Comparison between Policaptil Gel Retard and Metformin by Testing of Temporal Changes in Patients with Metabolic Syndrome and Type 2 Diabetes

Round 1

Reviewer 1 Report

In this manuscript, Giuseppina Guarino et al evaluates to verify the 39 short-term efficacy and safety of PGR under real-life conditions. The author has profiled 75 from each group and effect occurred for lipid profile, which improved significantly in the PGR group while keeping unchanged in the MET. In short, the aim of the study is clear, however, the reviewer has concern about the significant outcome of the study and a few corrections below will help to improve the quality of the manuscript.

Major concerns,

1. Since many studies conducted by metformin, and its effects varies by different concentration. Under what basis author designated 1500-2000 mg/day?
2. Study population- there was no data provided how the study populations are characterized as responsive or non-responsive patients? What are the parameters considered to differentiate these groups?
3. This is an interesting data that the PGR therapy effective that may involve in cardiovascular risk score. However, data shows not huge difference between the groups. describing these, need additional experiments in a greater number of patients.

Minor comments,

1. Need in detail provide a flow chart that summarizes the study design.
2. Results shortened and do explain and descriptive.
3. Also, each section has too many short paragraphs, I would recommend to merge some of those paragraphs. It will be easy for readers.

Author Response

Reply to Reviewer 1

We thank the reviewer for carefully reading and commenting the present paper and suggesting effective corrections which we leagerly accept. The language has also been revised.

Major concerns,

1. Since many studies conducted by metformin, and its effects varies by different concentration. Under what basis author designated 1500-2000 mg/day?

Reply: the amount was chosen based on our experience on the highest best tolerated dose to ensure adequate treatment adherence. A sentence was added to explaint that.

2. Study population- there was no data provided how the study populations are characterized as responsive or non-responsive patients? What are the parameters considered to differentiate these groups

Reply; 11% of patients shpwing low treatment adherence in both groups and only slight non-significant changes in the study parameters were considered non-responsive. A sentence was added to explain that.

3. This is an interesting data that the PGR therapy effective that may involve in cardiovascular risk score. However, data shows not huge difference between the groups. describing these, need additional experiments in a greater number of patients.

Reply: thanks for your comment. However, we can cansider PGR better than MET when looking at the singificant changes in lipid parameters and BMI, as clearly reported in the text and seen from Figs. 3 and 4. We agree that additional experimentws are needed in a greater number of patients and therefore we added a sentence about that in the  Limitations

Minor comments,

1. Need in detail provide a flow chart that summarizes the study design.

Reply: Fig 1 describes the study flowchart; moreover, we provide further details on the protocol within Fig.1 legend and the Methods section.

2. Results shortened and do explain and descriptive.

Reply: we attempted at  this somewhat uneasy task

3. Also, each section has too many short paragraphs, I would recommend to merge some of those paragraphs. It will be easy for readers.

Reply: several short paragraphs were merged and synthesized in the new version of the manuscript

Author Response File: Author Response.pdf

Reviewer 2 Report

Dear Authors, your work is interesting.

You further your work published recently [1] by comparing your results along a short-term timeline. You report at lines 309 – 400 that the previously approved Protocol n.1287, June 23, 2019, of the Ethical Committee of Vanvitelli University covers the current work extension. This brings me to the question: is this paper a self-repeat extension?

My conclusion by comparing your tables number 1 in both papers: you do not self-plagiarise. The data are different.
My conclusion by reading your previous text, in which you repeatedly report “. . . three months, and even more six months after treatment initiation.” So do you indeed self-plagiarise your previous work? If not: this should be clearly delineated that in previous work Figure 1, showing the T = 3 and T = 6 months is not the same as in this current paper.

You state your points well, except in Chapter 2. Chapter 2 needs improvement, I think. You find detailed remarks below.

Details, typos, suggestions for improvements, and discussions

For your reading convenience to be inserted words I sometimes propose in bold.

1. The chosen title is long. The Elsevier Publishing company reviewed the length of titles and concluded that long titles are less frequently referred to than short titles. Therefore I propose to shorten the title. By shortening, you also can illuminate what this paper adds to your previous work [1]. A suggestion is “Comparison between Policaptil Gel Retard and Metformin by testing of temporal changes in patients with Metabolic Syndrome and Type 2 Diabetes.”
   
   
2. Lines 28-29: could the sentence ‘… ad slowing carbohydrate and fat absorption rates.’ be improved by ‘slowing down absorption rates of carbohydrate and fat.’? I recommend also changing this sentence further at places in your paper because the word ‘down’ is also missing in Lines 38-39, 74, and 316.
   
   
3. Line 38: the word ‘ad’ at line 38 seems erroneous. ‘based on polysaccharides ad slowing carbohydrate and fat absorption rates’. Do you refer to advertisements of Policaptil? Or should it read: ‘based on polysaccharides and slowing down absorption rates of carbohydrate and fat.’?
   
   
4. Lines 61, 63, 72 refer to papers with brackets (1), (2), … But at line 78 you change your notation into [4]. Later in the paper at line 93 you change your notation again and at line 197 again. Please remove the inconsistent numbering layout of references.
   
   
5. Line 96. Here begins Chapter 2, which is in a bad shape. It should be improved. You can check the tex
6. Lines 109, 110, 163, 178, 402, 409 report ‘informed consent of participants’ 6 times. This is redundant.
   
   
7. Line 143, the bad formula layout could be improved by putting the division operation in-line with the in-line division symbol: / .
   
   
8. Lines 156 – 177, the character font of sections 2.3 and 2.4 until line 177 is slightly too large.
   
   
9. Line 180, to me it is unclear what ‘bis in die’ means.
   
   
10. Line 273, has a redundancy: As I understand it: Baseline and T0 are the same.
    
    
11. After Lines 284 and 290, the headers/titles of tables 3 and 4 are dissimilar: in-figure and as a capture:
    
    
12. Line 314, is ‘(Willd.) a typo?
    
    
13. Line 315. Would it be better for the reader to insert here reference to your previous work: ‘We already showed before, in [1] that PGR, a new …’ ?
    
    
14. Line 372, misses a reference in the sentence ‘… we also feel like stressing another finding from our paper, i.e., the PGR- …’. You should explicitly say here that this is a result of the previous paper. So the sentence should read: ‘… we also feel like stressing another finding from our previous paper [1], i.e., the PGR- …’.
    
    
15. Your references are completed including DOI number. Well done.
    
    

Reference

[1]      G. Guarino, T. Della Corte, F. Strollo, S. Gentile, Policaptil Gel Retard in adult subjects with the metabolic syndrome: Efficacy, safety, and tolerability compared to metformin, Diabetes Metab. Syndr. Clin. Res. Rev. 15 (2021) 901–907. doi:10.1016/J.DSX.2021.03.032.

Author Response

Reply to Reviewer 2

We are deeply indebted to the reviewer for carefully reading both present and previous papers and suggesting adequate corrections which we accept and immediately performed. 

Reviewer

You further your work published recently [1] by comparing your results along a short-term timeline. You report at lines 309 – 400 that the previously approved Protocol n.1287, June 23, 2019, of the Ethical Committee of Vanvitelli University covers the current work extension. This brings me to the question: is this paper a self-repeat extension?
My conclusion by comparing your tables number 1 in both papers: you do not self-plagiarise. The data are different.

Reply: The sentence "registration number n. 1287/bis as an extension of a previously approved protocol (reference n.10, Protocol registration trial n.1287, June 23, 2019)" stays for the fact that the two studies enrolled different patients (despite the experimental design being virtually the same ) with a different sample size: this depended on the need to use different subjects for  different studies according to a custom of scientific correctness, and led to different general data at enrollment  - as correctly noticed by the Reviewer -, with more numerous centers participating in the present study. The two studies had the same protocol because they were submitted to the Ethics Committee at the same time and, having a similar protocol with the same products, yet different aims, so that the present one was provided with the same number by adding “bis”.

Reviewer

My conclusion by reading your previous text, in which you repeatedly report “. . . three months, and even more six months after treatment initiation.” So do you indeed self-plagiarise your previous work? If not: this should be clearly delineated that in previous work Figure 1, showing the T = 3 and T = 6 months is not the same as in this current paper.

Reply: We can reassure the reviewer that, despite a strong similarities, the Figures from the wo studies refer to different patients, and a sentence was added to explain that immediately after mentioning for the Ethics Committee’s approval

Reviewer

You state your points well, except in Chapter 2. Chapter 2 needs improvement, I think. You find detailed remarks below.
Details, typos, suggestions for improvements, and discussions

For your reading convenience to be inserted words I sometimes propose in bold.

Reply: we sincerely thank the reviewer for the time and attention dedicated to improve  our paragraph point by point

1.The chosen title is long. The Elsevier Publishing company reviewed the length of titles and concluded that long titles are less frequently referred to than short titles. Therefore I propose to shorten the title. By shortening, you also can illuminate what this paper adds to your previous work [1]. A suggestion is “Comparison between Policaptil Gel Retard and Metformin by testing of temporal changes in patients with Metabolic Syndrome and Type 2 Diabetes.”

Reply:  we thank the Reviewer for suggesting a better suited title, i.e., "Comparison between Policaptil Gel Retard and Metformin by testing of temporal changes in patients with Metabolic Syndrome and Type 2 Diabetes", which in fact we approve and substitute for the previous one

2. Lines 28-29: could the sentence ‘… ad slowing carbohydrate and fat absorption rates.’ be improved by ‘slowing down absorption ratesof carbohydrate and fat.’? I recommend also changing this sentence further at places in your paper because the word ‘down’ is also missing in Lines 38-39, 74, and 316.

Reply: the sentence was changed as suggested

3. Line 38: the word ‘ad’ at line 38 seems erroneous. ‘based on polysaccharides ad slowing carbohydrate and fat absorption rates’. Do you refer to advertisements of Policaptil? Or should it read: ‘based on polysaccharides andslowing down absorptionrates of carbohydrate and fat.’?

Reply: it should read as “based on polysaccharides and slowing down absorption rates of carbohydrate and fat” and was amended

4. Lines 61, 63, 72 refer to papers with brackets (1), (2), … But at line 78 you change your notation into [4]. Later in the paper at line 93 you change your notation again and at line 197 again. Please remove the inconsistent numbering layout of references.
   Reply: notations have been amended and now only brackets are present

5. Line 96. Here begins Chapter 2, which is in a bad shape. It should be improved. You can check the text

Reply: thank you for your suggestions: we checked and changed the entire paragraph as shown by yellow-highlighted text  

6. Lines 109, 110, 163, 178, 402, 409 report ‘informed consent of participants’ 6 times. This is redundant.
   Reply: you are right, amended
7. Line 143, the bad formula layout could be improved by putting the division operation in-line with the in-line division symbol: / .
   Reply: amended
8. Lines 156 – 177, the character font of sections 2.3 and 2.4 until line 177 is slightly too large.
   Reply: amended
9. Line 180, to me it is unclear what ‘bis in die’ means.

Reply: changed into "twice a day"

10. 
    Line 273, has a redundancy: As I understand it: Baseline and T0 are the same.
    Reply: amended also in the legend of Figure 2

11. After Lines 284 and 290, the headers/titles of tables 3 and 4 are dissimilar: in-figure and as a capture:
    Reply: the legends of the two figures have been made uniform, as suggested
12. Line 314, is ‘(Willd.) a typo?
    Reply: thanks for finding out the typo, amended
13. Line 315. Would it be better for the reader to insert here reference to your previous work: ‘We already showed before, in [1] that PGR, a new …’ ?
    Reply: amended as suggested
14. Line 372, misses a reference in the sentence ‘… we also feel like stressing another finding from our paper, i.e., the PGR- …’. You should explicitly say here that this is a result of the previous paper. So the sentence should read: ‘… we also feel like stressing another finding from our previous paper [1], i.e., the PGR- …’.
    Reply: amended as suggested
15. Your references are completed including DOI number. Well done.
    Reference

[1]      G. Guarino, T. Della Corte, F. Strollo, S. Gentile, Policaptil Gel Retard in adult subjects with the metabolic syndrome: Efficacy, safety, and tolerability compared to metformin, Diabetes Metab. Syndr. Clin. Res. Rev. 15 (2021) 901–907. doi:10.1016/J.DSX.2021.03.032.

Reply: thanks, we tried to do so as much as possible 

Reviewer 3 Report

The manuscript of Guarino et al is of considerable relevance since the incidence rates of both metabolic syndrome and diabetes are steadily increasing.Moreover, the availability of innovative therapies can have a positive impact on patients' lives.

Unfortunately, the work has important limitations.

The method of randomization is not described.

Concomitant hypoglycemic therapies are not described. Insulin therapy is mentioned as an exclusion criteria, but other therapies are not known. It is unclear if patients are taking other therapies, although the authors conclude that policaptil gel retard may represent a valid alternative to metformin as a first line of treatment of metabolic syndrome.This aspect is important as the study population is made up of patients with diabetes and metabolic syndrome.

In addition, the metformin group was treated with 1500 mg or 2000 mg daily but it is unclear the reason but the reason for the choice is unclear (side effects?), while only one dose was available for the experimental treatment group.

As described, one of the limitations of the study is the small number, so it cannot be excluded that the results are attributable to other factors.

Lastly, some concerns remain on the possibility of modifying cardiovascular risk after just 6 months of observation.

Author Response

We thank the reviewer for carefully reading and commenting the present paper and suggesting effective corrections which we largely accept. The language has also been revised.

The manuscript of Guarino et al is of considerable relevance since the incidence rates of both metabolic syndrome and diabetes are steadily increasing. Moreover, the availability of innovative therapies can have a positive impact on patients' lives. Unfortunately, the work has important limitations.

The method of randomization is not described. 

Reply:the  randomization was performed by assigning the random numbers from random number tables to the treatment conditions

Concomitant hypoglycemic therapies are not described. Insulin therapy is mentioned as an exclusion criteria, but other therapies are not known. It is unclear if patients are taking other therapies, although the authors conclude that policaptil gel retard may represent a valid alternative to metformin as a first line of treatment of metabolic syndrome. This aspect is important as the study population is made up of patients with diabetes and metabolic syndrome.

Reply: thank you for your comment: the aim of the study was to compare GPR and Metformin head to head, in absence of any other treatment, as described in the text. In addition, PGR is more effective than MET at the same time on lipids and on BMI and not lower than MET on HbA1c and glycemia

In addition, the metformin group was treated with 1500 mg or 2000 mg daily but it is unclear the reason but the reason for the choice is unclear (side effects?), while only one dose was available for the experimental treatment group.

Reply: the amount was chosen based on our experience on the highest best tolerated dose to ensure adequate treatment adherence. A sentence was added to explain that.

As described, one of the limitations of the study is the small number, so it cannot be excluded that the results are attributable to other factors. Lastly, some concerns remain on the possibility of modifying cardiovascular risk after just 6 months of observation.

Reply: thanks for your comment. However, we can cansider PGR better than MET when looking at the significant changes in lipid parameters and BMI, as clearly reported in the text and seen from Figs. 3 and 4. However, the number of subjects enrolled, although small, was determined by the calculation of the sample size. We agree that additional experiments are needed in a greater number of patients and therefore we added a sentence about that in the  Limitations

Round 2

Reviewer 2 Report

Dear authors, a few instances in your text still need improvement:

Line 27, '... slowing carbohydrate and fat absorption rates ...' should read ' ... slowing down carbohydrate and fat absorption rates ...';

Between Lines 173 and 174 you should insert at least one blank spacing line.  The bullit list is not properly finished in Line 173.

Lines 300 and 301 contain Spanish text abusively: Qui sotto c’è da cambiare PGT in PGR 300 e T0 in Baseline

Line 326 has an inconsistency in brackets of the reference number: [10]. 

Further it is OK with your research paper. Well done!

Author Response

Please ess the attachment

Reviewer 3 Report

The paper of Guarino et al has improved but it still needs some enhancements.

As suggested in the previous review, the randomization method is not described. Please add it in the text.

Considering the previous comment on hypoglycemic therapies, please note that insulin therapy is added as an exclusion criterion. If patients do not take other hypoglycemic therapies by protocol, why do you insert insulin therapy among the exclusion criteria?

In the methods section, what does "have we analyzed a series of patients” mean?

What was the criterion for choosing the patients? Were they consecutive? Please clarify it in the text

In some figures we read T0 and in others baseline, please clarify reason for this choice or please modify  it.

Author Response

please see the attachment

Author Response File: Author Response.docx