Intensive Periodontal Treatment Does Not Affect the Lipid Profile and Endothelial Function of Patients with Type 2 Diabetes: A Randomized Clinical Trial

Round 1

Reviewer 1 Report

This manuscript described about the effects of intensive periodontal therapy (IPT) on lipid profile and vascular endothelial function of type 2 diabetic patients. However, this manuscript was poorly prepared and has serious problems, so it is necessary to respond to the comments described as below and modify this manuscript accordingly.

 

 

General Comments:

Table 1 shows only the results of CAL and probing pocket depth (PPD) as baseline periodontal status. The results of bleeding on probing (BOP), plaque control record (PCR), plaque index (PI) and gingival index (GI) should be described.

 

How did the authors calculate the values of CAL and PPD after measurement of all teeth to show these in tables?

 

Table 1 shows that the values of flow-mediated dilation (FMD) from both the Intervention group (IG) and the Control group (CG) at baseline. As both values (7.50 for IG and 8.12 for CG) seem to be normal, patients in both groups maybe has no endothelial dysfunction. The authors should select the patients who has abnormal values of FMD, such as less than 4% or between 4 and 7% as border value.

 

The patients of CG received oral hygiene instructions and supra-gingival mechanical debridement for 6 months. However, the values of high-sensitive C-reactive protein (hs-CRP) from CG patients were not reduced. Please describe this reason

 

Lines 249-250: The authors described that the values of triglyceride (TG) from IG at 3 and 6 months by IPT was significantly decreased than that from CG. However, tables 2 and 3 show no significant difference at both time points. Please carefully check both values and re-think about this sentence.

 

Please make the graph figures to show the changes of the values of FMD and biomarkers from both groups. This should make the readers easy to understand.

It is easier to understand the FMD and Biomarker of both groups by expressing changes over time in figures.

 

Please describe the reason why there is no significant difference about the FMD values at both 3 and 6 months between IG and CG as shown in Table 3. Therefore, it may not be possible to describe that patients in IG increased endothelium-dependent FMD compared to those in CG. Finally, could this study suggest that IPT improves endothelial function?

 

After periodontal treatment for 3 and 6 months, there was no significant difference about the values of low-density lipoprotein cholesterol (LDL-C), (total cholesterol (TC) and triglycerides (TG) between both groups. Therefore, the authors cannot conclude that the lipid profile had improved.

 

FMD is an index of endothelium-dependent vasodilation to assess vascular endothelial functional status. It is known that vascular endothelial dysfunction can be improved by diet therapy, drug therapy, exercise therapy, smoking cessation and so on. The sentence (Lines 218-219) described that exercise and smoking are not worth specific mention. Please describe about the diet and prescription during the IPT.

 

How did the authors calculate the values of CAL and PPD shown in Tables. Do these values mean average of each measurement?

 

Specific comments:

Please italicize both “Intervention” and “Control”. Please carefully check this issue throughout this manuscript.

Please unify “Control” or “control”. Please carefully check this issue throughout this manuscript.

Please show the unit of all biomarkers shown in Tables.

Line 71: Please spell “RCT” out. “Randomized Clinical Trial”

Line 229: Please change “FDM” to “FMD”.

Lines 229-239: Table 2 shows that the median values of FMD from IG and CG are 8.35 and 8.32, respectively, and no significant difference between both groups. Please carefully check both values and re-think about this sentence. Please delete “Table 3”, because the values at 6 months are not described in this sentence.

Line 246: Please change “HbA1C” to “HbA1c”. “c” should be small letter. Please carefully check this issue throughout this manuscript.

Line 333: Please change “Masi et al” to “Masi et al.”.

 

 

Author Response

The authors would like to thank the reviewers for their thorough feedback and suggestions. It has surely improved the quality of the manuscript.

Reviewer 1:

Table 1 shows only the results of CAL and probing pocket depth (PPD) as baseline periodontal status. The results of bleeding on probing (BOP), plaque control record (PCR), plaque index (PI) and gingival index (GI) should be described.

Author Response: We thank the reviewer for this correction. We have added plaque index and gingival indices in table 1, as requested. Please note that we did not assessed bleeding on probing (BOP) and plaque control record (PCR).

How did the authors calculate the values of CAL and PPD after measurement of all teeth to show these in tables?

Author Response: As indicated in each table, we calculated the median and the interquartile range.

Table 1 shows that the values of flow-mediated dilation (FMD) from both the Intervention group (IG) and the Control group (CG) at baseline. As both values (7.50 for IG and 8.12 for CG) seem to be normal, patients in both groups maybe has no endothelial dysfunction. The authors should select the patients who has abnormal values of FMD, such as less than 4% or between 4 and 7% as border value.

Author Response: Please note, it is beyond the scope of this study. We aimed at investigating periodontal treatment-related changes of endothelial function in diabetic patients. We only hypothesised a potential impact of periodontal therapy on fluctuations in endothelial function, not on endothelial dysfunction.

The patients of CG received oral hygiene instructions and supra-gingival mechanical debridement for 6 months. However, the values of high-sensitive C-reactive protein (hs-CRP) from CG patients were not reduced. Please describe this reason.

Author Response: We expected this result because the control group (CG) did not receive intensive periodontal treatment, which was delayed to 6 months. Supra-gingival mechanical debridement only partially reduces partially the local inflammation and did not affect the systemic inflammatory status. The results for the Intervention group (IG) revealed a significant improvement of hs-CRP over the time, because received the intensive periodontal treatment (supra and sub-gingival debridement; scaling and root planning, and possibly surgery).

Lines 249-250: The authors described that the values of triglyceride (TG) from IG at 3 and 6 months by IPT was significantly decreased than that from CG. However, tables 2 and 3 show no significant difference at both time points. Please carefully check both values and re-think about this sentence. Please make the graph figures to show the changes of the values of FMD and biomarkers from both groups. This should make the readers easy to understand. It is easier to understand the FMD and Biomarker of both groups by expressing changes over time in figures.

Author Response: We thank the reviewer for this correction. We have carefully checked and corrected the sentence. We have highlighted the correction in red in the text.

Author Response: We thank the reviewer for this suggestion. Please, find that tables are readable, and figures

Please describe the reason why there is no significant difference about the FMD values at both 3 and 6 months between IG and CG as shown in Table 3. Therefore, it may not be possible to describe that patients in IG increased endothelium-dependent FMD compared to those in CG. Finally, could this study suggest that IPT improves endothelial function?

Author Response: We thank the reviewer for this suggestion. We have added the following sentence: After a 6-months follow-up period, FMD values increased with respect to baseline values among patients of IG but were not statistically different. Follow-up FMD values were not significantly different between patients of intervention group and controls. Further, we have added the limitation of the study: This study represents the first in the literature assessing endothelial function and lipid profile in diabetic patients after intensive periodontal treatment, and further longitudinal studies are needed to define the real impact of periodontal therapy on these predictors of cardiovascular risk.

After periodontal treatment for 3 and 6 months, there was no significant difference about the values of low-density lipoprotein cholesterol (LDL-C), (total cholesterol (TC) and triglycerides (TG) between both groups. Therefore, the authors cannot conclude that the lipid profile had improved.

Author Response: We thank the reviewer for this correction. We noticed a difference, although not statistically significant. However, we have changed the sentence, as suggested.

FMD is an index of endothelium-dependent vasodilation to assess vascular endothelial functional status. It is known that vascular endothelial dysfunction can be improved by diet therapy, drug therapy, exercise therapy, smoking cessation and so on. The sentence (Lines 218-219) described that exercise and smoking are not worth specific mention. Please describe about the diet and prescription during the IPT.

Author Response: We have explained that exercise and smoking are not worth specific mention, because covariates were included in the statistical analysis. We only reported results. The diet and therapy did not change during the study.

How did the authors calculate the values of CAL and PPD shown in Tables. Do these values mean average of each measurement?

Author Response: As indicated in each table, we calculated the median and the interquartile range.

Specific comments:

Please italicize both “Intervention” and “Control”. Please carefully check this issue throughout this manuscript.

Author Response: We thank the reviewer for this suggestion. It has been modified, as requested.

Please unify “Control” or “control”. Please carefully check this issue throughout this manuscript.

Author Response: We thank the reviewer for this suggestion. It has been modified, as requested.

Please show the unit of all biomarkers shown in Tables.

Author Response: We thank the reviewer for this suggestion. It has been added.

Line 71: Please spell “RCT” out. “Randomized Clinical Trial

Author Response: We thank the reviewer for this suggestion. It has been modified, as requested.

Line 229: Please change “FDM” to “FMD”.

Author Response: We thank the reviewer for this correction. It has been changed, as requested.

Lines 229-239: Table 2 shows that the median values of FMD from IG and CG are 8.35 and 8.32, respectively, and no significant difference between both groups. Please carefully check both values and re-think about this sentence. Please delete “Table 3”, because the values at 6 months are not described in this sentence.

Author Response: We thank the reviewer for this suggestion. It has been modified, as requested.

Line 246: Please change “HbA1C” to “HbA1c”. “c” should be small letter. Please carefully check this issue throughout this manuscript.

Author Response: We thank the reviewer for this suggestion. It has been checked and modified, as requested.

Line 333: Please change “Masi et al” to “Masi et al.”

Author Response: We thank the reviewer for this correction. It has been modified, as requested.

 

Reviewer 2 Report

Comments to the authors:

 

The authors tried to show that lipid profile and endothelial function may be changed by intensive periodontal treatment in Type2 diabetes patients. Although the topic is interesting, there is some background information and data based discussion missing, and something misleading about their results.

 

Major concerns:

 

1. There is not enough information about how endothelial cell dysfunction affects lipid profile, and how lipid profile change affects type 2 diabetes improvement. Please add more information, for example, what kind of endothelial cell dysfunction was altered and what kind of lipid changed. Please add more information in the introduction or discussion section.

2. What is the abbreviation RCT in the introduction (line 71) ?

3. What information can you get from FMD? Are there any correlations between FMD results and lipid profile change? Please add more information.

4. In the material and methods, 2.6. Periodontal treatment, please explain more about treatment (for example, root planing) to allow non-dental field readers to understand its concept.

5. The authors wrote too many details of the results in the result section. Please re-organize and remove all the numbers so that we can see in the figure to simplify.

6. Please add the explanation of Group A and Group B.

7. Overall, there are many sentences that are hard to understand, for example, line 330, “Our findings do not agree with previous studies…”. Please rewrite what is your finding and how it is different from previous findings. 

8. Please fix typos and grammatical errors in the manuscript.

Author Response

The authors would like to thank the reviewers for their thorough feedback and suggestions. It has surely improved the quality of the manuscript.

 

Reviewer 2:

The authors would like to thank the reviewers for their thorough feedback and suggestions. It has surely improved the quality of the manuscript. The authors tried to show that lipid profile and endothelial function may be changed by intensive periodontal treatment in Type2 diabetes patients. Although the topic is interesting, there is some background information and data-based discussion missing, and something misleading about their results.

 

Major concerns:

There is not enough information about how endothelial cell dysfunction affects lipid profile, and how lipid profile change affects type 2 diabetes improvement. Please add more information, for example, what kind of endothelial cell dysfunction was altered and what kind of lipid changed. Please add more information in the introduction or discussion section.

Author Response: We thank the reviewer for this suggestion. More informations have been added, as follows: “Endothelial dysfunction is a pathological condition typified mainly by an imbalance of endothelial-dependent relaxing and contracting factors. In diabetes, lipotoxicity has the potential to affect the endothelial cell homeostasis and cause insulin resistance by decreasing endothelial NO synthase (eNOS) gene expression, and eNOS catalytic activity. The mechanism linking insulin resistance to endothelial dysfunction is complex and includes the release of excess free fatty acid release. This risk factor, in combination with hypertension, genetic predisposition, hyperglycemia, hyperinsulinemia, oxidative stress, and advanced glycation end products ,converge on the artery (center) promote atherogenesis”. References: Tabit, C.E.; Chung, W.B.; Hamburg, N.M.; Vita, J.A. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Reviews in Endocrine and Metabolic Disorders 2010, 11, 61-74; Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A. The assessment of endothelial function: from research into clinical practice. Circulation. 2012 Aug 7;126(6):753-67. doi: 10.1161/CIRCULATIONAHA.112.093245. PMID: 22869857; PMCID: PMC3427943.

What is the abbreviation RCT in the introduction (line 71)?

Author Response: It means randomized clinical trial. It has been spelled.

What information can you get from FMD? Are there any correlations between FMD results and lipid profile change? Please add more information.

Author Response: We did not correlate FMD and change in lipid profile. Correlation between the parameters was not our goal.

In the material and methods, 2.6. Periodontal treatment, please explain more about treatment (for example, root planing) to allow non-dental field readers to understand its concept.

Author Response: Please, note that the protocol has been detailed described, as follows: “The protocol of IPT consisted of single session of one-stage full-mouth disinfection (OSFM), which implicated, supra- and sub-gingival mechanical debridement scaling and manual root surface and calculus removal of all pockets (root planing), under local analgesia, within 24 hours in association with chlorhexidine application to all oropharyngeal niches (chairside and at home for 2 months after treatment)”.

The authors wrote too many details of the results in the result section. Please re-organize and remove all the numbers so that we can see in the figure to simplify.

Author Response: Thank you for your comment. Please, note that is not possible remove the MANCOVA results. The explanation regarding the results within-groups and between-groups, and covariates is not flexible.

Please add the explanation of Group A and Group B.

Author Response: Thank you for your correction. The groups identified Intervention and Control Group, erroneously. It has been checked and corrected.

Overall, there are many sentences that are hard to understand, for example, line 330, “Our findings do not agree with previous studies…”. Please rewrite what is your finding and how it is different from previous findings. 

Author Response: We thank the reviewer for this correction. This specific sentence has been modified, as follows: In contrast with our results, previous studies that investigated the impact of intensive periodontal treatment on endothelial dysfunction, demonstrated a short-term improvement of FMD after the periodontal therapy.

Please fix typos and grammatical errors in the manuscript.

Author Response: We thank the reviewer for this comment. We have rechecked the manuscript for orthographic and grammatical errors, and it has been edited accordingly.

 

 

Round 2

Reviewer 1 Report

This revised manuscript still has several critical defects.  Therefore, this paper needs more efforts to improve the quality for publication in this journal.

 

Figure which this reviewer recommended to the authors to make the readers easy to understand does not have yet added in the revised manuscript.

 

Lines 231-232: Table 2 shows that the median values of flow-mediated vasodilation (FMD) of Intervention group (IG) and Control group (CG) at 3 months are 8.35 and 8.32, respectively, and there is no statistically significant difference between two groups. These data are not correspondent with this sentence.

 

The values of follow-up FMD, low-density lipoprotein (LDL-C), total cholesterol (TC) and triglycerides (TG) between both groups were not statistically significant. Therefore, considering this manuscript title “Impact of Intensive Periodontal Treatment on Lipid Profile and Endothelial Function of Patients with Type 2 Diabetes: A Randomized Clinical Trial”, the authors should increase the number of cases and perform more statistical analyses following to show a statistically significant improvement result by intensive periodontal treatment (IPT).

Author Response

REVIEWER 1:

This revised manuscript still has several critical defects.  Therefore, this paper needs more efforts to improve the quality for publication in this journal.

Figure which this reviewer recommended to the authors to make the readers easy to understand does not have yet added in the revised manuscript.

Author Response: The figure have been added, as follows:

 

 

 

 

 

 

Lines 231-232: Table 2 shows that the median values of flow-mediated vasodilation (FMD) of Intervention group (IG) and Control group (CG) at 3 months are 8.35 and 8.32, respectively, and there is no statistically significant difference between two groups. These data are not correspondent with this sentence.

Author Response: Thank you very much. The sentence has been corrected, as follows: “As shown in Table 2 and 3, the differences between the median of FMD for Intervention Group and Control Group were not statistically different.”

The values of follow-up FMD, low-density lipoprotein (LDL-C), total cholesterol (TC) and triglycerides (TG) between both groups were not statistically significant. Therefore, considering this manuscript title “Impact of Intensive Periodontal Treatment on Lipid Profile and Endothelial Function of Patients with Type 2 Diabetes: A Randomized Clinical Trial”, the authors should increase the number of cases and perform more statistical analyses following to show a statistically significant improvement result by intensive periodontal treatment (IPT).

Author Response: Thank you very much for your comment. The title was a means to succinctly describe the potential impact of periodontal treatment. Based your comments, we have added the sample size limitation and corrected the title, as follows:

Title: Intensive Periodontal Treatment Does Not Affect the Lipid Profile and Endothelial Function of Patients with Type 2 Diabetes: A Randomized Clinical Trial.

Limitations of the study: The values of follow-up FMD, low-density lipoprotein (LDL-C), total cholesterol (TC) and triglycerides (TG) between both groups were not statistically significant. A larger sample is needed to define whether intensive periodontal treatment (IPT) might have an impact on lipid profile and endothelial function on patients with diabetes.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

1. What information can you get from FMD? Are there any correlations between FMD results and lipid profile change? Please add more information.

Author Response: We did not correlate FMD and change in lipid profile. Correlation between the parameters was not our goal.

Second Review: Do you know any papers mentioned about any correlations between FMD results and lipid profile change?　Also please add more information about FMD usage for general readers.

2. The authors wrote too many details of the results in the result section. Please re-organize and remove all the numbers so that we can see in the figure to simplify.

Author Response: Thank you for your comment. Please, note that is not possible remove the MANCOVA results. The explanation regarding the results within-groups and between-groups, and covariates is not flexible.

Second Review: Please simplify the result section. You do not need to describe everything with numbers. Readers can look at the numbers in the figures. And reorganize and rewrite with your  nice writing flow.

 

3. Please fix typos and grammatical errors in the manuscript.

Author Response: We thank the reviewer for this comment. We have rechecked the manuscript for orthographic and grammatical errors, and it has been edited accordingly.

Second Review: The revised manuscript still has typos and grammatical errors. Please make sure all the errors are fixed again.

 

New comments from second review:

 

1. Please switch IG and CG in figures. Usually the control group comes first.

2. Did any patients in the study group start treatment of any metabolic syndrome during the study?

3. In the abstract, please add more conclusions since you wrote as the aim “The aim of this 26 trial was to assess the benefits of intensive periodontal treatment (IPT) on the lipid profile and the endothelial function of diabetic patients.” Now we could only see the conclusions about endothelial function.

4. In discussion, “The results indicate that hs-CRP levels were similar between the 326 groups at 3 months while at 6 months they differed significantly. Is it because the intensive treatment has longer term effectiveness”. Please give references and discuss the reason.

Author Response

REVIEWER 2:

 

 

 

Second Review: The revised manuscript still has typos and grammatical errors. Please make sure all the errors are fixed again.

 

New comments from second review:

 

1. Please switch IG and CG in figures. Usually the control group comes first.

Author Response: Thank you so much for your suggestion. The IG and CG have been switched.

 

1. Did any patients in the study group start treatment of any metabolic syndrome during the study?

Author Response: No, no treatment.

 

1. In the abstract, please add more conclusions since you wrote as the aim “The aim of this 26 trial was to assess the benefits of intensive periodontal treatment (IPT) on the lipid profile and the endothelial function of diabetic patients.” Now we could only see the conclusions about endothelial function.

Author Response: Thank you so much for your suggestion. The following sentence has been added: Conclusions: An intensive periodontal treatment might improve endothelial function, suggesting a direct beneficial effect on the vasculature, possibly mediated by systemic inflammatory reduction. However, no statistically significant differences between groups were observed, and no benefits have been proved on lipid profile

 

1. In discussion, “The results indicate that hs-CRP levels were similar between the 326 groups at 3 months while at 6 months they differed significantly. Is it because the intensive treatment has longer term effectiveness”. Please give references and discuss the reason.

 

Author Response: Thank you so much for your correction. We apologize. This was a typo. We have corrected the sentence, as follows: The results indicate that hs-CRP levels were similar between the groups during the follow-up.

Author Response File: Author Response.pdf

Round 3

Reviewer 1 Report

This revised paper is improved. 

Reviewer 2 Report

I appreciate the reviewer's responses.

Please correct some typos and grammar in the manuscript. (For example, you could use google docs to make sure your writing is grammatically correct and no typos, ask other people to read the manuscript and ask if everything makes sense for them.)