Impacts of Glucagon-like Peptide-1 Receptor-Agonist (GLP-1 RA) Treatment for Metabolic Disturbances and Weight Gain in Patients on Clozapine/Olanzapine: A Systematic Review
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
Varshney et al. provide a review of the emerging evidence on GLP-1 receptor agonists (GLP-1 RAs) for mitigating the metabolic adverse effects of clozapine and olanzapine, highlighting potential benefits and existing gaps; my major comments were around discussion which reads as somewhat repetitive and would definitely require a more critical, analytically appraisal. Some comments below:
Introduction
The background is well-written but overly descriptive like the global prevalence and DALYs discussion could be condensed to make space for a sharper focus on the metabolic burden of clozapine/olanzapine
The transition from “eneral schizophrenia burden”to “GLP-1 RAs” feels abrupt, I would suggest adding bridging paragraph summarising why current mitigation strategies (lifestyle, metformin) may be insufficient, thereby justifying the author’s review.
statement that “further study is required” is generic please dicuss which gaps exist (lack of stratified data, insufficient safety analysis, limited long-term outcomes).
It would be useful to explicitly highlight why clozapine/olanzapine require separate consideration (is that they have the most severe metabolic risk profiles).
You state that meta-analysis was not possible please justify with more detail—what were the main sources of heterogeneity?
Please add all the search strategy and number as supplementary material
Please add a table explaining why 11 studies were excluded, with references included as supplementary material. Without this, the rigour of the review cannot be established as a systematic review; rather, it may be regarded as a narrative review or, at best, a scoping review.
The results are well written. One suggestion would be to move the data extraction table to supplementary material. The paper appears to be written for a clinician; however, it is quite lengthy, and a clinician is unlikely to have the time to read it in full. I recommend streamlining the presentation, possibly adopting a more concise approach to improve readability.
Discussion seems to be written in a academically very novice way, please grossly revise some point below
There is repetition regarding improvements in weight and blood glucose across different drugs, consolidated to avoid redundancy.
The discussion could more critically appraise the strength of the evidence like note the difference between RCTs and case series, and how this affects confidence in the conclusions
Need for further research, this section is thorough but somewhat repetitive.
Author Response
Reviewer 1:
Comment: Varshney et al. provide a review of the emerging evidence on GLP-1 receptor agonists (GLP-1 RAs) for mitigating the metabolic adverse effects of clozapine and olanzapine, highlighting potential benefits and existing gaps; my major comments were around discussion which reads as somewhat repetitive and would definitely require a more critical, analytically appraisal. Some comments below:
Response: The authors are grateful for the reviewer’s meticulous comments. We have revised the manuscript to the best of our ability as per the reviewer’s requests and believe that the manuscript has improved in quality as a result. Thank you.
Comment: Introduction - The background is well-written but overly descriptive like the global prevalence and DALYs discussion could be condensed to make space for a sharper focus on the metabolic burden of clozapine/olanzapine
Response: Thank you for this useful comment. We have trimmed down the discussion on the epidemiology of schizophrenia and – as the next comment has suggested – made a more focused discussion in the Introduction on management, particularly for metabolic side effects and what has been insufficient.
Comment: The transition from “general schizophrenia burden”to “GLP-1 RAs” feels abrupt, I would suggest adding bridging paragraph summarising why current mitigation strategies (lifestyle, metformin) may be insufficient, thereby justifying the author’s review.
Response: We are in agreement that is a useful comment and that this addition with strengthen the Introduction, partially be providing a clearer transition with out points. As the reviewer has suggested, we have added points about existing management approaches and how they have been insufficient overall. The following portion of text has now been added to the Introduction:
Notably, while current approaches to management, including dietary interventions, physical activity programs, and usage of metformin, have been shown to result in some amelioration of these side effects [18-20], they also can frequently be insufficient in addressing the extent of these problems for clozapine/olanzapine patients [21-24]; in some cases, these metabolic changes can be resistant to metformin [21-24], hence necessitating different and perhaps new forms of management.
Comment: statement that “further study is required” is generic please dicuss which gaps exist (lack of stratified data, insufficient safety analysis, limited long-term outcomes).
Response: Thank you. We have now updated this portion of the text to more clearly outline the specific existing gaps. The portion is listed as follows:
GLP-1 RAs may offer utility in addressing metabolic side effects of olanzapine/clozapine, but further research is needed., There remains a need to better understand impacts and potential side-effects with larger and more diverse populations, as well as a need to better evaluate the long-term outcomes for patients.
Comment: It would be useful to explicitly highlight why clozapine/olanzapine require separate consideration (is that they have the most severe metabolic risk profiles).
Response: This a useful addition, which we have now integrated into the manuscript, as requested by the reviewer. The following text has been added:
This is especially important in the case of these two forms of management due to the uniquely severe metabolic side-effect risk profile of clozapine and olanzapine in comparison of other anti-psychotic medications.
Comment: You state that meta-analysis was not possible please justify with more detail—what were the main sources of heterogeneity?
Response: Thank you for noting this. We have now more clearly elucidated the specific elements of the studies, and their associated data, that made it so that an effective meta-analysis was not possible for this review, which is listed as follows:
Due to the high heterogeneity of study designs (randomised control trials and their associated secondary data analyses, case reports, case series, and observational cohort studies) and data presented across included studies (manner in which body mass and changes in body mass, blood glucose control and changes, differences other metabolic parameters, and type of and extent of side effects were measured – as well as follow-up time and type of drug) an effective meta-analysis was not possible for this systematic review.
Comment:
Please add all the search strategy and number as supplementary material
Response: Thanks for the comment. We have now added a Supplementary Table which contains the search terms by database, along with the number of results by database.
Comment: Please add a table explaining why 11 studies were excluded, with references included as supplementary material. Without this, the rigour of the review cannot be established as a systematic review; rather, it may be regarded as a narrative review or, at best, a scoping review.
Response: As per the suggestion, we have now added an additional Supplementary Table to describe why studies were excluded – in doing so, we have ensured the rigour required for a systematic review – as noted by the reviewer.
Comment: The results are well written. One suggestion would be to move the data extraction table to supplementary material. The paper appears to be written for a clinician; however, it is quite lengthy, and a clinician is unlikely to have the time to read it in full. I recommend streamlining the presentation, possibly adopting a more concise approach to improve readability.
Response: We are appreciative of the comments here. We agree with the approach recommended by the reviewer and have now made the data extraction tables now instead Supplementary Tables in the manuscript. We believe that this will greatly improve the readability of the manuscript.
Comment: Discussion seems to be written in a academically very novice way, please grossly revise some point below
There is repetition regarding improvements in weight and blood glucose across different drugs, consolidated to avoid redundancy.
Response: Thank you for the useful, critical comments regarding our writing in the manuscript. We believe that this useful feedback is quite important for us to improve the quality of the manuscript and are hence grateful to the reviewer. Based on this comment, and comments from other reviews, we have extensively revised the Discussion section of this manuscript.
As per the comment here, we have reduced the redundancy here by shortening the length of the information provided regarding the different drugs.
Comment: The discussion could more critically appraise the strength of the evidence like note the difference between RCTs and case series, and how this affects confidence in the conclusions
Response: Thank you for this comment. We have expanded further on this important point early on in the Discussion section to make it clearer that any findings from this review need to be understood with a certain level of caution due to some aspects of the evidence coming from much weaker sources of evidence (such as case series and case reports). The following has been added in early on in the Discussion:
However, it must be noted that this evidence has come from a small number of RCTs, most of which were relatively short in duration; additional evidence beyond this came from considerably weaker data sources such as case reports, case series, and observational cohort studies. Therefore, it is important to exercise caution regarding the extent of generalizability of findings of this review.
In addition the above portion that was added to the manuscript, we have also noted in the limitations section the shortcomings of the existing evidence that has had to partially rely on case reports and case series due to a lack of available studies. By doing this, we have attempted to make it clear as possible what the limitations of this data are.
Comment: Need for further research, this section is thorough but somewhat repetitive.
Response: Thank you for pointing this out, and – upon further reads – we agree that this section of our manuscript was repetitive. We have significantly truncated this portion of the review, focusing much more on the most salient points, and avoiding repeating points that were specified earlier on in this manuscript. We believe that this section is now much more succinct, while still encapsulating the main points.
Reviewer 2 Report
Comments and Suggestions for Authors
Varshney et al. present a systematic review examining the impacts of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on metabolic disturbances and weight gain in patients treated with clozapine or olanzapine. The study addresses an important clinical issue given the high burden of antipsychotic-induced metabolic side effects, and it contributes valuable evidence suggesting that GLP-1 RAs may improve weight and glycemic outcomes in this population. The manuscript is generally well structured, but it requires substantial revisions to improve clarity, methodological transparency, and balance in interpretation. Specific comments and suggestions for improvement are outlined below:
Abstract:
It would strengthen the abstract to briefly note study types (e.g., RCTs) of the 15 studies
The phrasing “minimal side effects noted” is too general; specifying common adverse effects (e.g., gastrointestinal issues) would increase precision.
The conclusion should avoid overstatement (“GLP-1 RAs may offer an important role…”); it could better emphasize the limitations of current evidence.
Introduction:
The rationale for focusing specifically on clozapine and olanzapine is clear, but it would benefit from a sharper contrast with prior reviews that included broader antipsychotic classes
The objectives are clearly stated, but they should be aligned with the PICO framework (Population, Intervention, Comparator, Outcomes) for clarity.
Methods:
Was grey literature included? Is there possibility of publication bias?
Excluding non-English studies may also introduce potential language bias
The search strategy is well described but should include an example of the exact search string for reproducibility
Results:
The PRISMA flow diagram is presented, but numerical inconsistencies are present: the abstract mentions 15 included studies, whereas the results section indicates 14. This discrepancy needs resolution.
The reporting of efficacy outcomes is generally clear (e.g., weight and HbA1c reductions), but the narrative sometimes over-interprets findings from single small studies.
Adverse effects are under-reported; more detail on frequency and severity across studies should be given.
Discussion:
The potential psychosocial benefits (e.g., improved adherence due to reduced side effects) are an interesting hypothesis, but evidence is weak; this should be framed more tentatively.
The implications for updating treatment guidelines are overstated; the review should stress that evidence is preliminary and limited by small sample sizes and heterogeneity.
Implications of quality assessment needs to be highlighted.
Author Response
Reviewer 2:
Comment: Varshney et al. present a systematic review examining the impacts of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on metabolic disturbances and weight gain in patients treated with clozapine or olanzapine. The study addresses an important clinical issue given the high burden of antipsychotic-induced metabolic side effects, and it contributes valuable evidence suggesting that GLP-1 RAs may improve weight and glycemic outcomes in this population. The manuscript is generally well structured, but it requires substantial revisions to improve clarity, methodological transparency, and balance in interpretation. Specific comments and suggestions for improvement are outlined below:
Response: The authors are appreciative for the reviewer to take the time to provide these useful, and detailed comments for our manuscript.
Comment: Abstract: It would strengthen the abstract to briefly note study types (e.g., RCTs) of the 15 studies
Response: Thank you, as requested, we have now denoted the number of RCTs in the Abstract.
Comment: The phrasing “minimal side effects noted” is too general; specifying common adverse effects (e.g., gastrointestinal issues) would increase precision.
Response: We agree that this is a useful point. We have now more precisely specified the side effects, and the minimal impacts highlighted from the studies in our review.
Comment: The conclusion should avoid overstatement (“GLP-1 RAs may offer an important role…”); it could better emphasize the limitations of current evidence.
Response: Thank you. We have updated the wording to avoid overstatement and have emphasized the limitations and need for future research. The revised portion is listed below:
GLP-1 RAs may offer utility in addressing metabolic side effects of olanzapine/clozapine, but further research is needed., There remains a need to better understand impacts and potential side-effects with larger and more diverse populations, as well as a need to better evaluate the long-term outcomes for patients.
Comment: Introduction: - The rationale for focusing specifically on clozapine and olanzapine is clear, but it would benefit from a sharper contrast with prior reviews that included broader antipsychotic classes
Response: Thank you for this vital comment. We have attempted to revise this portion of the manuscript to give a clearer indication of what the existing evidence tells us, as well as the important limitations of using past reviews to guide the prescribing in the specific contexts of olanzapine/clozapine patients. The revised portion is listed below:
There is a basis to the possibility that GLP-1 RAs could have significant benefits as adjunct therapy to improve anti-psychotic induced metabolic disturbances by improving both weight and blood glucose based on some existing literature. A prior systematic review in 2018, on the usage of GLP-1 RAs in patients on antipsychotic medications, demonstrated the effectiveness of these drugs in improving cardiometabolic outcomes in these patients [28]. They showed that utilization of the GLP-1 RAs resulted in notably lower levels of blood glucose, and body mass with limited concerns of severe side-effects. Notably, the authors of that review noted that there was minimal evidence for patients treated on olanzapine/clozapine [28] due to limited sample sizes. Another review was conducted in 2023, which showed comparable, encouraging findings [29]. However, that review did not focus specifically on olanzapine/clozapine, and instead focused on antipsychotic drugs in totality. Therefore, the findings of the review did not provide adequately stratified data to make clinical recommendations for users of clozapine/olanzapine. This is especially important in the case of these two forms of management due to the uniquely severe metabolic side-effect risk profile of clozapine/olanzapine in comparison of other anti-psychotic medications. For these reasons, clear recommendations cannot be made based on prior reviews regarding the safety and effectiveness of GLP-1 RAs for patients on clozapine/olanzapine.
Comment: The objectives are clearly stated, but they should be aligned with the PICO framework (Population, Intervention, Comparator, Outcomes) for clarity.
Response: As requested, we have now more clearly utilized the PICO framework to highlight the basis of our objectives for this review. The following addition to the text has hence been made:
More precisely, we have focused on the study population being patients requiring olanzapine/clozapine due to a mental health diagnosis, the intervention being GLP-1 RAs for these patients, the comparator groups (when available) being those on standard treatments or placebos, and the outcomes being impact on weight and metabolic parameters (most pertinently, blood glucose levels), as well as any other benefits or adverse effects of treatment.
Comment: Methods - Was grey literature included? Is there possibility of publication bias? Excluding non-English studies may also introduce potential language bias
Response: Grey literature was excluded in this review based on the requirement for studies to be peer-reviewed. This contributing to potential publication bias has been denoted in the Limitations of the revised manuscript; as well, the point regarding language bias has now also been denoted in the Limitations.
Comment: The search strategy is well described but should include an example of the exact search string for reproducibility
Response: Thank you for this comment, which was also brought up by Reviewer 1. We have now included a Supplementary Table which contains the search terms by database, as well as the number of results by database.
Comment: Results: - The PRISMA flow diagram is presented, but numerical inconsistencies are present: the abstract mentions 15 included studies, whereas the results section indicates 14. This discrepancy needs resolution.
Response: We greatly apologise for this significant typo, and recognize the confusion that this may have caused. We can confirm that there are a total of 14 studies included in this review, and have revised the Abstract accordingly. Please be aware that we have also checked the manuscript in its entirety to identify and address any other noted typos.
Comment: The reporting of efficacy outcomes is generally clear (e.g., weight and HbA1c reductions), but the narrative sometimes over-interprets findings from single small studies.
Response: We have revised the manuscript, as best as possible to make it clear that any relevant findings from the smaller studies are to be considered alongside their very small sample size. In doing so, we have attempted to address the concern that the review has regarding over-interpretation from small studies.
Furthermore, as per the points requested by Reviewer 1, we have now made it clearer in the Discussion section also regarding the limits of the evidence from this review in totality due to the small sample sizes and other limitations of the studies (e.g. short time follow-up time).
Comment: Adverse effects are under-reported; more detail on frequency and severity across studies should be given.
Response: Thank you for denoting this. Upon further reading of this section, we did find that some revision was needed to describe the specifics of the side-effects. This portion of the text has now been revised, with the following detail now added:
However, despite the side-effects generally being low in severity, some side-effects were nonetheless still seen across participants in treatment groups. In the previously mentioned study [40],three participants discontinued the trial due to nausea, diarrhoea and dizziness, exacerbation of depression, and exacerbation of a Mallory-Weiss tear [40]. A differing study denoted that treatment groups had higher rates of nausea (p=0.008), and orthostatic hypotension (p=0.04) [38]. Specific side-effects noted in the treatment group of another RCT were transient nausea (n = 8), vomiting (n = 7), dizziness (n = 7), and diarrhea (n = 7) [44]. However, other side-effects of higher severity were not noted in this study [44]. Aside from the exacerbation of depression of one patient from the aforementioned study, across all other studies included in this review, there was no worsening of psychological / psychosocial health outcomes amongst all participants who were on the GLP-1 RAs.
Comment: Discussion:- The potential psychosocial benefits (e.g., improved adherence due to reduced side effects) are an interesting hypothesis, but evidence is weak; this should be framed more tentatively.
Response: As suggested, we have revised the wording here to make it clearer that this is a hypothesis, and not necessarily something that can be concluded from the evidence. We also highlight the limits of this hypothesis, and that the implications regarding adherence remain unclear.
Comment: The implications for updating treatment guidelines are overstated; the review should stress that evidence is preliminary and limited by small sample sizes and heterogeneity.
Response: Thank you for these valuable comments. We agree that the extent of the recommendations made were overstated. We have revised the wording heavily here and made it clearer that this may be something worthy of further consideration over time, especially in the future as better quality studies expect to emerge in the future regarding the evidence-base for this topic. The revised version has been made below:
In the future, it may be worthwhile to re-evaluate treatment guidelines to ensure that there are clearer, more concrete recommendations for GLP-1 RAs based on the demonstrated efficacy, safety, and tolerability. As the side-effects of olanzapine/clozapine have such a severe impact on quality of life and overall treatment outcomes, there may be potential for future revisions of these guidelines to address the severe metabolic side-effects of these drugs. However, it is important to reiterate that, at this time the evidence remains preliminary and limited by the studies that are heterogeneous, have small sample sizes, and have limited long-term follow-up.
Comment: Implications of quality assessment needs to be highlighted.
Response: Thank you. This has been now discussed as part of the Limitations section. The following addition has been made, with specific highlighting of the aspects of quality assessments here:
This has important clinical implications because it demonstrates that there still remains a stronger evidence base for clearer recommendations to be made about specific GLP-1 RAs for patients on clozapine/olanzapine. Connected to this point, due to the limited available of studies on this topic, this review had to partially rely on available evidence from case series and case reports, indicating a need for more larger-scale studies continuing to remain. Despite these limits, it is also worth reiterating that the quality assessments conducted for the included studies showed high levels of study quality across methodologies (though this should also be considered alongside recognition that problems linked with follow-up were a common issue).
Reviewer 3 Report
Comments and Suggestions for Authors
- Please acknowledge that you are writing a medical article. Most paragraphs are written in overly wordy. Please unify one word: blood sugar vs. blood glucose. The discussion from previous reviews could be done more concisely. Please revise all your language and adopt more formal scientific writing.
- One important aspect missing from your article in the discussion is medication adherence. In psychiatric populations, medication adherence is often considered as challenges. They sometimes forget doses, do not prefer daily/weekly injections, etc. In addition, please expand on the long-term implications of poor adherences/discontinuation, as this may limit metabolic benefits or contribute to variability in outcomes.
- Most studies are case reports/series with very small samples, and only a few RCTs with very short follow-up. Please reflect the strength of evidence.
Author Response
Reviewer 3:
Comment: Please acknowledge that you are writing a medical article
Response: In the Abstract, we have more clearly articulated this is systematic review is a medical article. Thank you for the comment.
Comment: Most paragraphs are written in overly wordy. Please unify one word: blood sugar vs. blood glucose.
Response: We agree that this is a valuable comment regarding our writing for this manuscript. Based on this comment, and the comments from the other peer-reviewers (Reviewers 1 and 2), we have substantially revised sections across the manuscript – most prominently in the Background and Discussion to remove excessive wordiness, to trim length, and to more effectively articulate our points. With these substantial changes, we feel that our manuscript now reads much more clearly.
Comment: The discussion from previous reviews could be done more concisely.
Response: Thank you for this valuable comment. We agree that – as a whole – being concise was a high priority and we have aimed to make many more areas of the manuscript more concise. However, on this particular point, we received a request by Reviewer 2 to expand on this particular point. Therefore, based on the importance of these particular points in justifying our review (whereas other parts of the Background are not as significant) we have trimmed other portions of our Introduction substantially, while concurrently making it clear in this particular portion that the gaps in the evidence from prior reviews serve as an important justification for this review, particularly in regard to its clinical relevance. Thank you once again for these points.
Comment: Please revise all your language and adopt more formal scientific writing.
Response: Thank you. As per this comment, and comparable comments from the other 2 reviewers, we have gone through the entirety of the manuscript to improve language and have adopted more scientific writing throughout As a result, we feel that the manuscript more concisely and clearly articulates the pertinent points in a scientific manner.
Comment: - One important aspect missing from your article in the discussion is medication adherence. In psychiatric populations, medication adherence is often considered as challenges. They sometimes forget doses, do not prefer daily/weekly injections, etc. In addition, please expand on the long-term implications of poor adherences/discontinuation, as this may limit metabolic benefits or contribute to variability in outcomes.
Response: We agree that these are very valuable points regarding the issues of adherence to GLP-1 RAs, and have been added – and integrated – to our already existing points mentioned regarding adherence. We feel that this discussion now more clearly elucidates the overall complexities here, and how this remains an important, but not clearly understood, area.
The addition made to the text is listed here:
One possible hypothesis for this is that the usage of the GLP-1 RAs may improve patient adherence to clozapine/olanzapine as it reduces some of the very undesirable side effects of these medications. In psychiatric patient populations, adherence to treatment is a common notable concern as some may forego treatment due to impacts of their illness, as well as for reasons such as a strong desire not to continue treatment, a lack of follow-up care, and shortage of resources [61]. While this may possibly improve for clozapine/olanzapine patients due to addressing of side-effects via GLP-1 RAs, it should also be noted that there may also be inherent challenges for patients to adhere to regular administration of GLP-1 RAs via injection. Regardless, it should be noted that this hypothesis and discussion regarding medication adherence was not formally analysed or evaluated in-depth in the studies included, and the implications regarding adherence remain unclear.
Comment: - Most studies are case reports/series with very small samples, and only a few RCTs with very short follow-up. Please reflect the strength of evidence.
Response: Thank you for bringing up this point. A similar point was made by Reviewer 1, and so we have made sure to meticulously make these points clear across the manuscript, with highlighting of the overall limits of this evidence due to these limits. As a result, we feel that the manuscript much more clearly highlights where the evidence currently stands, and that much more research is required on this topic based on the limited evidence-base. One such addition is made earlier on in the Discussion, where the following was stated:
However, it must be noted that this evidence has come from a small number of RCTs, most of which were relatively short in duration; additional evidence beyond this came from considerably weaker data sources such as case reports, case series, and observational cohort studies. Therefore, it is important to exercise caution regarding the extent of generalizability of findings of this review.
Round 2
Reviewer 1 Report
Comments and Suggestions for Authors
The manuscript has been significantly improved compared to the initial submission. I thoroughly reviewed the point-by-point response, and I can see that the authors have addressed the comments and provided clarifications for several points. I would recommend publishing the article at the discretion of the academic editor.
Reviewer 2 Report
Comments and Suggestions for Authors
The manuscript has been significantly improved compared to the initial submission. I thoroughly reviewed the point-by-point response, and I can see that the authors have addressed the comments and provided clarifications for several points.
