Table 2.

Systematic reviews.

Reference	Main findings	Limitations
Almeida A, Fagundes NCF, Maia LC, et al. Is there an association between periodontitis and atherosclerosis in adults? A systematic review. Curr Vasc Pharmacol 2018;16:569–82. doi:10.2174/1570161115666170830141852	A systematic review of 7 literature databases (to January 2017) uncovered 2138 studies; 4 were included in the review.The authors concluded that an association exists and is due to an increase in inflammatory mediators, specifically C-reactive protein and interleukin 6.	Based on few studies. Surrogate markers for end points.
Cheng F, Zhang M, Wang Q, et al. Tooth loss and risk of cardiovascular disease and stroke: a dose-response meta-analysis of prospective cohort studies. PLoS One 2018;13:e0194563. doi:10.1371/journal.pone.0194563	Meta-analysis included 17 cohort studies (through March 2017) with 879,084 participants and 43,750 cases. 28 reported on tooth loss and CVD; 8 reported on tooth loss and stroke. Tooth loss was associated with a significant risk of CVD and stroke. For every 2 teeth lost, coronary heart disease risk increased by 3% and stroke risk increased by 3%.	Tooth loss is an indirect surrogate marker for periodontitis. Included studies differed with respect to CVD outcomes: heart failure, myocardial infarction, coronary heart disease, ischemic heart disease. Outcomes were self-reported. Different conclusion compared to Peng et al.
D'Isidoro O, Perrotti V, Hui WL, et al. The impact of non-surgical therapy of periodontal disease on surrogate markers for cardiovascular disease: A literature review. Am J Dent 2019;32:191-200.	28 articles reviewed (through December 2018). The authors conclude: “The initial phase of periodontal therapy has a positive impact on the short-term reduction of a series of systemic markers that are considered as surrogate markers AVD” (atherosclerotic vascular disease).	Surrogate markers of CVD are used as outcome measures. Meta-analysis could not be done due to heterogeneity of the studies. Great variability in follow-up period (none-18 years).
Fiorillo L, Cervino G, Laino L, et al. Porphyromonas gingivalis, periodontal and systemic implications: a systematic Review. Dent J 2019;7. doi:10.3390/dj7040114	21 studies included from 2009-2019. Cardiology outcome measures: lipoprotein concentration, endothelial permeability, lipoprotein binding in the intima, CVD, CHD, chronic infection of the heart, atherosclerosis and atherosclerosis risk factors, cytokines. The authors conclude that “P. gingivalis has implications in the onset of different systemic pathologies, including rheumatoid arthritis, cardiovascular pathologies, and neurodegenerative pathologies,” after synthesis of the articles.	Porphyromonas gingivalis is used as a biomarker of periodontal disease. Of the included studies, 14 had moderate and 4 had high risk of bias. Cardiology end points were very variable.
Froum SJ, Hengjeerajaras P, Liu KY, et al. The link between periodontitis/peri-implantitis and cardiovascular disease: a systematic literature review. Int J Periodontics Restorative Dent 2020;40:e229-e33. doi:10.11607/prd.4591	51 articles from 1990 to 2020 included. The authors conclude that infection and inflammatory pathways can explain a link between periodontal disease and CVD, but because periodontal disease interventional studies have shown conflicting results on CVD, cause and effect cannot be ascribed. Too few studies on peri-implantitis to draw conclusions.	Outcome measurements concerning CVD and characterisation of periodontitis were very varied in the different studies.
Joshi C, Bapat R, Anderson W, et al. Detection of periodontal microorganisms in coronary atheromatous plaque specimens of myocardial infarction patients: A systematic review and meta-analysis. Trends Cardiovasc Med 2021;31:69-82. doi:10.1016/j.tcm.2019.12.005	14 studies investigating the presence of periodontal disease pathogens in plaque; 12/14 reported the presence of bacteria. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were the most frequently reported.	Mostly small studies and male-skewed. Few controls and high level of heterogeneity. DNA was also found in areas of the vasculature that are resistant to atherosclerosis, raising the question of causality.
Kaschwich M, Behrendt CA, Heydecke G, et al. The association of periodontitis and peripheral arterial occlusive disease-a systematic review. Int J Mol Sci 2019;20:2936. doi:10.3390/ijms20122936	17 studies included (through 12/2018). Both longitudinal studies and case-controlled studies reviewed. All studies identified an association between periodontal disease and peripheral arterial occlusive disease. 3 causative mechanisms leading to vessel damage highlighted: (1) periodontal pathogen colonisation of the vessel, (2) systemic inflammation, and (3) autoimmunity vs host protein(s) as a result of infection with the oral periodontal disease pathogen, which may combine with systemic inflammation (2).	Some studies used tooth loss as a biomarker of periodontal disease. Assessment for CVD varied and in some cases was self-reported.
Larvin H, Kang J, Aggarwal VR, Pavitt S, Wu J. Risk of incident cardiovascular disease in people with periodontal disease: a systematic review and meta-analysis. Clin Exp Dent Res 2021;7:109-22. doi:10.1002/cre2.336	Review of study results published between 1996 and October 2019. Included 32 longitudinal studies; 30 eligible for meta-analyses. Found a small but consistent increased risk of CVD associated with periodontal disease. Highest evidence was for stroke, followed by coronary heart disease. Evidence for myocardial infarction was not significant. Men and those with severe periodontal disease were at the highest risk for increased risk of CVD.	20 studies only investigated one sex (14 male, 6 female). In some studies, periodontal disease/CVD was self-reported. In 1 study, the outcome measure was hypertension. 21 studies were judged critical and 11 serious in terms of risk of bias as per ROBINS-I (evaluates the risk of bias in results reported for 2 or more interventions in nonrandomised studies). "Critical" suggests that the study is too problematic to draw any conclusions about the intervention.
Lavigne SE, Forrest JL. An umbrella review of systematic reviews examining the relationship between type 2 diabetes and periodontitis: position paper from the Canadian Dental Hygienists Association. Can J Dent Hyg 2021;55:57-67.	Asked the question: “For adults in good general health who are diagnosed with periodontal disease, will receiving non-surgical periodontal therapy (NSPT), as compared to not receiving NSPT, lower their risk for cardiovascular diseases?” Included published studies between 2007 and 2019. 7 studies reviewed, 6 with meta-analyses. The 1 study using cardiovascular events as an outcome measure was rated very low-quality due to high risk of bias as a result of deviations from the study protocol and lack of follow-up. The study provided “insufficient evidence to either support or refute whether NSPT (nonsurgical periodontal therapy) could prevent the recurrence of [cardiovascular] event.” “Biological plausibility” of an association has been shown by demonstration of increased levels of systemic cytokines and mechanistic studies based on this. Overall conclusion of this umbrella review was that no causal relationship between periodontal disease and CVD can be confirmed.	Only 1 study used cardiovascular events as an outcome measure; 6/7 studies used surrogate markers. 2 studies were of low quality.
Liu W, Cao Y, Dong L, et al. Periodontal therapy for primary or secondary prevention of cardiovascular disease in people with periodontitis. Cochrane Database Syst Rev 2019;12:CD009197. doi:10.1002/14651858.CD009197.pub4	2014 review updated in 2017 and now 2019. 2 new randomised control trials included. Inclusion criteria for CVD outcome were death and/or cardiovascular events, with a follow-up of at least 1 year. Overall conclusion: “For primary prevention of cardiovascular disease (CVD) in people diagnosed with periodontitis and metabolic syndrome, very low‐certainty evidence was inconclusive about the effects of scaling and root planning plus antibiotics compared to supragingival scaling. There is no reliable evidence available regarding secondary prevention of CVD in people diagnosed with chronic periodontitis and CVD.”	The primary prevention study showed low-certainty evidence that was inconclusive; only 1 death was recorded in the follow-up period. The secondary prevention study had too few patients with sufficient follow-up and did not report deaths.
Muñoz Aguilera E, Suvan J, Buti J, et al. Periodontitis is associated with hypertension: a systematic review and meta-analysis. Cardiovasc Res 2020;116:28-39. doi:10.1093/cvr/cvz201	Reviewed 81 studies published up to December 2018; 40 were included in a meta-analysis. Moderate-severe and severe periodontal disease were associated with hypertension, and prospective studies showed that periodontitis increased the likelihood of a hypertension diagnosis later. Periodontitis was associated with increases in both systolic and diastolic blood pressure. 3 studies researched potential mechanisms but only 1 showed differences with the hypertensive group. In that study, serum neutrophil enzymes (elastase and matrix metalloproteinases 8 & 9) were increased in periodontitis patients with hypertension, compared to hypertensive patients and healthy patients.	Interventional studies were inconclusive. (5 showed a decrease in blood pressure following periodontal therapy, whilst 6 showed no change. 1 study showed an increase in blood pressure 1 day after periodontal therapy.)
Natto ZS, Hameedaldain A. methodological quality assessment of meta-analyses and systematic reviews of the relationship between periodontal and systemic diseases. J Evid Based Dent Pract 2019;19:131-9. doi:10.1016/j.jebdp.2018.12.003	Assessment of 42 systematic reviews using 2 quality tools: Overview Quality Assessment Questionnaire and A Measurement Tool to Assess Systematic Reviews.	Outcome measures included a mix of conditions: diabetes, obesity, and CVD.
Peng J, Song J, Han J, et al. The relationship between tooth loss and mortality from all causes, cardiovascular diseases, and coronary heart disease in the general population: systematic review and dose-response meta-analysis of prospective cohort studies. Biosci Rep 2019;39:BSR20181773. doi:10.1042/BSR20181773	18 prospective studies from 1966-2018. Found a significant association between tooth loss and all-cause mortality, but not CVD/CHD. Dose-response analysis on 15 studies: 19,577 cases out of 306,807 participants. However, subgroup and sensitivity analyses showed inconsistencies.	Tooth loss is an indirect surrogate marker for periodontitis. Included studies differed with respect to CVD outcomes: heart failure, myocardial infarction, coronary heart disease, ischemic heart disease. Outcomes were self-reported. Different conclusion from Cheng et al.
Roca-Millan E, González-Navarro B, Sabater-Recolons MM, et al. Periodontal treatment on patients with cardiovascular disease: systematic review and meta-analysis. Med Oral Patol Oral Cir Bucal 2018;23:e681-90. doi:10.4317/medoral.22725	Review and meta-analysis of 10 clinical trials up to 2017. The authors found a statistically significant decrease in C-reactive protein and white blood cell levels in patients who had nonsurgical periodontal treatment in comparison to controls receiving no treatment.	Most outcomes were biomarkers of CVD. Some studies had no follow-up period or periods as short as 1 month. Longest follow-up period was 12 months. Small number of participants in many studies. Heterogeneity in diagnosis of periodontal disease and CVD. 2 studies included patients with underlying systemic disease. In one study, antibiotics were used.
Romandini M, Baima G, Antonoglou G, et al. Periodontitis, edentulism, and risk of mortality: a systematic review with meta-analyses. J Dent Res 2021;100:37-49. doi:10.1177/0022034520952401	Review of 57 studies including 5.7 million people. 10 had follow-up periods of more than 10 years. No included study had a high risk of bias. The meta-analyses showed that periodontitis/edentulism was associated with all-cause mortality and mortality from CVD, cancer, coronary heart disease, and cerebrovascular disease. Edentulism was also associated with mortality from pneumonia. Sensitivity analyses utilising only the highest-quality studies showed increased relative-risk levels. Analysis showed that periodontitis increased risk of all-cause and CVD mortality. The association was not affected by severity of periodontitis, but by age: the association was more evident in patients younger than 65.	In 12 studies, edentulism was self-reported. In 30 studies, the control group for edentulism was the presence of at least 1 tooth. Cause of tooth loss may not be periodontal disease. Relevant potential effect modifiers were not analysed.
Seitz MW, Listl S, Bartols A, et al. Current knowledge on correlations between highly prevalent dental conditions and chronic diseases: an umbrella review. Prev Chronic Dis 2019;16:E132. doi:10.5888/pcd16.180641	Umbrella systematic review focused on 10 chronic diseases with the highest burden in Germany and 3 most prevalent oral conditions. Of 32 studies included between 1995 and 2017, only 4 were rated as high-quality. Periodontitis was most often correlated with 1 chronic disease, whilst type 2 diabetes was the chronic disease most often correlated with a dental condition. Periodontitis and CVD was the most next frequently reported association.	2 included studies were low-quality. The strength of evidence was limited. The evidence to assess causality of these disease correlations remains unclear.
Taylor HL, Rahurkar S, Treat TJ, et al. Does nonsurgical periodontal treatment improve systemic health? J Dent Res 100:253-60. doi:10.1177/0022034520965958	A review of 52 systematic reviews on the effect of nonsurgical periodontal disease treatment on disease outcomes: diabetes (21 studies), adverse birth outcomes (15 studies), cardiovascular disease (8 studies), obesity (3 studies), rheumatoid arthritis (3 studies), and chronic kidney disease (2 studies). Most studies were found to use surrogate end points or biomarkers instead of disease end points. Using A MeaSurement Tool to Assess systematic Reviews (AMSTAR)-2, 92% of studies were rated low or critically low in terms of confidence levels due to nonregistration of the study protocol, lack of justification for study exclusion, risk of bias as a result of study inclusion, and inappropriate meta-analysis techniques. The authors concluded: “There is a dearth of robust evidence on whether nonsurgical periodontal treatment improves systemic disease outcomes.”	Included studies showed moderate heterogeneity; 2 were of low quality.
Voinescu I, Petre A, Burlibasa M, et al. Evidence of connections between periodontitis and ischemic cardiac disease-an updated systematic review. Maedica 2019;14:384-90. doi:10.26574/maedica.2019.14.4.384	This systematic review included 17 studies in English and French from 2014 to 2019. The authors note that “a significant relationship between the periodontal and cardiovascular pathology in 17 selected studies was observed,” but do not critically assess the studies in detail.	A “huge methodological heterogeneity” amongst the studies is noted by the authors. No randomised control studies were included. Only 40% of included studies had a control group. Cardiac diagnosis was heterogenous. In some studies, periodontal disease was self-reported. Sex and age data were not always stated in all studies. Only 2 studies gave race-related information. Diseases included varied widely amongst reviewed studies.

CHD, coronary heart disease; CVD, cardiovascular disease.