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. 2021 May 20;16(5):e0251916. doi: 10.1371/journal.pone.0251916

DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A meta-analysis

Yan Yang 1,#, Zixin Cai 1,#, Jingjing Zhang 1,*
Editor: Ghulam Md Ashraf2
PMCID: PMC8136680  PMID: 34015003

Abstract

Aims

DPP-4 inhibitors are predicted to exert a protective effect on the progression of coronavirus disease 2019 (COVID-19). We conducted this meta-analysis to investigate this hypothesis.

Methods

Four databases, namely, PubMed, Web of Science, EMBASE and the Cochrane Library, were used to identify studies on DPP-4 and COVID-19. The outcome indicators were the mortality of COVID-19. Funnel plots, Begg’s tests and Egger’s tests were used to assess publication bias.

Results

Four articles were included with a total of 1933 patients with COVID-19 and type 2 diabetes. The use of DPP-4 inhibitors was negatively associated with the risk of mortality (odds ratio (OR) = 0.58 95% confidence interval (CI), 0.34–0.99).

Conclusions

DPP-4 inhibitors may improve the mortality of patients with COVID-19 and type 2 diabetes. As few relevant studies are available, more large-scale studies need to be performed.

Introduction

A global pandemic of coronavirus disease 2019 (COVID-19) began in 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The widespread COVID-19 pandemic is reminiscent of two past epidemics of respiratory diseases caused by coronaviruses, the severe acute respiratory syndrome (SARS) epidemic in 2002 [2] and the Middle East respiratory syndrome (MERS) epidemic in 2012 [3]. The three major infectious respiratory diseases caused by coronaviruses that have caused epidemics in the 21st century are SARS, MERS and COVID-19. Because SARS-CoV and MERS-CoV enter and infect cells via dipeptidyl peptidase-4 (DPP-4) [4, 5], SARS-CoV-2 may also enter cells by binding to DPP-4. However, recent studies have shown that the SARS-CoV-2 spike protein does not interact with human membrane-bound DPP-4 (CD26) [6, 7]. Although DPP-4 does not function as the receptor in SARS-CoV-2 infections, DPP-4 inhibitors (DPP-4is), one of the new oral therapies for diabetes characterized by neutral weight and few adverse effects, is now used to improve insulin secretion as a treatment for T2DM [8], and researchers have speculated on whether DPP-4 inhibitors (DPP-4i) play a role in protecting against COVID-19 and their use as therapeutic drugs to improve outcomes in patients with COVID-19 and type 2 diabetes (T2DM) [9, 10].

An increasing number of studies have shown that T2DM is the comorbidity with the strongest negative effect on the prognosis of patients with COVID-19. Patients with T2DM who contract COVID-19 have a higher mortality rate and are more likely to develop severe COVID-19 [11, 12]. The collision of these two major global epidemics suggests that the correct use of anti-diabetic agents is an urgent issue that must be addressed. As DPP-4is are commonly used hypoglycemic agents, the relationship between DPP-4i use and COVID-19 has also attracted increasing attention, we conducted this meta-analysis to determine whether DPP-4is exert a protective effect on the development of COVID-19 mortality.

Although recent observational studies have described the relationship between the use of DPP-4is and COVID-19 [13, 14], no meta-analysis has been performed to synthesize this evidence. The purpose of this article was to systematically describe the relationship between the use of DPP-4is and the mortality of COVID-19 and provide evidence that can be used to guide the treatment of patients with diabetes during the COVID-19 pandemic.

Methods

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines, as described previously [15].

Article search strategy

We searched for articles published between September 28, 2020, and October 30, 2020. The PubMed (2013–2020, October 30), Cochrane Library (1960–2020, October 30), EMBASE (1960–2020, October 30) and Web of Science (1950–2020, October 30) databases were searched in this study. Searches for all published articles related to both DPP-4 and COVID-19 were performed. The following search terms were used: “dipeptidyl peptidase-4 inhibitors”, “Dpp4”, “DPP-4”, “saxagliptin”, “alogliptin”, “sitagliptin”, “linagliptin”, “vildagliptin”, “SARS”, “COVID-19”, “SARS-CoV-2”, and ‘‘2019 novel coronavirus”. Additional papers were identified by performing manual searches of the reference lists of relevant articles and tracking citations.

Selection criteria

Two reviewers (YY and ZC) independently reviewed all the eligible studies and selected those suitable for inclusion. Disagreements were settled by reaching a consensus or with the help of a third reviewer (JZ). All the articles included in this meta-analysis met the following criteria: (1) they contained information on DPP-4is and the outcomes of COVID-19, including mortality and the development of severe COVID-19; and (2) the subjects were patients with both COVID-19 and T2DM. Articles were excluded if they met the following criteria: (1) they lacked information or data necessary for the purpose of this meta-analysis and (2) they were published as letters, reviews, editorials, or conference abstracts.

Data extraction

All relevant articles were imported into EndNote X9 software and reviewed independently by two authors (YY and ZC). Discrepancies between authors were settled with the help of a third reviewer (JZ). The following information was extracted from the selected studies by two independent investigators: author, year, country, type of study, age, sample size, population and COVID-19 outcomes. All the extracted data were then imported into Excel.

Quality assessment of included studies

The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) [16]. We assessed the quality of all relevant studies based on the type of study, sample size, participant selection, representativeness of the sample, adequacy of follow-up, comparability (exposed-unexposed or case-control), and method of ascertaining cases and controls. A study with a score of 6 or more was defined as a high-quality study. The possible range of NOS scores is 0 to 9; studies scoring at least 7 have the lowest risk of bias. Those that scored 4–6 are assigned a modest risk of bias, and those scored <3 have the highest risk of bias.

Statistical analysis

All analyses were performed using Stata software (version 13.0). The correlations between DPP-4is and adverse outcomes were reported as the pooled odds ratios (ORs) and 95% confidence intervals (CIs). ORs > 1 represented a direct association, and those < 1 represented an inverse association. All results of the included studies were analyzed with random-effects models. I2 statistics were used to assess the degree of heterogeneity: 25%, 50%, and 75% represented low, moderate, and high degrees of heterogeneity, respectively. Begg’s and Egger’s tests and funnel plots were used to detect potential publication bias, with a p-value <0.05 suggesting the presence of bias. The trim-and-fill method was also used to obtain an adjusted effect size when publication bias was detected.

Results

Search results and study characteristics

The flowchart of the study selection process is shown in Fig 1. After a preliminary search of the selected electronic databases, 475 studies were identified. Then, 119 duplicates were eliminated. After further excluding 329 studies based on their titles and abstracts, 27 articles remained. Of those 27 articles, 23 were excluded after the full text was read for the following reasons: (1) insufficient participant information was provided (n = 12); (2) the original data regarding DPP-4i use were not provided (n = 7); and (3) the outcome of COVID-19 was the severity instead of the mortality of the disease (n = 4). Finally, 4 articles related to the use of DPP-4is and COVID-19 were included in this meta-analysis. The basic characteristics of the studies are shown in Table 1. Among the 4 studies included in this analysis, 1 was performed in France and 3 were performed in Italy (Table 1). All 4 included studies were published in 2020.

Fig 1. Flow diagram of the study selection process.

Fig 1

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Table 1. Description of eligible studies reporting the association between DPP-4i and the mortality of COVID-19.

Author Year Country Age Type of study Kind of DPP4i Time of DPP4i treatment Sample size Control group Population
Cariou [14] 2020 French 69.8 ± 13.0 A nationwide multicentre observational study ND prior to hospitalization 1317 ND Diabetes with COVID-19
Fadini [13] 2020 Italy 70.3 A case-control study ND prior to hospitalization 85 No DPP4i use T2D with COVID-19
Solerte [36] 2020 Italy 69 A Multicenter, Case-Control, Retrospective, Observational Study sitagliptin at the Time of Hospitalization 338 Insulin treatment T2D with COVID-19
Strollo [37] 2020 Italy 76.7 ±11.8 An observational study ND ND 193 ND T2D with COVID-19
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ND: Not Determined;

Quality assessment

The NOS mainly consists of three parts: sample selection, comparability of cases and controls, and exposure. All four included studies had NOS scores higher than 8, indicating no risk of bias in our analysis. Details of the risk of bias assessment are described in Table 2.

Table 2. Risk of bias assessment of the included studies according to the Newcastle-Ottawa Scale (NOS).

NOS items / Study ID Cariou Fadini Solerte Strollo
Is the case definition adequate? * * * *
Representativeness of the cases * * * *
Selection of controls * * * *
Definition of controls * * * *
Compatibility * ** ** *
Ascertainment of Exposure * * * *
Same method of ascertainment for cases and control * * * *
Non-response Rate * * * *
Total Score 8 9 9 8
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DPP-4i use and COVID-19 mortality

The results of the meta-analysis of the use of DPP-4is and the mortality of COVID-19 are shown in Fig 2. In general, the use of DPP-4is was associated with decreased mortality due to COVID-19 (OR = 0.58 95% CI, 0.34–0.99); No significant heterogeneity was observed (I2 statistic = 51.1%, p = 0.105) (Fig 2). The results of Egger’s and Begg’s tests (p>0.05) and an inspection of the funnel plots showed that publication bias did not exist among the studies (Fig 3). A sensitivity analysis was conducted by omitting one study at a time and showed that the results were stable (Fig 4).

Fig 2. Forest plots of ORs for the association between the DPP-4i use and the mortality of COVID-19.

Fig 2

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Fig 3. Funnel plot of the association between the DPP-4i use and the mortality of COVID-19.

Fig 3

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Fig 4. Sensitivity analysis of the effect DPP-4i use on the mortality of COVID-19.

Fig 4

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Discussion

Because the effects of DPP-4is on COVID-19 are inconsistent and vague, we conducted this meta-analysis to determine whether DPP-4is could be a treatment for patients with COVID-19 and diabetes. Our meta-analysis may support the hypothesis that the use of DPP-4is may exert a protective effect on COVID-19. Our findings showed that the use of DPP-4is is associated with decreased mortality due to COVID-19 or the risk of progression to mortality (Fig 2).

Mechanism underlying the relationship between DPP-4is and COVID-19

The mechanisms underlying the effect of DPP-4is on the outcomes of COVID-19 are not clear, but several mechanisms may provide some insights. First, DPP-4is, including sitagliptin, alogliptin, vildagliptin, saxagliptin and linagliptin, are drugs that are widely used to treat diabetes and approved by the Food and Drug Administration [17, 18]. Compared with insulin alone, DPP-4is combined with insulin effectively control blood glucose levels, and their effectiveness and safety are guaranteed [19, 20]; additionally, good glucose control can improve the prognosis and outcome of COVID-19 [21]. Therefore, the use of DPP-4is may also exert a beneficial effect on controlling glucose homeostasis in patients with COVID-19 and diabetes.

Second, DPP-4 has been suggested to be involved in the process of various inflammatory diseases [22, 23]. DPP-4 themselves directly promote T cell proliferation, CD86 expression, activation of the NF-κB signaling pathway and excessive production of inflammatory cytokines to lead to an imbalance of inflammation [9, 24], while severe cases of COVID-19 are characterized by excessive inflammation and the substantial production of pro-inflammatory factors [25, 26]. Moreover, it seems that Sitagliptin has proven efficacy against acute respiratory distress syndrome (ARDS), the common causes of COVID-19-related death, because this drug inhibits IL-6, IL-1, and TNF in individuals with lung injury [27]. In addition, DPP-4is also exert a direct anti-inflammatory effect on the lungs [27, 28]. Therefore, we postulate that DPP-4is themselves play a role in the treatment of COVID-19.

Additionally, glucagon-like peptide 1 (GLP-1), a gut-derived incretin, is secreted after a meal to promote insulin secretion and inhibit glucagon secretion, while GLP-1 not only plays a role in glucose control but also possesses anti-inflammatory properties [29, 30]. Since DPP-4 in the circulation degrades GLP-1 rapidly to maintain glucose homeostasis, the use of DPP-4is may promote the anti-inflammatory effect of GLP-1 and indirectly achieve the purpose of inhibiting inflammation in patients with COVID-19. Although DPP-4 degrades GLP-1 and GLP-1 exerts an anti-inflammatory effect, researchers have not determined whether DPP-4is also inhibit the degradation of GLP-1 in patients with COVID-19. The anti-inflammatory effect is only our conjecture at present, and further proof is needed.

Last but not least, DPP-4 levels are significantly increased in the blood of patients with obesity and obesity-induced metabolic syndrome [31–33], and these comorbidities can aggravate the outcome of patients with COVID-19 [34, 35]. Therefore, studies aiming to determine whether DPP- 4is are useful medicines to treat COVID-19 are important.

Theoretical and practical significance

DPP-4is are hypoglycemic agents commonly used to treat diabetes, but researchers have not clearly determined whether DPP-4is can continue to be used after a patient contracts COVID-19. For the first time, our study systematically analyzed the effect of DPP-4i use on the mortality of COVID-19 in patients with both T2DM and COVID-19 and found that the use of DPP-4is may exert protective effect on death due to COVID-19. Our research may provide guidance for the treatment of patients with T2DM during the COVID-19 pandemic. Moreover, the relationship between DPP-4 and COVID-19 requires further research.

Limitations of the study

First, because few randomized controlled studies, case-control studies, and cohort studies on the relationship between DPP-4is and COVID-19 have been performed, the sample size in this meta-analysis was too small and the conclusions are not convincing. Second, as many types of DPP-4is are available, more data are needed to confirm the relationship between the use of DPP-4is and the outcomes of COVID-19; more clinical studies need to be performed.

Conclusions

In summary, the use of DPP-4is may ameliorate the progression of COVID-19 or the mortality due to COVID-19; this information may help guide the treatment of patients with T2DM and COVID-19, but more well-designed research is urgently needed to support or refute our results.

Supporting information

S1 Checklist

(DOC)

Click here for additional data file. (63.5KB, doc)
S1 File. Full electronic search.

(DOCX)

Click here for additional data file. (16.9KB, docx)

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

This work was supported by grants from the National Natural Science Foundation of China [82070807, 91749118, 81770775, and 81730022], the Planned Science and Technology Project of Hunan Province [2017RS3015] and National Key Research and Development Program [2019YFA0801903 and 2018YFC2000100].

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Decision Letter 0

Ghulam Md Ashraf

17 Feb 2021

PONE-D-20-34362

DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis

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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

**********

4. 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

Reviewer #2: No

**********

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: DPP-4 Ace receptor are part of the receptor for viral entry. Studies from various European contries especially study from French Cohort has shown that the effect ACE inhibitor is neither harmful nor beneficial. Do they think same type of response from DPP-4 Inhibitor?

Page-3 paragraph 2= DPP-4 are neutral agents but not hypoglycemic agents. Sentence need to be modified.

Page-4, para 2.1= We started article started from...…..= sentence needs to be modified.

Page-6, search results.. what was the probable cause of duplication?

Page-9, paragraph 2 line3= DPP-4 should be replaced from DPP-4 inhibitor

Page-9 Para3= Is this phenomena agent specific or non-specific?

Outcome of results should be mentioned properly not in a sketchy manner.

The stratification of Covid-19 positive patients should have been done by using various tools like modified APACHE-2 and SOFA,MIMS etc.

In Discussion- Inconclusive. Number of subjects very less. It should have been compared with SGLT-2 inhibitors with or without ACE inhibitors.

Reviewer #2: The authors have conducted a meta-analysis of the existing studies on the effect of DPP4i use on COVID-19 mortality in T2DM patients. The findings are of great interest. However, the rationale of the study (SARS-CoV and SARS-CoV2 do not use DPP4 as the receptor, see Cell Study Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, Volume 181, Issue 2, 2020, Pages 271-280.e8,ISSN 0092-8674,

https://doi.org/10.1016/j.cell.2020.02.052.,

Jean K Millet, Javier A Jaimes, Gary R Whittaker, Molecular diversity of coronavirus host cell entry receptors, FEMS Microbiology Reviews, 2020;, fuaa057, https://doi.org/10.1093/femsre/fuaa057),

the presentation of the data (writing of the results section) and therefore the discussion is not adequate

The grammar and syntax are not up to Standard for smooth reading experience. In addition, there are spelling mistakes

**********

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PLoS One. 2021 May 20;16(5):e0251916. doi: 10.1371/journal.pone.0251916.r002

Author response to Decision Letter 0

21 Mar 2021

Dear Reviewers,

We were pleased that the reviewers agreed that “the findings are of great interest”. Thank you for the constructive comments and suggestions; we found them helpful for improving our manuscript. We have modified the manuscript according to these suggestions. Our responses to the comments on the manuscript are provided below.

Reviewer #1: DPP-4 Ace receptor are part of the receptor for viral entry. Studies from various European contries especially study from French Cohort has shown that the effect ACE inhibitor is neither harmful nor beneficial. Do they think same type of response from DPP-4 Inhibitor?

Thank you for the constructive comments. We presume that you would like us to include the results of the study by the Carious team [1]. The authors mentioned in their article that a significant difference in the effect of ACE inhibitors on COVID-19 was not observed (OR=1.43 95% CI, 0.99-2.08), and the effects of DPP-4 inhibitors were not significantly different, but they tended to exert a protective effect (OR=0.85 95% CI, 0.55-1.32). Interestingly, when we combined their results with the results of the other included studies [2-4], we ultimately observed a significantly different protective effect (Figure 2).

Page-3 paragraph 2= DPP-4 are neutral agents but not hypoglycemic agents. Sentence need to be modified.

Thank you for the constructive suggestion. We have modified this sentence to “DPP-4 inhibitors (DPP-4is), one of the new oral therapies for diabetes characterized by neutral weight and few adverse effects, is now used to improve insulin secretion as a treatment for T2DM” in the manuscript (lines 8 to 10 on page 3 ).

Page-4, para 2.1= We started article started from...…..= sentence needs to be modified.

Thank you for the kind reminder. We have modified this sentence in the revised manuscript (line 13 to 14 on page 4).

Page-6, search results.. what was the probable cause of duplication?

Thank you for the useful suggestion. When we searched different databases with the same keywords, the same documents or results are often retrieved. Here, we used Endnote to find duplicate results and avoid wasting effort in screening documents.

Page-9, paragraph 2 line3= DPP-4 should be replaced from DPP-4 inhibitor

Thank you for the constructive suggestion. We have replaced DPP-4 with DPP-4 inhibitor in our revised manuscript (line 18 on page 8).

Page-9 Para3= Is this phenomena agent specific or non-specific?

Outcome of results should be mentioned properly not in a sketchy manner.

We thank the reviewer for this constructive suggestion. DPP-4 degrades GLP-1, and GLP-1 exerts an anti-inflammatory effect, but researchers have not determined whether DPP-4is also inhibit the degradation of GLP-1 in patients with COVID-19. The anti-inflammatory effect is only our conjecture at present, and further proof is needed. We have added this explanation to the manuscript (lines 13-16 on page 9).

The stratification of Covid-19 positive patients should have been done by using various tools like modified APACHE-2 and SOFA,MIMS etc.

Thank you for the kind reminder. Unfortunately, since the available literature does not provide sufficient grouping information, we are unable to conduct this experiment based on this constructive suggestion.

In Discussion- Inconclusive. Number of subjects very less. It should have been compared with SGLT-2 inhibitors with or without ACE inhibitors.

Thank you for this constructive suggestion. We have added the control groups of our included researches in the Table 1. Unfortunately, due to the incomplete raw data of the included articles, it is unclear whether SGLT-2 inhibitors or ACE inhibitors is involved.

Reviewer #2: The authors have conducted a meta-analysis of the existing studies on the effect of DPP4i use on COVID-19 mortality in T2DM patients. The findings are of great interest. However, the rationale of the study (SARS-CoV and SARS-CoV2 do not use DPP4 as the receptor, see Cell Study Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, Volume 181, Issue 2, 2020, Pages 271-280.e8,ISSN 0092-8674,

https://doi.org/10.1016/j.cell.2020.02.052.,

Jean K Millet, Javier A Jaimes, Gary R Whittaker, Molecular diversity of coronavirus host cell entry receptors, FEMS Microbiology Reviews, 2020;, fuaa057, https://doi.org/10.1093/femsre/fuaa057),

We sincerely appreciate this constructive suggestion. Taking into account the latest developments on the role of DPP-4is in the entry of COVID-19 into cells, as you suggested, we have corrected and updated our manuscript (lines 3-4 on page 2 and lines 6-13 on page 3).

the presentation of the data (writing of the results section) and therefore the discussion is not adequate

Thank you for this constructive suggestion. We have modified the descriptions of the presentation of the data in the discussion section (line 5 on page 8).

The grammar and syntax are not up to Standard for smooth reading experience. In addition, there are spelling mistakes

Thank you for this valuable advice; we have modified the whole manuscript carefully. Moreover, we have submitted our manuscript to American Journal Experts for language editing, and the entire manuscript has been revised.

References

1. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia 2020;63(8):1500-1515.doi:10.1007/s00125-020-05180-x

2. Fadini GP, Morieri ML, Longato E, Bonora BM, Pinelli S, Selmin E, et al. Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes: A case-control study. Diabetes, obesity & metabolism 2020;22(10):1946-1950.doi:10.1111/dom.14097

3. Solerte SB, D'Addio F, Trevisan R, Lovati E, Rossi A, Pastore I, et al. Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study. Diabetes care 2020;43(12):2999-3006.doi:10.2337/dc20-1521

4. Strollo R, Maddaloni E, Dauriz M, Pedone C, Buzzetti R, Pozzilli P. Use of DPP4 inhibitors in Italy does not correlate with diabetes prevalence among COVID-19 deaths. Diabetes research and clinical practice 2021;171:108444.doi:10.1016/j.diabres.2020.108444

Attachment

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Decision Letter 1

Ghulam Md Ashraf

15 Apr 2021

PONE-D-20-34362R1

DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis

PLOS ONE

Dear Dr. Zhang,

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Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

**********

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 Changes required. Manuscript accepted after revision. The revised paper has incorporated all the required changes. After correction the paper has achieved excellence. Hence accepted.

Reviewer #2: The authors have addressed some of my comments.

However, they need to address additional concerns that have arisen due to oversight and/or not adequately addressing them on the revision.

1. Last para on Pg8 of the manuscript, did the authors mean DPP4 or DPP4 inhibitors

2. Reference 27 is not directly related to ARDS although it could be extrapolated from an LPS-induced mouse model. The way it is written, it seems that Sitagliptin has proven efficacy against ARDS

**********

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: Yes: Pinaki Dutta

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Attachment

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PLoS One. 2021 May 20;16(5):e0251916. doi: 10.1371/journal.pone.0251916.r004

Author response to Decision Letter 1

21 Apr 2021

Dear Reviewers,

We were pleased that the reviewers agreed that “the findings are of great interest”. Thank you for the constructive comments and suggestions; we found them helpful for improving our manuscript. We have modified the manuscript according to these suggestions. Our responses to the comments on the manuscript are provided below.

Reviewer #2: The authors have addressed some of my comments.

However, they need to address additional concerns that have arisen due to oversight and/or not adequately addressing them on the revision.

1. Last para on Pg8 of the manuscript, did the authors mean DPP4 or DPP4 inhibitors

Thank you for the constructive comments. We have replaced the “DPP4 inhibitors” with “DPP4” in the revised manuscript (lines 19 on page 8).

2. Reference 27 is not directly related to ARDS although it could be extrapolated from an LPS-induced mouse model. The way it is written, it seems that Sitagliptin has proven efficacy against ARDS

Thank you for the useful suggestion. We have redescribed this sentence as you suggested in our revised manuscript (lines 2 to 3 on page 9).

Attachment

Submitted filename: Response letter.docx

Click here for additional data file. (16.6KB, docx)

Decision Letter 2

Ghulam Md Ashraf

6 May 2021

DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis

PONE-D-20-34362R2

Dear Dr. Zhang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once 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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ghulam Md Ashraf, 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 #2: (No Response)

**********

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 #2: Yes

**********

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

Reviewer #2: Yes

**********

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 #2: Yes

**********

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 #2: Yes

**********

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 #2: My comment

2. Reference 27 is not directly related to ARDS although it could be extrapolated

from an LPS-induced mouse model. The way it is written, it seems that Sitagliptin

has proven efficacy against ARDS

Author's response

Thank you for the useful suggestion. We have redescribed this sentence as you

suggested in our revised manuscript (lines 2 to 3 on page 9).

What the authors wrote

Moreover, it seems that Sitagliptin "has proven efficacy" against acute respiratory distress syndrome (ARDS), the common

causes of COVID-19-related death, because this drug inhibits IL-6, IL-1, and TNF in

individuals with lung injury [27].

My suggestion was that Reference 27 pertains to work with LPS in "mice" which is NOT ARDS in "humans" but may mimic some of the features. Therefore, the authors "CANNOT" make statements such as above. Please correct the statement to accurately reflect the utility of Sitagliptin

**********

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 #2: No

Acceptance letter

Ghulam Md Ashraf

11 May 2021

PONE-D-20-34362R2

DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis

Dear Dr. Zhang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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PLOS ONE Editorial Office Staff

on behalf of

Dr. Ghulam Md Ashraf

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PLOS ONE

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