Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
Open accessAI snapshot
Written from the paper’s full text.
TL;DR
This reply defends a joint advisory on nutrition during GLP-1 obesity therapy, agreeing with critics on terminology and research gaps while emphasizing muscle and bone monitoring. It argues that fat-free mass loss in GLP-1 trials often exceeds proposed thresholds, raising concerns about sarcopenic obesity and weight regain after treatment cessation.
Key findings
- The authors agree that fat-free mass and skeletal muscle mass are distinct and that standardized terminology and method choice—such as DXA versus MRI or CT—matter for interpreting body composition during GLP-1 treatment.
- They cite prior thresholds that fat-free mass loss should remain below 22% in women and 25% in men, but note a review of 28 GLP-1 trials found DXA-measured fat-free mass losses of 20–40%, with most trials averaging more than 25%.
- They warn that weight regain after stopping GLP-1s typically restores fat but not lost fat-free mass, and that high cessation rates after 1–2 years could worsen sarcopenic obesity and metabolic health.
- They note tirzepatide data showing reduced intramuscular fat alongside modest muscle volume reductions, and call for more frequent multimodal monitoring and research on measurement methods, muscle strength, and organ fat.
Methods
- This is a reply/correspondence to three critiques of a joint advisory; it is not an original study and reports no new data collection or primary analysis.
- The authors synthesize cited literature and prior recommendations, including a review of 28 clinical trials, to support their advisory positions.
- No formal systematic review, meta-analysis, or statistical method is described.
Limitations
- The paper states that many questions remain uncertain and require further research, including optimal dietary patterns with GLP-1s, implementation strategies, and effects of different body composition measurement methods.
- It acknowledges that nutrition and lifestyle interventions are underprioritized in industry-funded GLP-1 trials and current clinical care.
- Evident from the text: as a reply letter, it presents expert consensus and selective citations rather than new empirical evidence; no limitations section or formal risk-of-bias assessment is included.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 17 cited sources checked · 0 supported · 0 flagged
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
Sarcopenic obesity is associated with increased all-cause mortality.
“Sarcopenic obesity poses increased risk of a range of adverse outcomes, including a potential increase in fractures among those using GLP-1 therapy (particularly among women) [5] and all-cause mortality [7], yet may not be as readily apparent in those with obesity compared to normal-weight individuals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Benz, 2024, Sarcopenia and sarcopenic obesity and mortality among older people, JAMA. Netw. Open. source
Not checked in the free run.
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
In longer-term studies of other weight-loss interventions, weight regain restored fat mass but did not restore the fat-free mass that had been lost.
“Studies of other weight loss interventions with longer follow-up have shown that, when weight is regained over time, fat mass is regained but not lost fat-free mass [5].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Greenway, 2025, Semaglutide and tirzepatide to treat obesity, N. Engl. J. Med. source
Not checked in the free run.
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
For people on GLP-1 therapy, especially women, fractures may become more common.
“Sarcopenic obesity poses increased risk of a range of adverse outcomes, including a potential increase in fractures among those using GLP-1 therapy (particularly among women) [5] and all-cause mortality [7], yet may not be as readily apparent in those with obesity compared to normal-weight individuals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Greenway, 2025, Semaglutide and tirzepatide to treat obesity, N. Engl. J. Med. source
Not checked in the free run.
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
Sarcopenic obesity is linked to a higher risk of several adverse outcomes.
“Sarcopenic obesity poses increased risk of a range of adverse outcomes, including a potential increase in fractures among those using GLP-1 therapy (particularly among women) [5] and all-cause mortality [7], yet may not be as readily apparent in those with obesity compared to normal-weight individuals.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
A review of 28 clinical trials of GLP-1 therapy found that loss of DXA-measured fat-free mass ranged from 20% to 40%.
“However, a recently reported review of 28 clinical trials of GLP-1 therapy identified that loss of DXA-measured fat-free mass, a rough surrogate for skeletal muscle, ranged between 20% and 40%, with most trials demonstrating average losses of >25% [6].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Dubin, 2024, Glucagon-like peptide-1 receptor agonist-based agents and weight loss composition: filling the gaps, Diabetes Obes, Metab.
Not checked in the free run.
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
Industry-funded GLP-1 trials have so far given too little priority to nutrition interventions in how they are run and reported.
“We agree with Ibsen and colleagues that more research is needed to understand how nutrition interventions can be optimally integrated into the care of individuals treated with GLP-1s—and that this critical question has been insufficiently prioritized in the conduct and reporting of industry-funded GLP-1 trials to date.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ibsen and colleagues
Not checked in the free run.
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
In most of the 28 clinical trials reviewed, average loss of DXA-measured fat-free mass was greater than 25%.
“However, a recently reported review of 28 clinical trials of GLP-1 therapy identified that loss of DXA-measured fat-free mass, a rough surrogate for skeletal muscle, ranged between 20% and 40%, with most trials demonstrating average losses of >25% [6].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Dubin, 2024, Glucagon-like peptide-1 receptor agonist-based agents and weight loss composition: filling the gaps, Diabetes Obes, Metab.
Not checked in the free run.
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
For 25 years, many studies have linked weight loss to better muscle metabolism, such as less intramuscular adipose tissue.
“Over the past 25 years, numerous studies have demonstrated that mass loss is associated with metabolic improvements in muscle, including reductions in intramuscular adipose tissue [9].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Goodpaster, 2000, Intramuscular lipid content is increased in obesity and decreased by weight loss, Metabolism source
Not checked in the free run.
- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
Several clinical practice guidelines and the FDA's approval for GLP-1 use state that nutrition and lifestyle care are fundamental to obesity treatment.
“Indeed, as detailed in the Advisory, multiple clinical practice recommendations, and the FDA approval for GLP-1 use, specify that nutrition and lifestyle care are foundational for obesity treatment.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Advisory
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- cites FDA approval
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- Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.
Current clinical care for people on GLP-1s gives too little priority to nutrition and other lifestyle interventions.
“Likewise, as highlighted in the Advisory, we agree that nutrition and other lifestyle interventions are insufficiently prioritized in current clinical care for such individuals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Advisory
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- May combine two claims. 3
- Classified as probably not a substantial claim. 2
May combine two claims.
Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.Tirzepatide has been reported to lower intramuscular fat while causing only modest decreases in muscle volume.
“At the same time, recent data demonstrate reductions in intramuscular fat infiltration alongside modest reductions in muscle volume with tirzepatide [8], underscoring the nuanced body composition changes that can occur during GLP-1-induced weight loss.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Sattar, 2025, Tirzepatide and muscle composition changes in people with type 2 diabetes (SURPASS-3 MRI): a post-hoc analysis of a randomised, open-label, parallel-group, phase 3 trial, Lancet. Diabetes, Endocrinol
Not checked in the free run.
May combine two claims.
Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.Many patients stop GLP-1 therapy after one to two years and then regain weight.
“This is particularly concerning for GLP-1s given the high rates of cessation after 1 to 2 years, with subsequent weight regain [4], which could exacerbate sarcopenic obesity and worsen metabolic health over time.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Mozaffarian, 2025, Nutritional priorities to support GLP-1 therapy for obesity: a joint advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society, Am. J. Clin. Nutr.
Not checked in the free run.
May combine two claims.
Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.The distinction between fat-free mass and skeletal muscle mass is supported by methodological standards for body composition research and by proposed definitions of body composition components.
“Distinguishing fat-free mass from skeletal muscle mass is well-supported by methodological standards for body composition research [2] and proposed definitions for various body composition components [3].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Prado, 2024, Methodological standards for body composition – an expert-endorsed guide for research and clinical applications: levels, models, and terminology, Am. J. Clin. Nutr.
Not checked in the free run.
- cites [3] Heymsfield, 2024, Are lean body mass and fat-free mass the same or different body components? A critical perspective, Adv. Nutr. source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.Providing comprehensive nutrition and lifestyle assessment and care to people on GLP-1s can be done in clinical practice.
“We do not believe such a comprehensive assessment and care is infeasible in clinical practice.”
Quote in the paperNot a substantial claim- Rests on an assumption: Health systems, medical education, and clinical pathways already carry out complex assessments and care in areas other than nutrition.
- Rests on an assumption: These institutions often lack comparable organization for proper nutrition assessment and care.
Classified as probably not a substantial claim.
Premisecitation§ Reply to GM Tinsley et al.; DB Ibsen et al.; and EJ Dhurandhar et al.The guidance summarized from the USPSTF, major clinical societies, and the FDA aligns with the Advisory's recommendation for a comprehensive, multicomponent lifestyle intervention centered on nutrition.
“All these are consistent with the Advisory, recommending a comprehensive, multicomponent lifestyle intervention focusing on nutrition.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Advisory
Not checked in the free run.
The paper relies on this without support.
DXA is unable to separate skeletal muscle from other lean tissues.
“for example, dual-energy X-ray absorptiometry (DXA), which provides a practical assessment of regional lean mass but cannot distinguish between skeletal muscle mass and other lean tissues, compared with MRI and computed tomography (CT), which offer more granularity at the organ and tissue level, albeit with higher cost and complexity.”
The paper relies on this without support.
MRI and CT give finer detail at the organ and tissue level than DXA, though they cost more and are more complex.
“for example, dual-energy X-ray absorptiometry (DXA), which provides a practical assessment of regional lean mass but cannot distinguish between skeletal muscle mass and other lean tissues, compared with MRI and computed tomography (CT), which offer more granularity at the organ and tissue level, albeit with higher cost and complexity.”
The paper relies on this without support.
Sarcopenic obesity can be harder to notice in people with obesity than in normal-weight people.
“yet may not be as readily apparent in those with obesity compared to normal-weight individuals.”
The paper relies on this without support.
Strong evidence already exists for dietary patterns that support metabolic health.
“Robust evidence already supports optimal dietary patterns for metabolic health; it need not be reinvented for every patient group.”
The paper relies on this without support.
Health systems, medical education, and clinical pathways already carry out complex assessments and care in areas other than nutrition.
“Modern health systems, medical education, and clinical care pathways currently implement complex assessments and care outside nutrition.”
The paper relies on this without support.
These institutions often lack comparable organization for proper nutrition assessment and care.
“These institutions are often not similarly organized for appropriate nutrition assessment and care.”
Cites
Intramuscular lipid content is increased in obesity and decreased by weight loss
Goodpaster, B. H., Theriault, R., Watkins, S. C., & Kelley, D. E. (2000) · Metabolism · doi:10.1016/s0026-0495(00)80010-4 · Cited by 526 · see citing works
Sarcopenia and Sarcopenic Obesity and Mortality Among Older People
Benz, E., Pinel, A., Guillet, C., Capel, F., Pereira, B., De Antonio, M., Pouget, M., Cruz-Jentoft, A. J., Eglseer, D., Topinkova, E., et al. (2024) · JAMA Network Open · doi:10.1001/jamanetworkopen.2024.3604 · Cited by 261 · see citing works
Sattar, N., Neeland, I. J., Dahlqvist Leinhard, O., Fernández Landó, L., Bray, R., Linge, J., & Rodriguez, A. (2025) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(25)00027-0 · Cited by 106 · see citing works
Prado, C. M., Gonzalez, M. C., Norman, K., Barazzoni, R., Cederholm, T., Compher, C., Jensen, G. L., Abe, T., Barbosa-Silva, T. G., Bosy-Westphal, A., et al. (2025) · The American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2025.05.022 · Cited by 106 · see citing works
Are lean body mass and fat-free mass the same or different body components? A critical perspective
Heymsfield, S. B., Brown, J., Ramirez, S., Prado, C. M., Tinsley, G. M., & Gonzalez, M. C. (2024) · Advances in Nutrition · doi:10.1016/j.advnut.2024.100335 · Cited by 96 · see citing works
Tinsley, G. M., & Heymsfield, S. B. (2024) · Journal of the Endocrine Society · doi:10.1210/jendso/bvae164 · Cited by 81 · see citing works
Dubin, R. L., Heymsfield, S. B., Ravussin, E., & Greenway, F. L. (2024) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.15913 · Cited by 47 · see citing works
Are metabolic adaptations to weight changes an artefact?
Müller, M. J., Heymsfield, S. B., & Bosy‐Westphal, A. (2021) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqab184 · Cited by 42 · see citing works
Mozaffarian, D., Agarwal, M., Aggarwal, M., Alexander, L., Apovian, C. M., Bindlish, S., Bonnet, J., Butsch, W. S., Christensen, S., Gianos, E., et al. (2025) · Obesity Pillars · doi:10.1016/j.obpill.2025.100181 · Cited by 28 · see citing works
Self-citationFat‐Free Mass: Friend or Foe to Metabolic Health?
Oliver, C. J., Climstein, M., Rosic, N. N., Bosy‐Westphal, A., Tinsley, G. M., & Myers, S. P. (2025) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13714 · Cited by 26 · see citing works
Semaglutide and Tirzepatide to Treat Obesity
Greenway, F. L. (2025) · New England Journal of Medicine · doi:10.1056/nejme2507452 · Cited by 7 · see citing works
Flagged first, then by citations
- Authors
- Stanford, F. C., Sannidhi, D., Butsch, W. S., Apovian, C. M., Agarwal, M., Aggarwal, M., Alexander, L., Bindlish, S., Bonnet, J., Christensen, S., Gianos, E., Gulati, M., Gupta, A., Horn, D., Kane, R. M., Saluja, J., Callahan, E. A., & Mozaffarian, D.
- Affiliations
- Harvard University (US)
- University of California San Diego (US)
- Cleveland Clinic (US)
- Brigham and Women's Hospital (US)
- University of Alabama at Birmingham (US)
- University of Florida Health (US)
- Stanford Medicine (US)
- Lenox Hill Hospital (US)
- UConn Health (US)
- George Washington University (US)
- The University of Texas at Austin (US)
- Duke University (US)
- Tufts University (US)
- Corresponding author
- Mozaffarian, Dariush
- ORCID
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2025-11
- Volume
- 122
- Issue
- 5
- Pages
- 1531-1533
- ISSN
- 0002-9165 (ISSN-L)
- PMC
- PMC13041736
- OpenAlex
- W4414216847
- Cited by
- 0
- References
- 10
- Type
- journal article
- Language
- en
- Open access
- Locations
- American Journal of Clinical Nutrition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Duke University Duke Clinical Research Institute
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Body Composition Measurement Techniques
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- skeletal muscle, fat-free mass, body composition, anti-obesity drugs, evidence-based practice
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