVD jumped to 3.21 (1.27-8.09). Finally, the data demonstrate that the likelihood of CVD was highest in those with diabetes and either intermediate or high CRP levels, with reported odds ratios for CVD of 6.01 (2.54-14.20) and 7.73 (3.99-14.95), respectively.

The Insulin Resistance Atherosclerosis Study (IRAS) provided evidence demonstrating that inflammation is associated with insulin sensitivity, even in patients without diabetes.²² The study found a strong independent association between the levels of CRP and insulin sensitivity. Higher levels of CRP are associated with a greater degree of insulin resistance. Serum concentrations of CRP and other markers of inflammation were significantly related to the development of type 2 diabetes in 1,047 non-diabetic subjects followed for 5 years in the IRAS.²³ The IRAS investigators concluded that chronic inflammation has emerged as a new risk factor for type 2 diabetes. In the context of this paper, this could imply that untreated periodontitis, which is a well-known chronic inflammatory condition, might increase a person's risk for the development of type 2 diabetes. Therefore, future studies should be designed to address this issue, and appropriate management of chronic oral inflammation in patients should be a priority for all dental professionals.

Metabolic Control (HbA_1c) and Periodontitis

Prospective randomized clinical trials such as the Diabetes Complication and Control Trial (DCCT)²⁴ and the U.K. Prospective Diabetes Study (UKPDS)²⁵ found that improved control of blood glucose reduces the risk of a number of long-term complications, particularly retinopathy, nephropathy, and neuropathy.²⁶ The potential for intensive glycemic control to reduce CVD is emerging, as supported by epidemiological studies^27,28 and a meta-analysis²⁹ but has not yet been demonstrated in a randomized clinical trial. The major marker of metabolic control for physicians is the level of glycosylated hemoglobin (HbA_1c), which is a long-term marker of control measuring the patient's average glycemia over the past 2 to 3 months³⁰ (unlike blood glucose, which fluctuates daily and as we eat). HbA_1c levels of 4% to 6% are normal; < 7% is considered good diabetes control; 7% to 8% is moderate control; and with > 8%, action is suggested to improve control. Clinical Practice Recommendations of the American Diabetes Association for the Standards of Medical Care in Diabetes⁷ suggest that the A_1c goal for patients in general is < 7%, but that for the individual patient, < 6% is preferred if this can be accomplished without significant hypoglycemia. The less stringent goals are for patients with a history of severe hypoglycemia, patients with limited life expectancies, very young or old individuals, and those with comorbid conditions. Aggressive glycemic management may reduce morbidity in patients with severe acute illness, perioperatively, following acute myocardial infarction, and in pregnancy.

It is the primary objective of most physicians to keep these levels low to prevent long-term complications. HbA_1c testing is recommended at least twice a year for patients with stable glycemic control and quarterly for those not meeting glycemic goals.⁷ It is interesting that similar recommendations exist for periodontal maintenance visits for patients who are well-controlled versus those who require more careful monitoring. The use of point-of-care testing for HbA_1c enables timely decisions on therapy changes, when needed, which may not only apply to physicians but also dental practitioners considering more invasive surgical procedures.

Poorly controlled diabetic patients are at greater risk for developing periodontitis and will not respond as well to dental therapy. For this reason, the patient's physician should be contacted to determine the level of the patient's glycemic control. The poorly controlled patient, under the care of their physician, should be motivated to achieve better control of his or her diabetes in order to facilitate an optimal response to periodontal therapy and to better manage or prevent the development of other long-term complications. Patients who are unable to control their diabetes are much more difficult for dental professionals to manage and may require the use of adjunctive therapeutics, in addition to traditional mechanical therapy, such as either systemically administered or locally applied antimicrobials and/or host modulatory therapy, as part of the treatment regimen. The consequence of poor periodontal management of a diabetic patient is that an unresolved infection and a significant proinflammatory response can lead to insulin resistance, making it difficult for the diabetic patient and their physician to achieve optimal glycemic control. In the future, dentists will most likely develop a closer relationship with physicians to monitor patients for changes in oral health. Improvements in biochemical diagnostics for periodontitis might allow physicians, nurses, and even patients to send samples to a centralized laboratory for evaluation and preliminary detection of periodontal inflammation and breakdown, with subsequent referral to the oral health care provider for a complete oral evaluation and treatment.

The Importance of Managing Periodontal Disease in the Diabetic

Two studies have demonstrated that diabetic subjects with severe periodontitis are at greater risk for developing nephropathy and CVD which can both affect mortality in this patient population. Thorstensson et al⁵ in an 11-year follow-up of subjects demonstrated that diabetics with severe periodontitis had a greater prevalence of proteinuria indicative of nephropathy and a greater number of cardiovascular complications. These oral-systemic associations in diabetics have been confirmed most recently by Saremi et al,⁴ who reported that periodontal disease is strongly predictive of mortality from ischemic heart disease and diabetic nephropathy in a population of Pima Indians with type 2 diabetes. In an 11-year follow-up, the age and sex-adjusted death rates of the type 2 diabetics increased with their severity of periodontitis. There is no doubt that optimal oral health is essential to the medical management of the diabetic patient.

Practical Steps For the Dental Professional

Instructions to diabetic patients on how to help prevent or keep periodontal disease under control should include twice daily brushing and flossing at least once a day to remove the bacterial plaque from the teeth. The use of powered toothbrushes may be necessary, and mouth rinses or toothpastes with antiseptic agents may be recommended as adjuncts to mechanical plaque removal to provide optimal homecare. Triclosan is present in a toothpaste (Colgate® Total®), currently available in the United States. Triclosan is a substantive antibacterial agent that adheres to the oral mucosa and hard and soft tissues for up to 12 hours. Colgate Total is approved by the FDA to aid in the prevention of gingivitis, plaque, and caries and accepted by the ADA for the prevention and treatment of tooth decay, gingivitis, plaque above the gum line, and bad breath and, in the case of the whitening variants, to whiten teeth by removing surface stains. Placebo controlled studies in high risk subjects, such as smokers³¹ and individuals with recurrent periodontitis³², following non-surgical periodontal therapy showed that periodontal disease progression was significantly inhibited by use of a triclosan/copolymer dentifrice as compared to use of a regular fluoride toothpaste control, as measured by improvements in gingival inflammation, probing depths, and probing attachment levels. These results suggest that an oral hygiene regimen including use of a triclosan/copolymer dentifrice may improve healing and sustain the short term effects of non-surgical therapy in high risk individuals. From in vitro studies, it is clear that triclosan has broad spectrum potential to inhibit multiple parallel and sequential pathways in the inflammation cascade. The potential upstream effects of triclosan have been demonstrated through inhibition of enzyme and cytokine (IL-1β and TNF-α) stimulated production of prostanoids (PGE₂), whereas the potential downstream effects of triclosan have been shown through inhibition of bone resorption in parathyroid-hormone-induced release of calcium from bone cultures.³³

Regular visits to the dentist are necessary to assess the patient's periodontal status and to determine the frequency needed for professional cleanings to remove any plaque missed and to remove and prevent calculus from forming that can no longer be removed by homecare. Assessment of all risk factors for periodontitis with risk reduction strategies is important for the optimal management of the diabetic patient. This is especially true of smoking, which is not only a significant risk factor for periodontal disease but also for CVD, which has an increased risk for mortality in diabetics. Smoking cessation should be encouraged. Eating a balanced diet, weight loss strategies, exercise, and compliance with medical and dental treatments should be encouraged to maintain control of blood glucose levels, since this will help the patient to be more resistant to periodontal infection and promote improved wound healing and therapeutic responses.

If the patient visiting the dental practitioner has been diagnosed with periodontitis, appropriate treatment should be initiated as soon as possible to control or prevent further destruction of tooth-supporting tissues and tooth loss. The most common procedure to reduce the bacterial load is scaling and root planing (SRP). Depending on the severity of a patient's condition, they may need more visits and the use of a local anesthetic. Another consideration may include the adjunctive use of systemic antimicrobial agents or the adjunctive use of locally applied antimicrobials, such as Arestin®, Atridox® or PerioChip®. More advanced cases may require a surgical therapy, which should be preceded by optimal metabolic control because the healing response is critical for optimal post-surgical responses.

The first case series to demonstrate that periodontal therapy could affect glycemic control in people with diabetes was published in 1960.³⁴ This report indicated that type 1 diabetics with periodontitis had a reduction in required insulin doses following a variety of therapies: SRP, localized gingivectomy, selected tooth extraction, and systemic use of antibiotics. A recently published meta-analysis³⁵ of 10 intervention trials including 456 patients revealed that periodontal therapy resulted in a decrease in absolute HbA_1c of ~0.4% and that the addition of systemic antibiotics resulted in an average absolute reduction of 0.7%.

In addition to reducing the bacterial challenge, another important treatment modality, known as host modulatory therapy, involves reducing the levels of proinflammatory mediators and inhibiting the enzymes that are destroying the periodontal tissues. To date, the only available adjunctive medication aimed specifically at modulating the host response is a pharmaceutical product called Periostat® (a subantimicrobial dose of doxycycline hyclate). Studies have shown that when used during and after SRP, Periostat significantly improved the result of the standard treatment, helped to prevent further progression of the periodontal disease, and resulted in less tooth loss. Although the initial studies did not include diabetic patients, recently reported pilot clinical studies using this two-pronged approach in the treatment of diabetic patients demonstrated similar clinical results,³⁶ with improvements in the diabetic control of patients as assessed by significant reductions in HbA_1c levels.^36,37 It is interesting to note that this same dental host modulatory therapy was used in a pilot medical trial to assess its usefulness as an agent to prevent acute coronary syndromes.³⁸ In this study it significantly reduced systemic levels of the cytokine IL-6, consequently reducing hsCRP levels, and it also inhibited the enzymes responsible for the disruption of atheromatous plaques.

Conclusion

Periodontitis is the sixth complication of diabetes, an important risk factor that needs to be controlled in order to improve overall health. It is known that the more complications a diabetic individual may have, the more likely they are to develop other complications of diabetes. Periodontitis has been associated with other well-known complications such as retinopathy,³⁹ nephropathy,⁴⁰ and angiopathy.⁵ A recent study in type 2 diabetics has associated periodontitis with mortality in diabetic patients from nephropathy and CVD.⁴ Just as physicians closely monitor diabetic patients for control, compliance, and overall systemic health, it is incumbent upon dental care providers to do the same because periodontal disease can be monitored and controlled with careful attention to home care and regular visits to the dentist who, with newly developed treatments, can manage periodontal disease better than ever before.

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About the Author

Maria Emanuel Ryan, DDS, PhD
Professor and Director of Clinical Research School of Dental Medicine
Stony Brook University