37 minute read
Management of the Glycemic Index Through Periodontal Management With Pharmacological Agents
Christian Pretto, DDS, completed his Doctor of Dental Surgery at the University of Toronto in 2021. He currently works as a general dentist in Thunder Bay, Ontario. Conflict of Interest Disclosure: None reported.
Joshua Tordjman, DDS, graduated from the University of Toronto Faculty of Dentistry in 2021. He is completing his hospital dental residency at Mount Sinai Hospital in Toronto, Ontario. Conflict of Interest Disclosure: None reported.
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Aviv Ouanounou, BSc, MSc, DDS, is an associate professor in the department of clinical sciences (pharmacology and preventive dentistry), Faculty of Dentistry at the University of Toronto. He is a fellow of the International College of Dentistry, the International Congress of Oral Implantologists, the American College of Dentistry and the Pierre Fauchard Academy. Conflict of Interest Disclosure: None reported.
ABSTRACT
Background: Periodontitis and its negative effects on systemic health can affect patients with Type 2 diabetes mellitus (T2DM) and glycemic management in particular. The chronic inflammatory response elicited in response to the bacterial biofilm present in individuals with periodontitis may propagate the chronic inflammation seen in patients with T2DM.
Types of studies: This review focuses on current literature exploring the management of periodontitis through pharmacological agents and nonsurgical treatment to regulate the glycemic index in T2DM patients.
Results: Chronic periodontitis can affect glycemic control and influence the development and severity of diabetic complications. A cyclical relationship can be formed where uncontrolled hyperglycemia propagates a chronic inflammatory response leading to both increased insulin resistance and increased damage to periodontal tissues.
Practical implications: Current evidence suggests that scaling and root planing significantly reduce HbA1c levels in T2DM patients with chronic periodontitis, however, the use of antibiotics to treat periodontitis as adjuncts is equivocal in this matter. Doxycycline and minocycline may have an effect if administered locally, however, more research is needed. Similarly, there is limited research examining the effect of azithromycin on glycemic control.
Keywords: Periodontitis, diabetes, SRP, HbA1c, antibiotics
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Periodontitis and its consequences on the oral cavity have been researched extensively. The shift in the oral microbiome toward anaerobic gram negative bacteria and an enhanced chronic inflammatory response can result in permanent alterations to the periodontium characterized by collagen degradation, alveolar bone loss and eventual tooth loss. 1 More recently, however, the link between periodontitis and its negative effects on systemic health has been a popular research topic, in particular its relationship with diabetes and glycemic management. A hallmark of Type 2 diabetes mellitus (T2DM), both in the initiation and propagation of the disease, is a cytokineinduced chronic low-grade inflammatory response resulting in insulin resistance. 2 It is believed that the chronic inflammatory response elicited in response to the bacterial biofilm present in individuals with periodontitis may propagate the chronic inflammation seen in individuals with Type 2 diabetes. This process may be driven through the production of similar proinflammatory cytokines and activation of pathways linked to insulin resistance. 3 Therefore, it has been hypothesized that chronic periodontitis can affect glycemic control and influence the development and severity of diabetic complications. This review focuses on the findings of current literature exploring the management of periodontitis through pharmacological agents and nonsurgical treatment to regulate the glycemic index in individuals Type 2 diabetes.
Periodontitis
Periodontitis is a chronic multifactorial inflammatory disease of the periodontium. It is characterized by the gradual irreversible loss of the alveolar bone leading to compromised masticatory function, tooth mobility and eventual tooth loss. 4 Despite the multifactorial nature of the disease, the progression from a healthy periodontium to periodontitis is dependent largely on the shift of the oral microbiome from a symbiotic state to a dysbiotic one. 5 FIGURE 1 depicts the categorization of bacterial groups into their six respective complexes based on their properties and pathogenicity, with red complex bacteria having a strong association with the development of periodontitis. Tannerella forsythia, Porphyromonas gingivalis and Treponema denticola are pathogens that are associated with the development of multiple clinical parameters of periodontitis, including increased pocket depth and bleeding on probing. 6–8 These red complex bacteria are rarely found in isolation and are often associated with the presence of bacteria of the orange complex, highlighting the dynamic relationship that exists in periodontal pockets. 8 Additionally, Aggregatibacter actinomycetemcomitans, part of the blue complex, has also been associated with certain forms of periodontitis. 9 The ecological plaque hypothesis was built on previous theories and proposed that changes in the environment could disrupt the dynamic equilibrium that exists between the host and the resident microflora, favoring the overgrowth of periodontal pathogens, including those in the red complex. 10 These changes arise from a multitude of factors including diet, salivary composition and pH as well as inflammation. 11 It is understood that chronic inflammation drives the progression from gingivitis to periodontitis. Initial, nonspecific plaque accumulation leads to an inflammatory response and subsequent gingivitis. The increased gingival crevicular fluid and blood present create an ideal environment for pathogens associated with periodontitis to thrive, creating a shift to a pathogenic microflora. Despite the fact that chronic inflammation is the primary driver in this ecological shift, the increase in prominence of pathogens such as P. gingivalis can further propagate the inflammatory response. 11 Given the role of inflammation in periodontitis, systemic manifestations of inflammation have also been noted, including prolonged states of hyperglycemia. 12
Type 2 Diabetes Mellitus
T2DM is an endocrine disorder characterized by a diminished physiological response to insulin, resulting in a persistent state of hyperglycemia. 13 Despite the advancement in prevention and management of T2DM, both personal and financial burdens imposed by the disorder remain prominent. In 2017, the direct medical costs of diagnosed diabetes was approximately $237 billion in the U.S. alone, in addition to $90 billion due to reduced productivity associated with diabetes. 14 Complications associated with unmanaged blood glucose levels in individuals with T2DM are well documented. Complications include, but are not limited to, diabetic neuropathy, nephropathy, macro- and microvascular complications, retinopathy, impaired wound healing and an increased risk for infection. 15,16 Given the negative implications of poorly managed blood glucose levels, accurate monitoring is essential in order to minimize the impact of the disease on one’s quality of life. Glycated hemoglobin (HbA1c) remains the gold standard marker for assessing glycemic control in individuals with T2DM. 17 HbA1c measurements provide insight into the average blood glucose levels over the past 60 to 90 days, as plasma levels of glucose directly relate to levels of glycated hemoglobin. 18 While blood glucose tests represent a snapshot at the time at which a test was performed, tests for Hb1Ac accurately depict trends over a longer period and directly relate to the risk of development of long-term complications associated with diabetes. 18 TABLE 1 depicts the established ranges of Hb1AC, dividing individuals into nondiabetic (4.0%-5.6%), prediabetic (5.7%-6.4%) and diabetic (> 6.5%). To minimize complications associated with the disorder, lifestyle modifications such as diet and exercise as well as maintaining an HbA1c below 7% are recommended.18 Any improvement in glycemic control in diabetic patients will reduce complications as a direct and indirect result of diabetes. 19
Relationship Between Periodontitis and Type 2 Diabetes
The impact of uncontrolled hyperglycemia and diabetes on the development and progression of periodontitis is well documented. 20–22 In recent years, the idea of a bidirectional relationship between the two diseases has emerged. The deleterious effects of prolonged hyperglycemic states on the periodontium are well known. Impaired neutrophil function, including decreased response to chemotaxis and phagocytosis as well as increased inflammatory response, has been observed. 23 In addition, impaired bone matrix production, altered collagen synthesis and increased collagen degradation was found in gingival fibroblasts of diabetic patients. Administration of insulin has been shown to prevent these destructive impacts to the periodontium. 23 The recent link examining periodontitis and its effects on diabetes, however, is routed in the chronic activation of the innate immune system. Increased production of proinflammatory cytokines and chronic activation of the innate immune system can shift the microflora to a pathogenic variation with an increase in prominence of periodontal pathogens. 24 Ultimately, this can result in periodontal breakdown and the eventual progression from gingivitis to periodontitis. Furthermore, as stated previously, the accumulation of periodontal pathogens can further propagate the inflammatory response through the release of inflammatory mediators such as IL-1B, TNF-a and PGE2 from monocytes, among other cells. 25 While several risk factors including obesity, lack of exercise and smoking have been identified in the development of T2DM, chronic lowgrade inflammation is being increasingly explored as the underlying mediator in the progression of the disease. 26 Therefore, it has been suggested that an overgrowth of gram-negative periodontal pathogens may be related to elevated insulin resistance and impaired glycemic control. 3 The result would be a positive feedback loop in which poorly controlled diabetes can lead to periodontitis, and the accumulation of periodontal pathogens can further propagate a chronic immune response leading to increased insulin resistance.
Nonsurgical Treatment of Periodontitis and Type 2 Diabetes Mellitus
Currently, there are several means by which dentists aim to improve periodontal conditions. Scaling and root planing (SRP), brushing and flossing, pharmacotherapy and surgical intervention or a combination of those previously mentioned are options considered to manage periodontitis. The treatment of the disease presents inherent problems due to the nature of biofilms and the resistance they have to host defenses and antimicrobials. The gold standard for the nonsurgical management of periodontitis is SRP. 27 It is well acknowledged that SRP reduces microbial load in addition to improving clinical parameters of periodontitis including probing depth (PD) and bleeding on probing (BOP). Despite the significant reduction in microbial load, several studies have demonstrated that within eight weeks recolonization occurs gradually, eventually reaching pretreatment levels. 27–29 This is largely due to the inability for SRP to completely eradicate periodontal pathogens as a result of both operator and instrument limitations. Additionally, routine oral hygiene practices by the patients themselves may be ineffective, as bacteria
associated with the red complex are often found adjacent to the gingival epithelium deeper in periodontal pockets. 8 The use of antimicrobials to manage periodontal disease as an adjunct to mechanical therapy has become increasingly explored in recent years. Given the influence of pathogenic bacteria in the progression of periodontitis, antimicrobials would appear to have a strong position in the management of the disease. However, antibiotics are less effective due to the complexity of biofilms as well as possessing antimicrobial resistance determinants. 30 Studies have shown that both pathogenic and commensal bacteria can act as reservoirs for antibiotic resistance genes, with horizontal transfer of these genes occurring in the biofilm. 30 Therefore, while not recommended to be used alone, studies have examined the use of SRP with adjunctive antimicrobial administration to improve clinical outcomes of periodontal therapy compared to SRP alone.
Antimicrobials are not, however, the only adjunct being examined with SRP in periodontal patients. Melatonin, a hormone which has been found in the oral cavity, has been shown to be significantly lowered in periodontitis patients. 31 A recent double-blind, placebo-controlled, single-center study of 50 diabetic periodontitis patients demonstrated that combined nonsurgical treatment with systemic melatonin treatment provided simultaneous improvements in both periodontal condition and glycemic control after eight weeks when compared with nonsurgical treatment alone. 32
A Cochrane Systematic Review reported that SRP alone was effective at improving glycemic control, but the effect seen was only significant for four months posttherapy. It was shown that HbA1c levels were significantly reduced (0.29%) at three to four months posttherapy, but only 0.02% after six months posttherapy. 33 The review also compared multiple studies that examined SRP alone versus SRP with antimicrobial therapy and found no significant difference in HbA1c levels at three to four months posttherapy when antimicrobials were added. 33 In a 12-month single-center, investigator-blinded, randomized study of surgical periodontal treatment and subgingival SRP of 264 moderate to severe periodontitis patients with Type 2 diabetes, HbA1c levels were reported to drop significantly (0.6%) versus the control group (supragingival scaling and polishing). 34 In a clinical trial of 100 patients with T2DM, nonsurgical therapy significantly reduced HbA1c levels when compared with a no-treatment control group. Importantly, when patients were stratified on the basis of HbA1c levels, poor glycemic control patients revealed 11.8% and 14.9% decreases in HbA1c levels at three and six months posttreatment, respectively. 35 The authors reported after multiple linear regression analysis, the higher the HbA1c level at baseline, the greater the decrease in value, and this was independent of the diabetic treatment that the patient was taking. 35 It should be noted however that in a six-month single-masked, randomized clinical trial of 514 patients with moderate to severe chronic periodontitis and physician diagnosed diabetes mellitus, no statistically significant difference in HbA1c levels were noted between the treatment group that received SRP and a chlorhexidine mouthwash and the control group. 36 Enrollment criteria required that participants had an HbA1c ≥ 7% and < 9% and therefore could not dismiss that individuals outside of this range may experience a decrease in HbA1c following nonsurgical periodontal treatment. Additionally, the study did not examine the use of systemic or topical antibiotics as an adjunct to nonsurgical periodontal therapy as well as surgical periodontal treatment. 36 Overall, additional research into the use of nonsurgical treatment for periodontitis should be conducted, further examining its use as a means of improving glycemic control in poorly controlled T2DM patients.
Antimicrobials in the Treatment of Periodontitis
A wide selection of antimicrobials have been proposed as adjuncts to SRP with an aim to improve periodontal conditions in cases of chronic periodontitis that do not respond to SRP alone (TABLE 2). Antimicrobial agents used in the treatment of periodontitis should be specific for pathogens responsible for the development and progression of the disease. 37 Unfortunately, no single antibiotic is completely effective at targeting all pathogenic bacteria found in periodontal pockets. To address this issue, pairing antibiotics or adding an adjunct, such as amoxicillin and metronidazole or amoxicillin and clavulin, respectively, offers a broader coverage and has been explored to better manage periodontitis and, subsequently, HbA1c levels. 38 Minocycline, doxycycline and macrolides have also been examined for their potential to improve glycemic control through their use in periodontal therapy. 39,40
Doxycycline
Doxycycline is a member of the tetracycline family of antibiotics, inhibiting bacterial protein synthesis through interruption of translation. Doxycycline has a bacteriostatic effect with a wide spectrum of activity, demonstrating effectiveness against both aerobic and anaerobic gram-positive and gram-negative bacteria. 41 Additionally, doxycycline has been shown to down regulate the expression of inflammatory cytokines including IL-1, IL-6, TNFɑ and PGE2. 42 Given the role of doxycycline in the modulation of inflammatory pathways in addition to its antimicrobial effects, its use in management of periodontitis and the glycemic index would appear justified. The recommended dose of systemic doxycycline in conjunction with SRP in the management of periodontitis is 100 mg BID the first day, followed by 100 mg QD. 41 One of the first attempts to manage HbA1c through systemic antimicrobial therapy was with doxycycline. Grossi et al. studied 113 Native Americans with periodontal disease and T2DM who received SRP with topical water and systemic doxycycline (100 mg) for two weeks, topical 0.12% CHX and systemic doxycycline (100 mg) for two weeks, topical povidone-iodine and systemic doxycycline (100 mg) for two weeks, topical 0.12% CHX and placebo or topical water and placebo (control). 43 After three months, the doxycyclinetreated groups displayed significantly reduced HbA1c levels (approximately 10% reduction from the pretreatment values), the greatest reduction among all treatment groups. 43 Since then, the use of doxycycline to manage periodontitis and subsequently HbA1c levels has had mixed results. Singh et al. explored the use of oral doxycycline (100 mg QD on the first day followed by BID for the subsequent 14 days) with SRP relative to SRP alone to treat periodontitis and manage blood glucose levels. It was demonstrated that SRP with doxycycline has a significant reduction in HbA1c levels at three months posttherapy relative to SRP alone (mean difference of 0.78% relative to 0.6% respectively). 44 A randomized clinical trial examined 50 prediabetic (fasting blood glucose levels between 100 mg/dL to 125 mg/dL) patients with periodontal disease who were treated with SRP with or without oral doxycycline (100 mg). They reported that both groups had a significant reduction in fasting blood glucose levels compared with baseline after six months. However, there were no significant differences between groups with and without doxycycline. 45 In a longitudinal randomized case-control study examining the effects of SRP with and without oral doxycycline (100 mg) on glycemic control of 66 prediabetic and periodontitis patients, HbA1c levels were significantly reduced in both groups (SRP with and without oral doxycycline) relative to baseline. However, there was no significant difference between both groups with regard to HbA1c levels. 46 A meta-analysis of 143 patients with chronic periodontitis and T2DM who received SRP and doxycycline compared with SRP alone showed no significant difference with doxycycline and HbA1c levels compared to the control group, however, all groups had lower overall HbA1c levels. The dosages used for periodontal therapy varied from low dose (20 mg BID for three months) to normal dosage (100 mg/day for 15 days) to preloading dosages (200 mg initial dose, 100 mg for two weeks). 47 Therefore, there is evidence to suggest that doxycycline may have an effect on improving glycemic control; however, there are studies suggesting the opposite.
Minocycline
Minocycline, like doxycycline, belongs to the class of antibiotics known as tetracyclines. Minocycline shares several characteristics with doxycycline, including its mechanism of action targeting bacterial protein synthesis as well as its broad spectrum of activity. 41 An advantage of minocycline relative to other antibiotics is its lipid soluble properties, allowing increased penetration into secretions such as saliva and gingival crevicular fluids (GCF). 37,48 Minocycline can be found in GCF at levels five times that found in blood. 48 Tetracyclines, including minocycline, have found success in the treatment of aggressive forms of periodontitis, largely due to their effectiveness against A. actinomycetemcomitans. 37 Minocycline is frequently administered topically to increase its availability and minimize systemic side effects. Topical administration of minocycline in the
form of minocycline HCL microspheres has been shown to significantly reduce red complex bacteria relative to SRP alone. 49,50 Additionally, adjunctive local administration of minocycline has been shown to improve probing depths when compared to SRP alone. 50 Preparations for topical minocycline microspheres include 1 mg of minocycline hydrochloride supplied in either 1 or 12 unit-dose cartridges. 51 Dosing is variable and dependent on the size, shape and number of periodontal pockets being treated. Treatment regimens are up to three treatments at three-month intervals in pockets with depths of 5 mm or greater. 51 Given the effectiveness of minocycline in reducing red complex bacteria and improving periodontal conditions, several studies have examined the efficacy of minocycline on the management of HbA1c levels when used to treat periodontitis. In a randomized clinical trial, 28 poorly controlled T2DM patients with chronic periodontitis (HbA1c >/= 8.5% for over five years) were treated with SRP with and without subgingival minocycline (2% gel) versus supragingival plaque control for six months. The results showed that HbA1c was reduced between the three-month and six-month mark, with 64.3% of patients in the SRP group and 57.1% of patients in the SRP plus minocycline group showing improvements in HbA1c levels; however, there was no significant difference between the groups. 38 This trial had a very small sample size and could be expanded to increase the power of the study and better determine the nature of minocycline as an adjunct treatment for management of glycemic control. This research group had also shown previously that subgingival minocycline ointment significantly improved periodontal parameters by reduced probing depths, clinical attachment loss, gingival index and IL-1b content in the gingival crevicular fluid per site. The group attributed this to the antimicrobial nature of the drug. 52 Another study examining the use of minocycline was conducted to examine the effects the antibiotic had on TNF-a levels, a product of adipose tissues known to play a role in insulin resistance as well as microbial load and HbA1c levels. The study examined 13 T2DM patients treated only with local minocycline administration (10 mg) into each periodontal pocket once per week for one month. A significant reduction in the number of microorganisms in the periodontal pockets was reported, as well as a reduction in circulating TNF-a levels. Furthermore, HbA1c levels were significantly reduced (0.8%). 53 It is important to note the low sample size of this group and the lack of a control group in this study. Minocycline, like doxycycline, may also improve glycemic control, however, more research with a larger sample size is needed.
Azithromycin
Macrolide antibiotics, which include azithromycin, are a class of antibacterial agents that function through the disruption of translation and subsequent inhibition of protein synthesis. 54 Azithromycin has garnered interest for its possible use in both treatment of periodontitis and modulation of HbA1c levels. It has a broad spectrum that is particularly effective against anaerobes and gram negative bacilli. 41 Azithromycin accumulates well in GCF due to its ability to be taken up by phagocytes, acting as reservoirs for the drug. 55 In addition, azithromycin has been found to remain at levels above the minimum inhibitory concentration for P. gingivalis, P. intermedia and A. actinomycetemcomitans two weeks following administration. 56 The sustained activity may be linked to the high intracellular concentration of azithromycin in phagocytes, relative to other pharmacological agents. While the antimicrobial effects of azithromycin are well documented, studies have shown that it also has effects on GCF volume and inflammatory marker production. 57 GCF volume has repeatedly been shown to correlate with gingival inflammation. GCF volume has been shown to be decreased in individuals on azithromycin therapy with minimal plaque for the first seven days following initiation, highlighting its possible role in suppression of inflammation. 57 Additionally, a decrease in levels of pro-inflammatory cytokines including IL-1B, IL-8 and TNF-a has been observed in the GCF of individuals taking azithromycin. 57 Azithromycin is typically prescribed as 500 mg QD for four to seven days. 41 A randomized clinical trial treated 105 Type 1 and Type 2 diabetic patients with moderate periodontitis with SRP with or without azithromycin (500 mg/day for three days) or azithromycin (500 mg/day for three days) with supragingival prophylaxis. There was no decrease in HbA1c levels when patients were treated with azithromycin and supragingival prophylaxis. However, there was a significant decrease of 0.8% in HbA1c within the azithromycin plus SRP group compared with the placebo- SRP group (0.3% reduction) after nine
GCF volume has repeatedly been shown to correlate with gingival inflammation.
months. 58 Therefore, azithromycin alone may not have an effect on glycemic control but may in fact have an adjunctive effect once the bacterial source is mechanically disrupted.
Amoxicillin and Amoxicillin/ Metronidazole
Amoxicillin is an antibiotic derivative of penicillin G, targeting cell wall synthesis to inhibit bacterial replication through bactericidal means. As a result, amoxicillin has a broad spectrum of activity against gram-positive bacteria, while also having increased coverage of gram-negative relative to penicillin. 59 As discussed previously, the biofilm that exists in periodontal pockets harbor antibiotic resistance genes that can be transferred among the bacteria. In particular, beta lactamase activity is frequently found in biofilms of individuals with periodontitis, cleaving the beta lactam ring of amoxicillin, rendering it ineffective. 59 Therefore, amoxicillin is often given in combination with a beta lactamase inhibitor such as clavulanic acid or an adjunctive antibiotic such as metronidazole to increase coverage. 37 Metronidazole targets bacteria through DNA synthesis inhibition, covering a spectrum consisting primarily of obligate anaerobes, both gram-positive and negative. 59 The typical dose of amoxicillin and metronidazole for management of periodontal disease is 500 mg TID for 14 days and 400 mg TID for 14 days respectively. 60,61 Studies have looked at the utilization of amoxicillin alone as well as in combination with metronidazole to manage HbA1c levels when used to treat chronic periodontitis. A recent clinical trial evaluated 60 prediabetic patients with chronic periodontitis who received SRP and amoxicillin (500 mg TID for five days) compared to a control group who received no periodontal treatment during the three-month period. Both fasting plasma glucose and HbA1c levels were significantly reduced in the treatment group four months after treatment began. It is important to note however that these patients were not randomly assigned according to the study. 62 Due to the significant improvement in glycemic control, perhaps chronic periodontitis should be treated more aggressively in prediabetic patients in order to improve glycemic status. The DIAPERIO randomized controlled clinical trial assessed 91 diabetic (Type 1 and Type 2) patients who were given SRP and systemic amoxicillin (2 g/ day for seven days) compared with a no-treatment group (who were later given the same procedures due to ethical reasons after the trial was over). After three months, no statistical difference was found in HbA1c levels between both groups. 63 In a one-year randomized placebo-controlled clinical trial, SRP with the combination of amoxicillin and metronidazole had no effect on HbA1c levels in 58 T2DM patients with chronic periodontitis compared to baseline measurements and SRP alone. However, the authors note that larger sample sizes might be necessary in order to examine glycemic control properly. 60
Discussion
This review discusses different nonsurgical treatments of periodontitis and the concomitant effect on glycemic control (TABLE 3). The relationship between T2DM and chronic periodontitis is bidirectional, where T2DM is a risk factor for periodontitis and periodontitis increases systemic inflammation markers that can worsen glycemic control. 64 Due to the two-way relationship, a cycle is created where glycemic status is poorly controlled, leading to an increase in vascular complications, impairing periodontal healing and thus increasing inflammation (FIGURE 2). The resulting increase in serum inflammatory mediators may worsen insulin resistance and subsequently diabetic complications. 64 Further compounding the issue periodontal inflammation has on glycemic control is the fact that diabetic individuals have an exaggerated immune response to a periodontal bacterial challenge relative to healthy individuals. 65 Local periodontal bacteria produce byproducts leading to an increase in serum inflammatory mediators and cytokine production by the host. 66 Persistent states of hyperglycemia prime monocytes in diabetic individuals, which may be one mechanism by which diabetics elicit a more profound inflammatory response to periodontal pathogens and develop more severe periodontitis. 65,67
A key mediator in the development of insulin resistance and subsequently diabetes is the production of advanced glycation end products (AGEs). 68 AGEs are proteins, amino acids or lipids that have become glycated as a result of exposure to reducing sugars. Increases in AGEs in diabetic individuals are a result of an increase in circulating glucose concentrations, AGE precursors and oxidative stress. Increases in AGEs are becoming increasingly linked to the development of insulin resistance. 68 Several studies, including one by Guo et al., have demonstrated a significant increase in both ROS and AGEs in individuals with periodontal disease. 5 It has also been shown that periodontitis is associated with increased expression of the transmembrane receptor protein for advanced glycation end products (RAGE) and a decrease in circulating soluble RAGE (sRAGE). 69 sRAGE acts as a decoy receptor, lacking the signaling capabilities of RAGE. 69 AGEs interact with RAGE on monocytes and macrophages residing in GCF and elicit a potent inflammatory response. 70 The result is an increase in proinflammatory cytokines including TNF-a and IL-1b, which is commonly seen in both T2DM and periodontal disease. 67,70 Therefore, management of periodontitis may decrease systemic inflammation, allow for better glycemic management and help reduce insulin resistance.
It is well known that SRP in chronic periodontitis patients improves periodontal conditions, as seen by the marked improvements observed in the clinical parameters that define the disease when SRP is conducted. However, the systemic effects, such as better glycemic control through improved Hb1Ac levels, that result from improved periodontal health are less documented. It is proposed that the mechanical disruption of underlying biofilms residing in gingival pockets can disrupt the cyclical relationship that exists between periodontitis and T2DM (FIGURE 2). A possible mechanism for this effect can be seen through a reduction of serum inflammatory mediators, hs- CRP and TNF-a, as reported by Artese et al. Another possible mechanism can be through the reduction of IL- 1b, a pro-inflammatory cytokine, in the gingival crevicular fluid following SRP. 71,72 This decrease in systemic inflammation may improve insulin resistance in T2DM and allow for better management of HbA1c levels. 64
While SRP is the gold standard for the nonsurgical treatment of periodontitis, the limitations with regards to both operator ability and instrument design leave room for improvement. Adjunctive use of antimicrobials with SRP has been proposed as a way to further improve both clinical periodontal parameters as well as manage blood glucose levels in patients with diabetes and periodontal disease. Results from studies examining the adjunctive use of various antimicrobials with SRP compared to SRP alone to improve glycemic control yield mixed results. Doxycycline and minocycline were suggested to have a positive relationship with reducing HbA1c levels when given systemically. However, just as many papers report no significant relationship. Local delivery of antimicrobials is reported to have more effect on glycemic control; however, these studies have low sample sizes. Lack of standardization among studies represents a potential issue that makes comparing studies and making inferences on the potential applicability of the results difficult. Variation in antimicrobial regimens and doses, study populations, time between treatment and assessment as well as the reporting of means when there may be significant individual variation all represent issues making the comparison of studies difficult. Future studies should aim to maintain a standard in both treatment and evaluation, increasing the length of clinical trials and exploring other antimicrobials that have not been evaluated yet in terms of glycemic control. Azithromycin is one drug that should be researched more in depth, as there was a positive relationship when used adjunctively with SRP. 73 Furthermore, systemic markers of inflammation should be examined for mechanisms of glycemic fluctuations as a result of periodontitis. The effect of surgical periodontal treatment on glycemic control in patients with Type 2 diabetes should also be investigated more thoroughly. Newer treatments of periodontitis, such as a gum diode laser, warrant further investigation as well. The diode laser, at a wavelength of 980 nanometers and a power of 2 watts, has been shown to have bactericidal effect on most bacteria, including anaerobes, as a result of elevated tissue temperatures. 74 Finally, naproxen or other NSAIDs to target inflammatory mediators should be evaluated as well.
In conclusion, additional research into the management of HbA1c in T2DM patients should be conducted, particularly in instances of poorly controlled diabetes. Additionally, the practice of prescribing systemic antimicrobials with the aim of improving glycemic control should be reevaluated.
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THE CORRESPONDING AUTHOR, Aviv Ouanounou, BSc, MSc, DDS, can be reached at aviv.ouanounou@dentistry.utoronto.ca.
