PONE-D-20-13427

Comparisons between dipeptidyl peptidase-4 inhibitors and other classes of hypoglycemic drugs using two distinct biomarkers of pancreatic beta-cell function: a meta-analysis

PLOS ONE

Dear Dr. Takahashi,

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Tatsuo Shimosawa, M.D., Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: N/A

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In the manuscript entitled "Comparisons between dipeptidyl peptidase-4 inhibitors and other classes of hypoglycemic drugs using two distinct biomarkers of pancreatic beta-cell function: a

meta-analysis", authors compared, by meta-analysis of published literatures, effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-beta and proinsulin-to-insulin ratio (PIR). They found that DPP-4i is superior to aGI but inferior to GLP-1RA regarding both HOMA and PIR. In addition, PIR is found to show inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, while there are no differences between DPP4i and met or SGLT2i.

Analysis has been well conducted and the reviewer agrees with their main conclusion. My concern is about use of HOMA parameters in general. As discussed in ref. 8, HOMA-beta shows activity of beta-cells but never helth status of beta-cell. An increased HOMA-beta in SU users is sometimes mistakenly interpreted. The data in this MS clearly showed this fact. Authors should discuss the abuse of HOMA modeling in DISCUSSION.

Reviewer #2: This study conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-β and proinsulin-to-insulin ratio (PIR). The main finding included that HOMA-β and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GI; both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues; PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-β showed no significant differences between DPP-4 inhibitors and the two others. I have several suggestions for the authors to consider:

1. As described in the abstract, the aim of this study was to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-β and proinsulin-to-insulin ratio (PIR). However, the conclusion highlighted the application of HOMA-β and PIR rather than the special effects of DPP-4 on HOMA-β and PIR relative to other drugs. The conclusion seems to be beyond the major purpose of the study.

2. Why didn’t authors include the Embase in the literature search?

3. Please show the detailed search strategies.

4. Why didn’t authors exclude the study in which background medications include insulin? For example, Shi C 2019 (Reference 64). The use of exogenous insulin may lead to incorrect values of HOMA-β and PIR.

5. In the introduction, authors posed two questions: whether these incretin-related drugs have advantage over other hypoglycemic drugs by exhibiting pancreatic beta-cell function preserving effect; whether there are different effects of beta-cell function preservation between DPP-4 inhibitors and other classes of hypoglycemic drugs using both HOMA-β and PIR as biomarkers. In the discussion, however, authors mainly discussed the advantage and/or disadvantage of HOMA-β and PIR as the biomarkers to assess the effect of various hypoglycemic agents on the beta-cell function in the discussion. Therefore, has the study already answered the questions posed in the introduction?

6. What is the criterion to determine whether or not HOMA-β or PIR is a suitable biomarker for comparisons of beta-cell function preserving effect between hypoglycemic drugs with different mechanisms of action?

7. According to the meta-analysis, if HOMA-β and PIR are used together to assess the effect of various hypoglycemic drugs on beta-cell function preservation, how would the results be explained? Namely, should be the results of HOMA-β and PIR consistent or not? If consistent, what does it suggest? If inconsistent, what does it suggest?

For different hypoglycemic drugs, how to appropriately use HOMA-β and PIR?

8. English needs revision. Some linguistic errors have been made. A final check of the language by a native English speaking person may lead to the necessary improvements.

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Reviewer #1: No

Reviewer #2: No

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Comparisons between dipeptidyl peptidase-4 inhibitors and other classes of hypoglycemic drugs using two distinct biomarkers of pancreatic beta-cell function: a meta-analysis

PONE-D-20-13427R1

Dear Dr. Takahashi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once you change Line 344:  Replacing 'pancreatic preserving effect' with 'beta-cell preserving effect’ and it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Tatsuo Shimosawa, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors did a good job and further improved the manuscript in which the reviewer’s comments were adequately answered. A minor revision was suggested as below:

Line 344: Suggest replacing 'pancreatic preserving effect' with 'beta-cell preserving effect’.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No