New Insights into the Role of SGLT-2 Inhibitors in the Prevention of Dementia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The overall manuscript aims at providing a review the potential applicability of using SGLT-2 inhibitors in the prevention of dementia. Authors describe the mechanisms and current limitations with dementia therapy option. Use of SGLT-2 inhibitors, their mode of action and applications in preclinical and clinical studies are detailed. The manuscript content reads good and is certainly relevant for the scientific community. However, there are opportunities to improve the readability in terms of presentation style. The general comment is to include more tables and figures. Authors would also need to make sure to provide references for all relevant statements. Please find the comments below which would need to be considered for further revisions.

1.      ‘Various systems’ mentioned in abstract- what kind of systems and what are the implications?

2.     Section 1.3, paragraph 1 lines do not have supportive references

Please make sure to provide reference for each clinical trial mentioned throughout the manuscript.

3.     Section 1.4, line : “There were also other factors that might influence the progression of dementia was in research” – is confusing and does not make sense, please correct.

4.     Section 1.4: line:  “Previous systematic review had also found a significant association between diabetes and the risk of cognitive impairment and dementia, with diabetic patients having a 1.25- to 1.91-fold increased risk” – no supporting reference provided here.

5.     Page 3, line: “SGLT-2 inhibitors have emerged as potential candidates due to their pleiotropic effects, which extend beyond glucose control to include neuroprotective and anti-inflammatory properties”- please add supporting reference.

6.     It is recommended to convert section 2 into tables capturing animal studies and human studies from published literature or the authors could add table along with the text (making text concise and elaborating details via table) for more clarity and readability.

7.     It is also recommended to consider providing a schematic along with the current text to show the different mechanisms of action (section 3). Along with this, consider providing some more figures which can either be schematics like these or figures reproduced from literature support based on journal guidelines upon getting copyright permissions as needed.

8.     Section 5: please avoid redundant statements. It would be good to address the limitations in a more elaborate manner.

Author Response

Dear editor and reviewer:

 

We sincerely appreciate the valuable comments and suggestions provided by the reviewer. We have carefully considered each point and have made the following revisions to improve our manuscript.

 

Reviewer: 1

 

The overall manuscript aims at providing a review the potential applicability of using SGLT-2 inhibitors in the prevention of dementia. Authors describe the mechanisms and current limitations with dementia therapy option. Use of SGLT-2 inhibitors, their mode of action and applications in preclinical and clinical studies are detailed. The manuscript content reads good and is certainly relevant for the scientific community. However, there are opportunities to improve the readability in terms of presentation style. The general comment is to include more tables and figures. Authors would also need to make sure to provide references for all relevant statements. Please find the comments below which would need to be considered for further revisions.

 

Ans: Thank you very much for your thoughtful review and valuable suggestions. We appreciate your attention to our work and look forward to improving the manuscript to better convey its significance and contribution to the scientific community. Based on your suggestions, we made some modifications.

 

Reviewer 1's Comments:

 

1."Various systems" mentioned in the abstract - what kind of systems and what are the implications?

 

Ans: Thank you for your valuable feedback. We have revised the abstract to clarify the term 'various systems' by specifying the biological systems affected by SGLT-2 inhibitors, such as the cardiovascular and renal systems. Additionally, we have included a more detailed description of the implications to enhance the reader's understanding.

 

2.Section 1.3, paragraph 1 lines do not have supportive references.

Ans: We have revised this section carefully and added appropriate references to support the claims made in this paragraph. All clinical trial mentions will be properly cited to ensure comprehensive support for the statements.

 

3.Section 1.4: "There were also other factors that might influence the progression of dementia was in research" – is confusing and does not make sense.

Ans: We have revised this sentence for clarity. A clearer phrasing could be: “Recent research also identified other factors influencing the progression of dementia, such as disruptions in the kynurenine pathway.” in Section 1.4.

 

4.Section 1.4: "Previous systematic review had also found a significant association between diabetes and the risk of cognitive impairment and dementia, with diabetic patients having a 1.25- to 1.91-fold increased risk" – no supporting reference provided here.

Ans: We have revised the reference for the systematic review that supports this statement in Section 1.4.

33. Xue M, Xu W, Ou YN, Cao XP, Tan MS, Tan L, et al. (2019) Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies. Ageing research reviews. 55, 100944.

 

5.Page 3, line: “SGLT-2 inhibitors have emerged as potential candidates due to their pleiotropic effects, which extend beyond glucose control to include neuroprotective and anti-inflammatory properties" – please add supporting reference.

Ans: We have revised a relevant reference here, citing studies that support the neuroprotective and anti-inflammatory effects of SGLT-2 inhibitors, to substantiate this statement in Page 3.

48. Hassanein EHM, Saleh FM, Ali FEM, Rashwan EK, Atwa AM, Abd El-Ghafar OAM. (2023) Neuroprotective effect of canagliflozin against cisplatin-induced cerebral cortex injury is mediated by regulation of HO-1/PPAR-γ, SIRT1/FOXO-3, JNK/AP-1, TLR4/iNOS, and Ang II/Ang 1-7 signals. Immunopharmacology and immunotoxicology. 45(3), 304-16.
49. Heimke M, Lenz F, Rickert U, Lucius R, Cossais F. (2022) Anti-Inflammatory Properties of the SGLT2 Inhibitor Empagliflozin in Activated Primary Microglia. Cells. 11(19).

 

6.It is recommended to convert section 2 into tables capturing animal studies and human studies from published literature or to add a table along with the text for more clarity and readability.

Ans: Thank you for your thoughtful suggestions. We value your suggestion to improve clarity and readability by including tables in Section 2. The new tables will provide a detailed introduction to animal studies, including the types of SGLT2, mechanisms, key findings, while the accompanying text will provide more context and depth to the discussion. As a comparison to another table on human observational studies, this adjustment aims to present the information in a more structured and accessible format, thereby enhancing the overall comprehensibility of this section.

 

7.Consider providing a schematic in Section 3 to show the different mechanisms of action and provide more figures.

Ans: We will incorporate a schematic diagram illustrating the mechanisms of action to enhance visual appeal and understanding.

 

8.Section 5: please avoid redundant statements. It would be good to address the limitations in a more elaborate manner.

Ans: Thank you for your constructive feedback. We will carefully revise Section 5 to remove any redundant statements and streamline the text for clarity.

 

Thank you again for your insightful suggestions, which have greatly contributed to improving our study. We hope these revisions address your concerns.

 

Sincerely, Cheng-Hsien Hung

Reviewer 2 Report

Comments and Suggestions for Authors

I received for review a review article entitled "New insights into the role of SGLT-2 Inhibitors in the Prevention of Dementia", prepared by Cheng-Hsien Hung et al., which was submitted to the Neurology International (IF=3.2). Cognitive dysfunctions are an important problem for modern medicine. This phenomenon is becoming even more important as we observe the aging of society, especially in developed countries. Dementia generates problems related to the care of the elderly, which is associated with an economic burden for the state and the families of people providing care for the elderly. Therefore, expanding knowledge about the pathogenesis of dementia, as well as the possibilities of prevention and treatment, therefore plays an important role. In my opinion, the topic taken up by the Authors is therefore important. The manuscript, although it presents a certain scientific and cognitive value, requires significant corrections and adjustments, the proposals of which I would like to present below.

1)     The abstract is unacceptably short. The most important information about the results of the literature review should also be presented.

2)     It is worth mentioning the importance of oxidative stress in the pathogenesis of diabetes complications. It is worth mentioning the importance of insulin resistance in the pathogenesis of diabetes. On the other hand, it has been shown that among the components of the metabolic syndrome, it is the component associated with obesity and insulin resistance that makes the greatest contribution to the mutual relationship between the metabolic syndrome and oxidative stress (10.3390/antiox11010079). On the other hand, oxidative stress also plays an important role in the pathogenesis of neurodegenerative diseases.

3)     The term "glycosylated hemoglobin" should not be used but "glycated hemoglobin" because it is a product of non-enzymatic glycation and not a product of enzymatically catalysed glycosylation.

 

4)     The text should be checked and corrected for minor editorial, stylistic and linguistic errors.

Comments on the Quality of English Language

The text should be checked and corrected for minor editorial, stylistic and linguistic errors.

Author Response

Dear editor and reviewer:

 

We sincerely appreciate the valuable comments and suggestions provided by the reviewer. We have carefully considered each point and have made the following revisions to improve our manuscript.

Reviewer: 2

 

I received for review a review article entitled "New insights into the role of SGLT-2 Inhibitors in the Prevention of Dementia", prepared by Cheng-Hsien Hung et al., which was submitted to the Neurology International (IF=3.2). Cognitive dysfunctions are an important problem for modern medicine. This phenomenon is becoming even more important as we observe the aging of society, especially in developed countries. Dementia generates problems related to the care of the elderly, which is associated with an economic burden for the state and the families of people providing care for the elderly. Therefore, expanding knowledge about the pathogenesis of dementia, as well as the possibilities of prevention and treatment, therefore plays an important role. In my opinion, the topic taken up by the Authors is therefore important. The manuscript, although it presents a certain scientific and cognitive value, requires significant corrections and adjustments, the proposals of which I would like to present below.

Thank you very much for your thoughtful review and valuable suggestions. Your feedback is extremely helpful in enhancing the readability, depth, and scholarly value of our manuscript. We will carefully address each of your comments.

 

 

1)     The abstract is unacceptably short. The most important information about the results of the literature review should also be presented.

Ans: Thank you for your feedback regarding the abstract. We agree that it requires a more detailed summary of the literature review results. We will revise the abstract to include the most significant findings, including key insights into the potential neuroprotective effects of SGLT-2 inhibitors, their mechanisms, and their implications for dementia prevention. This revision will ensure that the abstract provides a comprehensive overview of the manuscript.

 

2)     It is worth mentioning the importance of oxidative stress in the pathogenesis of diabetes complications. It is worth mentioning the importance of insulin resistance in the pathogenesis of diabetes. On the other hand, it has been shown that among the components of the metabolic syndrome, it is the component associated with obesity and insulin resistance that makes the greatest contribution to the mutual relationship between the metabolic syndrome and oxidative stress (10.3390/antiox11010079). On the other hand, oxidative stress also plays an important role in the pathogenesis of neurodegenerative diseases.

Ans: Thank you for highlighting this important aspect. We will expand the discussion to include the role of oxidative stress in the pathogenesis of diabetes complications and neurodegenerative diseases. We will also address the role of insulin resistance, particularly its association with obesity and its contribution to oxidative stress and metabolic syndrome, as highlighted in the referenced study. This addition will provide a more comprehensive understanding of the interconnected mechanisms linking diabetes and neurodegeneration in paragraph 7 in Section 4.

 

3)     The term "glycosylated hemoglobin" should not be used but "glycated hemoglobin" because it is a product of non-enzymatic glycation and not a product of enzymatically catalysed glycosylation.

Ans: We will revise the manuscript to use the term “glycated hemoglobin” throughout, correcting the use of “glycosylated hemoglobin” as suggested.

 

4)     The text should be checked and corrected for minor editorial, stylistic and linguistic errors.
Ans: Thank you for your observation. We will carefully review the entire manuscript for any editorial, stylistic, or linguistic errors and make the necessary corrections to improve readability and overall quality.

 

 

Thank you again for your insightful suggestions, which have greatly contributed to improving our study. We hope these revisions address your concerns.

 

Sincerely, Cheng-Hsien Hung

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I received for review a revised version of the review article entitled "New insights into the role of SGLT-2 Inhibitors in the Prevention of Dementia", prepared by Cheng-Hsien Hung et al., which was submitted to the Neurology International (IF=3.2). In my opinion the paper has been significantly improved. I have no further critical comments. I recommend the paper for publication in its current form.