Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Abstract

Line 17-20 the sentences are not clear. Suggest changing to "Participants continued medication use for four weeks without RT (GLP-1) followed by an 8-week RT program with medication (GLP-1+RT). Or something similar as the current language is not clear for the study design.

 

Line 22, as you did for body mass list the change in kg for fat mass and the %fat. It is important to have data in the abstract and not just p values.

 

 

Materials and Methods

 

Line 82, what was the exclusion criteria for the study and where were the participants recruited?

 

Would be good to include a CONSORT diagram to show how many people were recruited, screened and enrolled since this was an exploratory study and will help to inform others conducting similar work.

 

Line 155, rate of perceived exertion needs to be corrected to "rating" of perceived exertion as it is not a rate.

Line 155, list the RPE scale. Was it a modified Borg Scale 0-10, or 6-20?

 

Line186, a power analysis was performed but in an exploratory or pilot study, typically a power analysis is not performed since the data from the pilot study is used to inform a sample size for a follow up study that is appropriately powered. Although the authors do have some significant findings, why did they not recruit enough participants to complete at least 28 as their power analysis demonstrated?

 

Line 186, what study or studies were used to calculate the power? This reference should be provided.

 

Results

 

Line 201, how many participants were enrolled as 11 completed the study but important to know how many started.

 

Line 225, would be good to show the absolute data for RMR to know if there was a trend for change in RMR between measurement timepoints. This is important when understanding body comp changes.

 

Line 261, why did the authors not show data for all participants in Figures 4 and 5? If this was intentional, say that the data is an average of the 11 participants. However, the individual data is preferred.

 

Discussion

Overall well written and the authors appropriately reported the significant limitations of the study.

 

Line 310, replace "saw" with "showed"

 

Abbreviations

 

Change RPE "rate" of perceived exertion to "rating"

Author Response

Comment 1: Line 17-20 the sentences are not clear. Suggest changing to "Participants continued medication use for four weeks without RT (GLP-1) followed by an 8-week RT program with medication (GLP-1+RT). Or something similar as the current language is not clear for the study design.

Response 1: Thanks for pointing this out, it was unclear. We've amended the language to make it clearer. 

Comment 2: Line 22, as you did for body mass list the change in kg for fat mass and the %fat. It is important to have data in the abstract and not just p values.

Response 2: We have included unit changes for fat mass and %fat within the abstract. 

Comment 3: Line 82, what was the exclusion criteria for the study and where were the participants recruited?

Response 3: We included exclusion criteria starting at line 86, immediately following the inclusion criteria. We have also included where participants were recruited from and how they were recruited. 

Comment 4: Would be good to include a CONSORT diagram to show how many people were recruited, screened and enrolled since this was an exploratory study and will help to inform others conducting similar work.

Response 4: We have included a CONSORT diagram demonstrating enrollment, participation, and attrition across the duration of this study. 

Comment 5: Line 155, rate of perceived exertion needs to be corrected to "rating" of perceived exertion as it is not a rate. + Line 155, list the RPE scale. Was it a modified Borg Scale 0-10, or 6-20?

Response 5: We have switched rate to rating. Thanks for pointing this out. It was a Borg 1-10. We have added that immediately following the previous sentence so it's clear. 

Comment 6: Line186, a power analysis was performed but in an exploratory or pilot study, typically a power analysis is not performed since the data from the pilot study is used to inform a sample size for a follow up study that is appropriately powered. Although the authors do have some significant findings, why did they not recruit enough participants to complete at least 28 as their power analysis demonstrated?

Response 6: Very fair question to ask. I would agree that a power analysis isn't necessary per se for a pilot or exploratory study such as this. We lean towards including in most manuscripts as it is frequently requested and helps us be forthright and transparent with regards to our study design and findings. That being said, this project was a thesis. Funding was limited. We secured a student research grant through an organization and a good chunk of monies from that went to pay for participants' parking passes... on our university... as they monetize everything (sob story, I know). That being said, we had to cap our sample at 11 due to financial and time constraints, though we believe the data are strong for the sample size. 

Comment 7: Line 186, what study or studies were used to calculate the power? This reference should be provided.

Response 7: We have included two studies as references for our sample size, both of which are near or are below our intended sample size.

Comment 8: Line 201, how many participants were enrolled as 11 completed the study but important to know how many started.

Response 8: We have specified our original enrollment in this area of the manuscript- which was 12. One dropped due to time conflicts. We have included this in the consort diagram as well. 

Comment 9: Line 225, would be good to show the absolute data for RMR to know if there was a trend for change in RMR between measurement timepoints. This is important when understanding body comp changes.

Response 9: We have included a table demonstrating data for BMI, RMR, FBG, and HbA1c over the 3 visits of this study. 

Comment 10: Line 261, why did the authors not show data for all participants in Figures 4 and 5? If this was intentional, say that the data is an average of the 11 participants. However, the individual data is preferred.

Response 10: This was a stylistic preference by the first author, mainly to help convey the overall patterns in the ultrasound-derived data across time. We believe it helps portray the direction we theorize these variables should change within the context of this type of intervention. We have added in language to make it clear that both Figures 4 and 5 represent the mean and SD of all 11/pooled participants. 

Comment 11: Line 310, replace "saw" with "showed"

Response 11: Amended.

Comment 12: Change RPE "rate" of perceived exertion to "rating"

Response 12: Amended. 

 

Thanks for your feedback, politeness, and kindness. It is greatly appreciated!

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript provides a detailed analysis of changes in body composition, skeletal muscle morphology, muscle strength, resting energy expenditure, and carbohydrate metabolism parameters in individuals taking semaglutide. The manuscript also examines the implementation of resistance training in patients receiving this treatment. This is of considerable practical value, as the increasingly widespread use of glucagon-like peptide-1 receptor agonists and therapies based on multiple incretin agonism requires that the assessment of treatment efficacy not be limited solely to the extent of total body weight reduction.  The primary focus should be on reducing body fat while preserving as much muscle mass, strength, fitness, proper nutritional status, and bone health as possible. Therefore, the assessment of muscle mass and fitness should be an integral part of research on this treatment. This manuscript may serve as a valuable source of pilot study data. However, due to its limitations, it cannot be presented as a study proving the effectiveness of resistance training in preserving muscle mass or accelerating fat loss during semaglutide treatment.

The authors rightly point out that lean body mass is not the same as skeletal muscle mass. In the context of obesity treatment, it is not enough to simply determine how many kilograms a patient has lost. It is necessary to assess the contribution of individual tissues to this change and whether the weight loss occurred at the expense of strength, physical fitness, and the body’s functional reserves. This is particularly important in older adults, patients with type 2 diabetes, individuals with low baseline muscle mass, and patients at risk of developing sarcopenia. This is because lean body mass includes not only muscle but also water, internal organs, bone tissue, connective tissue, and other non-fat components. For this reason, a decrease in lean body mass should not automatically be interpreted as equivalent to a loss of muscle tissue. Similarly, a slight increase in lean body mass is not sufficient evidence of muscle hypertrophy, as it may result from changes in hydration or glycogen stores. The inclusion of ultrasound constitutes a valuable component of the study. The morphology of selected muscles can provide supplementary information regarding the overall assessment of body composition. However, caution is warranted, as the absence of a change in the thickness of one or more examined muscles does not prove the preservation of total skeletal muscle mass, just as a local change cannot be automatically generalized to the entire body.

The most significant limitation of the study is the absence of a control group that received semaglutide therapy without exercise during the same time period, at a comparable stage of treatment, and for an identical duration. All participants first underwent a four-week treatment period without supervised exercise, followed by an eight-week period of semaglutide administration combined with resistance training. This means that the order of the two phases was fixed and not randomized. In this setup, the effect of exercise cannot be separated from the effect of time. The second phase was simultaneously the later phase, the longer phase, and the phase occurring at a different point in the course of pharmacological therapy. Any change observed between the second and third visits may therefore result from exercise, the continued effect of the medication, dose adjustments, changes in appetite, changes in energy intake, increased participant motivation, the natural course of weight loss, or a combination of all these factors.
The four-week period preceding the training cannot be treated as an equivalent control group. It was half as long, always occurred first, and could have coincided with a different stage of the response to the medication. The rate of weight loss during semaglutide treatment does not have to be linear. It may depend on the current dose, time since treatment initiation, drug tolerance, the intensity of the appetite-suppressing effect, and the extent of prior weight loss. For this reason, the claim that resistance training “accelerated” weight loss or fat loss is not entirely reliable.

Furthermore, the body’s response to an energy deficit does not necessarily follow a linear pattern. In the initial phase of weight loss, changes in water and glycogen may play a larger role, whereas in later stages, the rate of weight loss may slow down as a result of energy adaptation. In some individuals, adjusting the semaglutide dose may, conversely, lead to a renewed increase in appetite suppression. Simply dividing the total change by the number of weeks does not account for these effects. This also affects the accuracy of the dietary model assessment. The most underdeveloped aspect of the interpretation is dietary intake. Reported energy intake averaged approximately 1097-1258  kcal per day, and protein intake averaged approximately 53-63 g per day. With an average body weight of approximately 85 kg, this amounts to roughly 0.62-0.74 g of protein per kilogram of body weight per day. If these values even partially reflect actual intake, the participants may have been in a significant energy deficit and consuming relatively little protein relative to the goal of maintaining or building lean body mass.
Of course, self-reported dietary intake carries a risk of underestimation. However, the interpretation cannot be limited to the conclusion that the dietary data may have been inaccurate. Both genuinely low intake and a large reporting error have methodological implications. In the first case, low energy and protein availability may have limited muscle adaptation. In the second, the impact of nutrition on the results cannot be reliably controlled.

Of particular importance is the lack of assessment of appetite and gastrointestinal symptoms. Nausea, feeling full quickly, constipation, vomiting, or food aversions can affect total food intake and the ability to complete a planned training session. Recent studies on GLP-1 therapy emphasize the need for concurrent monitoring of protein intake, micronutrient adequacy, muscle function, body composition, and bone health.

Another point worth discussing in more detail is that the mean duration of prior semaglutide use was approximately nine months, with a standard deviation of about six months, and the mean dose was approximately 1,3 mg, with a standard deviation of about 0,9 mg. Such a wide range indicates that participants may have been at completely different stages of treatment. Some may have been in the early dose-escalation phase, some may have reached a stable maintenance dose, and others may have been in the weight-loss plateau phase.

The results suggest a significant time effect for body weight, but not for BMI. Since the height of adult participants does not change significantly over 12 weeks, BMI is a direct mathematical transformation of body weight. The discrepancy between the results of these two analyses warrants further investigation.

The manuscript focuses on muscles and lean body mass but barely addresses bone health. This is a significant gap, as rapid weight loss may affect bone mineralization as well as calcium and vitamin D intake.
Future studies should consider bone densitometry, assessment of bone mineral content, markers of bone turnover, and data on fractures and activities that impact the skeleton. In the current manuscript, the absence of such measurements should at least be noted as a limitation. Current frameworks for assessing the quality of weight loss during GLP-1 therapy take bone health into account alongside muscle mass and physical function.

Author Response

Comment: The manuscript focuses on muscles and lean body mass but barely addresses bone health. This is a significant gap, as rapid weight loss may affect bone mineralization as well as calcium and vitamin D intake. Future studies should consider bone densitometry, assessment of bone mineral content, markers of bone turnover, and data on fractures and activities that impact the skeleton. In the current manuscript, the absence of such measurements should at least be noted as a limitation. Current frameworks for assessing the quality of weight loss during GLP-1 therapy take bone health into account alongside muscle mass and physical function.

Response: This is noteworthy and is of relevance to future studies. We have included this towards the of the discussion as part of our summary of future directions. 

Comment: Of particular importance is the lack of assessment of appetite and gastrointestinal symptoms. Nausea, feeling full quickly, constipation, vomiting, or food aversions can affect total food intake and the ability to complete a planned training session. Recent studies on GLP-1 therapy emphasize the need for concurrent monitoring of protein intake, micronutrient adequacy, muscle function, body composition, and bone health.

Response: You are correct in that we did not report appetite or GI effects/symptoms within this study. We agree with your sentiments here. We have included this as a future direction for studies alongside examining how bone health is impacted by GLP-1 w/ and w/o RT. 

Comment: This manuscript may serve as a valuable source of pilot study data. However, due to its limitations, it cannot be presented as a study proving the effectiveness of resistance training in preserving muscle mass or accelerating fat loss during semaglutide treatment.

Response: We agree. We explicitly (within the original submission) discuss the challenges of this study within the limitations section, starting at around line 403. We outline the lack of a control group, variability in dosing/dose duration, how we attempted to control for some of these limitations. Moreover, we emphasize that these results should be interpreted cautiously due to these limitations. Our conclusion frames our findings as RT as an adjunct to GLP-1 use, in that our findings were largely positive and there is likely largely/only benefits to be gained from their combination. 

Comment: The morphology of selected muscles can provide supplementary information regarding the overall assessment of body composition. However, caution is warranted, as the absence of a change in the thickness of one or more examined muscles does not prove the preservation of total skeletal muscle mass, just as a local change cannot be automatically generalized to the entire body.

Response: We agree in that there's not a clear-cut relationship between localized changes in muscle size/morphology and whole body mass (though we speculate, based upon some of this data, and other data we've generated, that they align well - future study idea!). In addressing the MT data, we generally aimed to highlight it was localized muscle size. We amended one sentence in the MT discussion. Line 377 - looking at patterns between changes in MT and changes in FFM. "though this is speculative and should be approached conservatively."

Comment: The four-week period preceding the training cannot be treated as an equivalent control group. It was half as long, always occurred first, and could have coincided with a different stage of the response to the medication. The rate of weight loss during semaglutide treatment does not have to be linear. It may depend on the current dose, time since treatment initiation, drug tolerance, the intensity of the appetite-suppressing effect, and the extent of prior weight loss. For this reason, the claim that resistance training “accelerated” weight loss or fat loss is not entirely reliable.

Response: These are all excellent points. We've gone through these sections of the discussion, softened the stance and interpretation, while also highlighting potential factors that could alternatively explain these observations. 

Comment: The results suggest a significant time effect for body weight, but not for BMI. Since the height of adult participants does not change significantly over 12 weeks, BMI is a direct mathematical transformation of body weight. The discrepancy between the results of these two analyses warrants further investigation.

Response: We were perplexed by this as well, and your reasoning makes sense. We've examined the data, and the values/analyses are correct, there were no significant changes in BMI. 

Comment: Another point worth discussing in more detail is that the mean duration of prior semaglutide use was approximately nine months, with a standard deviation of about six months, and the mean dose was approximately 1,3 mg, with a standard deviation of about 0,9 mg. Such a wide range indicates that participants may have been at completely different stages of treatment. Some may have been in the early dose-escalation phase, some may have reached a stable maintenance dose, and others may have been in the weight-loss plateau phase.

Response: Great point. In the original submission, we discuss this as a limitation of the study design (lines 444-452. We believe how this was originally written encapsulates and addresses the concerns of this comment and makes it abundantly clear to readers the implications of this within this study. Thus, we left this section of the discussion as is. We also attempted to address this by using dose and dose duration as covariations, which still considering residual confounding as a limitation for our findings. 

Comment: Furthermore, the body’s response to an energy deficit does not necessarily follow a linear pattern. In the initial phase of weight loss, changes in water and glycogen may play a larger role, whereas in later stages, the rate of weight loss may slow down as a result of energy adaptation. In some individuals, adjusting the semaglutide dose may, conversely, lead to a renewed increase in appetite suppression. Simply dividing the total change by the number of weeks does not account for these effects. This also affects the accuracy of the dietary model assessment. The most underdeveloped aspect of the interpretation is dietary intake. Reported energy intake averaged approximately 1097-1258  kcal per day, and protein intake averaged approximately 53-63 g per day. With an average body weight of approximately 85 kg, this amounts to roughly 0.62-0.74 g of protein per kilogram of body weight per day. If these values even partially reflect actual intake, the participants may have been in a significant energy deficit and consuming relatively little protein relative to the goal of maintaining or building lean body mass.
Of course, self-reported dietary intake carries a risk of underestimation. However, the interpretation cannot be limited to the conclusion that the dietary data may have been inaccurate. Both genuinely low intake and a large reporting error have methodological implications. In the first case, low energy and protein availability may have limited muscle adaptation. In the second, the impact of nutrition on the results cannot be reliably controlled.

Response: These are great points. We've expanded this section of the discussion to consider the implications of the dietary intake being accurate/reliable, while addressing this as an area of investigation and concern in future studies. 

Reviewer 3 Report

Comments and Suggestions for Authors

Author has conducted the study to examine the effects of semaglutide and resistant training on body composition, muscle mass, glycemic regulation and metabolic rate in patients with overweight or obesity. There is limited evidence of effects of resistant training on patients with GLP-1 agonist.   The study supports the existing evidence and there are several limitations including small sample size, no constant dose across the study group ignores the variation in the effect of resistance training on muscle mass, absence of control group.  I do not feel that this paper contributes compelling new information to the field that is clinically actionable or transforms the approach to obesity treatment with GLP1 agonist.

Author Response

Thanks for reviewing this manuscript. Your comments aren't really actionable per se, and your feedback vs comments don't align, so we made no adjustments to the manuscript from this feedback.

In your comments, you mention that there is limited evidence of the effects of resistance training on folks using GLP-1 agonist. This manuscript does so and it is new data. We believe this is a huge strength and begins the discussion of examining the combined effects of medication with exercise. You then proceed to state that this study doesn't add compelling new information, but the study and its data are novel. Most importantly, we saw positive or maintained effects in muscle composition and fat free mass in the context of using GLP-1 - all while participants' performed a modest, feasible RT program. Yes, there are limitations to the study design but this study has excellent ecological validity. If you were to go find a study with data to support the stance that the data aren't compelling, I think your argument could have more merit, but as it stands, this study is one of the first examining the combo of RT with GLP-1 - which is realistic and relevant now and moving forward. 

Thanks again for your time. 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Appreciate the relevant revisions to the manuscript. The current version, which addresses all limitations and highlights elements worthy of further investigation, is significant. In its current form, this manuscript is worth attention and provides a better, more accurate understanding of the discussed topic. 

Author Response

Thanks for the feedback!