GLP-1RA Essentials in Gastroenterology: Side Effect Management, Precautions for Endoscopy and Applications for Gastrointestinal Disease Treatment

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 The authors provided a comprehensive review of glucagon-like peptide-1 receptor agonists (GLP-1-RAs), a type 2 diabetes (T2DM) treatment. They systematically detailed the mechanism of action of GLP-1-RA and its positive effects on weight loss, liver diseases such as NASH and NAFLD, and cardiovascular diseases. On the other hand, they described the side effects of GLP-1-RA including gastrointestinal (GI) disorders and the possibility of an increased incidence of pancreatic and thyroid neoplasms. Three E's (education and explanation, escalation to an appropriate dose, and effective management of GI side effect) was explained as a way to deal with side effects in the gastrointestinal tract, and its management was shown with specific details such as initial administration methods. Finally, they also presented an alternative approaches of weight loss, which works in mechanical means such as Plenity. This paper is very well written about GLP-1-RA, including its adverse effects for GI tract and management of them, and would contribute to the understanding of the field. However, the following minor issue need authors' attention.

 Although Table 1 provides an overview of each GLP-1-RA drug and is very useful information, it would be better to briefly mention the differences and characteristics of each drug in the main text.

Comments for author File: Comments.docx

Author Response

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Reviewer 2 Report

Comments and Suggestions for Authors

This is a very accurate, well-documented update on GLP1-RA side effects and precautions.

At the endoscopic precautions, I would add the risk of prolonged procedure time due to residues and the risk of missing small lesions due to the same reason.

 

Author Response

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Reviewer 3 Report

Comments and Suggestions for Authors

The paper presents the current state of knowledge. I have no objections to the selection of the literature uzut for the preparation of this publication. I also have no concerns regarding ethical issues and conflict of interest as stated by the authors.

A few comments for consideration

1. I would suggest considering the addition of a limitations paragraph in which the authors would possibly address the selection of the literature and also analyze the limitations of the cited literature data.

2. I also suggest shortening the conclusions, they should be based on the analysis of the literature.  Conclusions are not an abstract, they should be shortened and based only on the analyzed data of other authors. Conclusions are not a summary of the article.

Author Response

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Reviewer 4 Report

Comments and Suggestions for Authors

The Title and also the Abstract cover the main aspect of the work.

In Introduction and in Background the authors have presented well-structured data regarding the structure, mechanisms of action, clinical indications and pharmacokinetics of glucagon-like peptide-1 receptor agonists (GLP-1-RAs). Table 1 summarized current approved available GLP-1-RAs drugs.

Comments regarding Table 1:

-some of the commercial names for the GLP-1-RAs are missing (for instance Eperzan for albiglutide, Bydureon for exenatide, Rybelsus for oral semaglutide;

 

-Eperzan was withdrawn by the producer GSK, and this mention must be inserted into the table.

-in all lines of Table 1, the cited references from [7] to [12] do not correspond to the information from the table (possibly references are mixed up). Please verify!

-diabetic retinopathy complications and worsening (stated for dulaglutide) may be encountered also for liraglutide and semaglutide (according to a meta-analysis published in 2022 - Yoshida Yet al. Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes - A systematic review and meta-analysis. J Diabetes Complications. 2022 Aug;36(8):108255. doi: 10.1016/j.jdiacomp.2022.108255. Epub 2022 Jul 5. PMID: 35817678). It may be useful to mention in the Table 1.

-Comment 2: in Line 157, it may be useful to cite the randomized trial as [15], because at the end of the paragraph, both [15] and [16] were cited, but the randomized trial is only [15].

 Section 3

Comments regarding Table 2

-In study [17], liraglutide was associated with significant increase in liver-to-spleen attenuation rate (liver steatosis and liver-to-spleen attenuation rate are inversely correlated).

-In study [19], the decrease of histological inflammation was certified by NASH activity score, while Brunt classification, also improved in the study, is a more complex score. The accurate comment in the table may be “Six subjects who continued liraglutide for 96 weeks showed a decrease in histological inflammation as determined by NASH activity score and stage as determined by Brunt classification,..”

-In study [21], the weight loss was -5.5±1.2 for exenatide versus -0.2±0.8; the difference was 5.3 instead of 5.7 [-5.5 – (-0.2)=-5.3].

-In study [13], the accurate statement according to the study was increases adipose tissue insulin sensitivity.

-In study [23], the more accurate affirmation is “In the weight management trial of patients with ..”. Also, ALT reductions of 6%-21% instead of 69-21%. In [23] abstract mentioned that in the cardiovascular outcomes trial NO significant ALT reduction was noted at 0.5 mg/week, although in full text of [23] is stated that “A reduction was also seen for the lower 0.5 mg/week dose at week 30 but this was not sustained to week 56”-see reference [23] full text.

-Comment 2: in Line 241 the affirmation “Approximatively 10% of patients will discontinue semaglutide because of GI complaints, which may be slightly higher than other GLP-1-analogs” need citation.

-Comment 3: in Line 287 the affirmation “the FDA has stated that there is no conclusive evidence that GLP-1-RAs therapy is linked to pancreatic cancer “ need citation.

 Section 5

-Comment 1: in Line 453, a more accurate affirmation is “-upon confirmation of pancreatitis, GLP-1-RAs should not by reinitiated.”

The Conclusions are clear.

References

-The correspondence between titles cited and text must be verified (see Comments regarding Table 1 from Introduction and Background).

-There are some typing errors in the References: [19], [24], [59], [113]

No concerns about the validity of the study were detected.

Author Response

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