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Cited by 152Pharmacology and Obesity TreatmentNutrition and Health in AgingDiabetes Treatment and Management

Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?

Open access
Locatelli, João Carlos, Costa, Juliene Gonçalves, Haynes, Andrew, Naylor, Louise H., Fegan, P. Gerry, Yeap, Bu B., Green, Daniel J.·2024·Diabetes Care
DOI 10.2337/dci23-0100
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Abstract

This narrative review highlights the degree to which new antiobesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight loss in randomized trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Liraglutide and semaglutide (GLP-1RA), tirzepatide (GLP-1 and GIP receptor dual agonist), and retatrutide (GLP-1, GIP, and glucagon receptor triple agonist) are peptides with incretin agonist activity that induce ∼15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. However, these agents also cause rapid and significant loss of lean mass (∼10% or ∼6 kg), comparable to a decade or more of aging. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration >10 weeks can elicit large increases in lean mass (∼3 kg) and strength (∼25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared with either alone. Retaining lean mass during incretin therapy could blunt body weight (and fat) regain on cessation of weight loss pharmacotherapy. We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy to optimize changes in body composition by preserving lean mass while achieving fat loss.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that incretin-based obesity therapies produce substantial fat loss but also meaningful lean mass loss, and proposes tailored resistance training as an adjunct to preserve muscle. It synthesizes trial and exercise literature and hypothesizes that preserving lean mass may reduce weight and fat regain after pharmacotherapy cessation, though this remains untested.

Key findings

  • Incretin therapies produce roughly 15–24% weight loss: semaglutide 14.9% (−15.3 kg) over 68 weeks, tirzepatide 20.9% (−22.1 kg) over 72 weeks, and retatrutide 24.2% (−26.4 kg) at 48 weeks.
  • Body composition analyses show lean mass loss alongside fat loss: semaglutide was associated with 13.9% (−6.9 kg) lean mass loss, and tirzepatide with an absolute lean mass decrease of 6 kg (10.9%), despite a rise in lean mass percentage. Liraglutide trials reported smaller lean mass losses, such as 0.5–1.5 kg depending on dose.
  • Resistance training is more effective than endurance training for improving or preserving lean mass: in one crossover study, resistance training increased lean mass by 1.2 kg versus 0.4 kg for endurance training; in dieting older adults, resistance training resulted in less lean mass loss (−1 kg, −2%) than combined training (−1.7 kg, −3%) or endurance training (−2.7 kg, −5%).
  • After stopping incretins, weight regain is common: semaglutide withdrawal led to regaining 67% (12.2 kg) or 55% (6.1 kg) of lost weight, and tirzepatide withdrawal led to regaining 54.5% (12 kg). The authors hypothesize that resistance-training preservation of lean mass could reduce rebound weight and fat gain, but this is proposed rather than demonstrated.

Methods

  • Narrative review, not a systematic review or meta-analysis, synthesizing randomized trials, observational studies, and prior meta-analyses on incretin pharmacotherapy, body composition, exercise training, and weight regain.
  • Includes a table summarizing body composition changes from incretin studies and figures illustrating trial results and hypothesized effects; dual-energy X-ray absorptiometry is discussed as a common lean mass measure, while MRI and computed tomography are noted as gold standards but impractical for widespread use.
  • No new primary data collection or formal quantitative synthesis; the final model of resistance training effects on weight, fat, and lean mass after incretin cessation is explicitly hypothetical.

Limitations

  • The paper states that large randomized controlled trials have generally not reported body composition or lean mass outcomes, that few studies have addressed body composition, and that no studies have used individually tailored resistance training combined with incretins. It also notes that the key exercise-plus-liraglutide trial used endurance rather than resistance training, was not designed to test exercise plus incretin as primary weight-loss therapy, and that semaglutide and tirzepatide have larger weight and lean mass effects than liraglutide.
  • The paper states uncertainty about whether slower dose titration would reduce lean mass loss, whether lean mass loss has long-term detrimental cardiovascular effects, whether resistance training prevents strength deficits, and whether the proposed prevention of rebound weight gain will be confirmed in future studies.
  • Evident from the text: as a narrative review, it lacks a systematic search and formal quality appraisal; body composition findings come from varied samples and methods, including DXA, bioimpedance, and air displacement plethysmography; and the central claims about resistance training preserving lean mass and reducing fat regain during or after incretin therapy are extrapolated from other settings rather than directly tested.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2337/dci23-0100

Cites

97 of 97 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

39 of 61 cited sources checked · 16 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Individuals in the lowest muscle mass tertile had an 81% higher risk of cardiovascular events compared with those in the highest tertile.

    “Recent evidence indicates that individuals in the lowest muscle mass tertile had an 81% higher risk of cardiovascular events compared with those in the highest muscle mass tertile (45)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Tyrovolas, 2020, Skeletal muscle mass in relation to 10 year cardiovascular disease incidence among middle aged and older adults: the ATTICA study, J Epidemiol Community Health source

      The Results and Table 3 report a hazard ratio of 0.19 for the highest muscle-mass tertile relative to the lowest, which is the reference group. That means an 81% lower hazard in the highest tertile relative to the lowest—not an 81% higher hazard in the lowest relative to the highest. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Elderly individuals with low strength have a 50% higher likelihood of all-cause mortality than those with normal strength at the same age.

    “Elderly individuals classified as having low strength have a 50% higher likelihood of death from all-cause mortality compared with those with normal strength at the same age (44).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [44] Ruiz, 2008, Association between muscular strength and mortality in men: prospective cohort study, BMJ source

      The Results report that men in the lowest strength third had an all-cause mortality rate 1.50 times that of men in the middle third, but that figure is for the cohort overall, not specifically older men. In the age-stratified Results, the lowest-to-highest strength comparison ranges from 1.4-fold to 2.2-fold across age groups. The study included only men, so it does not establish the stated figure for elderly individuals generally. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Excess adipose tissue impairs muscle recruitment and activation even in young individuals.

    “evidence indicates that excess adipose tissue impairs muscle recruitment and activation, even in young individuals (38).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Tomlinson, 2014, The impact of obesity on skeletal muscle architecture in untrained young vs. old women, J Anat source

      The Methods and Discussion report muscle size, architecture and contraction torque in young and older women, but do not assess muscle recruitment or activation. Searches for recruitment and voluntary or neural activation found no passage establishing the claimed impairment in young individuals. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • Premisecitation

    Greater incretin-induced body weight reduction induces larger improvements in HbA1c, triglycerides, ALT, waist circumference, and blood pressure.

    “while greater incretin-induced body weight reduction induces larger improvements in HbA 1c , triglycerides, ALT, waist circumference, and blood pressure (48)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Małecki, 2023, Predictors of ≥15% weight reduction and associated changes in cardiometabolic risk factors with tirzepatide in adults with type 2 diabetes in SURPASS 1-4, Diabetes Care source

      The Results (Characterization of Achieving Different Categorical Measures of BW Reduction With Tirzepatide) associate greater weight reduction with larger improvements in all five listed measures. The paper studied tirzepatide-treated adults with type 2 diabetes and reports associations; it does not establish that weight reduction caused those improvements or that the finding applies to incretin treatments generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Individuals with obesity have lower muscular strength than normal-weight counterparts when strength is adjusted for body mass.

    “individuals with obesity possess lower levels of muscular strength than normal-weight counterparts when strength is adjusted for body mass (35).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] Tomlinson, 2016, The impact of obesity on skeletal muscle strength and structure through adolescence to old age, Biogerontology source
  • May combine two claims. 33
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    In a 68-week semaglutide 2.4 mg trial in 140 individuals with overweight or obesity, body weight decreased 14.9% (15.3 kg), fat mass decreased 24.7% (10.4 kg), and lean mass decreased 13.9% (6.9 kg).

    “In the context of a body weight reduction of 14.9% (À15.3 kg) and fat reduction of 24.7% (À10.4 kg), individuals also lost an average of 13.9% of their total LM (À6.9 kg) (17).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Wilding, 2021, Once-weekly semaglutide in adults with overweight or obesity, N Engl J Med source

      The Abstract reports 14.9% (15.3 kg) mean weight loss at week 68 with semaglutide. “Change in Body Composition” reports reduced fat and lean mass in a 140-participant DXA subpopulation, but our copy does not give the claimed 24.7% (10.4 kg) or 13.9% (6.9 kg) reductions. The full trial enrolled 1,961 participants, not 140. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In 23 older individuals, after 18 weeks, resistance training increased knee extensor maximal torque by 41.7% in men and 15.8% in women; muscle quality increased 33.7% in males versus 8.8% in females.

    “A study of 23 older individuals (71 years) observed that, after 18 weeks, RT increased knee extensor maximal torque by 41.7% in men and 15.8% in women.Differences in muscle quality were also reported, whereby muscle quality increased by 33.7% in males compared with 8.8% in females (63).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [63] Da Boit, 2016, Sex differences in the response to resistance exercise training in older people, Physiol Rep source

  • May combine two claims.

    Premisecitation

    Both cognitive restraint and moderate to vigorous physical activity were associated with less weight regain.

    “Both cognitive restraint and moderate to vigorous physical activity were associated with less weight regain.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [78] Jensen, 2022, Exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment, Nat Commun source

  • May combine two claims.

    Premisecitation

    Semaglutide administration is associated with lean mass loss of 13.9% (6.9 kg) over 68 weeks, while tirzepatide induced a 10.9% (6 kg) loss over 72 weeks.

    “As discussed above, Sema administration is associated with an LM loss of 13.9% ($6.9 kg) over a period of 68 weeks (17), while Tz induced a 10.9% (6 kg) loss over 72 weeks of therapy (20).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [17] Wilding, 2021, Once-weekly semaglutide in adults with overweight or obesity, N Engl J Med source

      The Change in Body Composition section (page unavailable) reports that lean body mass decreased in absolute terms in the semaglutide DXA subpopulation. Our copy does not give the claimed 13.9% or 6.9 kg lean-mass loss, although it confirms the trial’s 68-week duration. The tirzepatide result is attached to a different citation and is not assessed here. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [20] Jastreboff, 2022, Tirzepatide once weekly for the treatment of obesity, N Engl J Med source

  • May combine two claims.

    Premisecitation

    The exercise group increased lean mass by 3.4% (2.1 kg) compared with the liraglutide group (0.0 kg; 95% CI -1.0 to 1.1), while the combination group increased lean mass by 0.8% (0.5 kg).

    “The exercise group increased LM by 3.4% (12.1 kg) compared with the Lira group (0.0 kg; 95% CI À1.0 to 1.1), while the combination group also exhibited an increase of 0.8% (10.5 kg).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [77] Lundgren, 2021, Healthy weight loss maintenance with exercise, liraglutide, or both combined, N Engl J Med source

      The Metabolic Health-Related End Points section (page not supplied) reports increased lean mass with exercise, and the Discussion (page not supplied) says the combination preserved lean mass. Our copy does not give the claimed 3.4%, 2.1 kg, 0.8%, or 0.5 kg changes, or the liraglutide group's 0.0 kg estimate and confidence interval; preservation alone does not establish an increase in the combination group. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    From the third to fourth decade onwards, aging is accompanied by loss of strength of around 2.5-4.0% per year, with leg strength declining despite habitual endurance exercise in active older adults.

    “Studies indicate that, from the third to fourth decade onwards, aging is accompanied by loss of strength of around 2.5-4.0%per year (73), with leg strength declining despite habitual endurance exercise in active older adults (74).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [73] Mitchell, 2012, Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review, Front Physiol source

      The Function section reports that strength declines with advancing age at an average rate of 2–4% per year, supporting the approximate rate. It does not establish that this rate begins in the third or fourth decade; the early-onset ages discussed in the Size section concern muscle mass, not strength. The endurance-exercise clause has a separate citation and is not assessed here. No page numbers were supplied for these passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [74] Marcell, 2014, Leg strength declines with advancing age despite habitual endurance exercise in active older adults, J Strength Cond Res source

  • May combine two claims.

    Premisecitation

    In 107 elderly individuals with obesity, after 12 months, the exercise group increased lean mass by 2.3% (1.3 kg), while the diet-plus-exercise and diet-only groups decreased lean mass by 3.1% (-1.8 kg) and 5.2% (-3.2 kg).

    “A study comparing the independent and combined effects of caloric restriction and exercise in 107 elderly (70 years) individuals with obesity reported that, after 12 months, the exercise group increased LM by 2.3% (11.3 kg), while the dietplus-exercise and diet-only groups experienced decreases in LM of 3.1% (À1.8 kg) and 5.2% (À3.2 kg).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [70] Villareal, 2011, Weight loss, exercise, or both and physical function in obese older adults, N Engl J Med source

      The Results section (Body Weight and Composition; page unavailable) reports the stated directions and kilogram changes in lean mass for all three groups, and the Methods describe a one-year trial of 107 older adults with obesity. However, the citing sentence as printed says the exercise group gained 11.3 kg, whereas the source reports 1.3 kg. The supplied paraphrase corrects that figure. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a recent study, after a 36-week lead-in with tirzepatide 10 or 15 mg inducing 20.9% (22.1 kg) weight reduction, continued tirzepatide for 52 weeks produced an additional 5.5% (4.7 kg) reduction (total 25.8%, 26.8 kg), while placebo regained 54.5% (12 kg) of total body weight loss.

    “After a 36-week lead-in involving Tz treatment (10 mg or 15 mg), which induced weight reduction of 20.9% (À22.1 kg), individuals were randomized to continued Tz treatment for another 52 weeks (additional weight reduction of 5.5% or À4.7 kg, totaling À25.8%, or À26.8 kg, over the 88-week treatment period) or placebo injections (regaining 54.5%, or 12 kg, of the total body weight loss during the 36-”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [83] Aronne, 2024, Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial, JAMA source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    After 12 months, the combination of liraglutide and exercise produced greater weight loss (3.5% or 3.4 kg) than liraglutide alone (0.7% or 0.7 kg); the exercise-only group increased body weight by 2% (2.0 kg).

    “After 12 months, greater weight loss was observed in the combination group (Lira 1 exercise, 3.5% or À3.4 kg) than the Lira-only group (0.7% or À0.7 kg).The exercise-only group increased body weight by 2% (12.0 kg).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] Lundgren, 2021, Healthy weight loss maintenance with exercise, liraglutide, or both combined, N Engl J Med source

  • May combine two claims.

    Premisecitation

    In the Lundgren et al. study, after an initial 8-week caloric restriction, participants with obesity lost an average of 12% (13 kg) body weight, 5.1 kg lean mass, and 7.3 kg fat mass.

    “After an initial 8-week period of caloric restriction during which participants with obesity lost an average of 12% ($13 kg) of their initial body weight, 5.1 kg LM, and 7.3 kg fat mass, this study randomized 195 participants (42 ± 12 years) to four groups: placebo, exercise (combined training), Lira alone, or Lira 1 exercise (Fig. 5).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [77] Lundgren, 2021, Healthy weight loss maintenance with exercise, liraglutide, or both combined, N Engl J Med source

      The Low-Calorie Diet section reports a mean weight loss of 13.1 kg (12%) over eight weeks. Table 1 shows lower fat and lean mass after the diet, but its before-and-after groups differ in size (215 versus 195), and it does not report mean losses of 7.3 kg fat mass or 5.1 kg lean mass. Those exact figures are not verified by our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In that study, fat loss was greater in the combination group (3.5% or 4.7 kg) than in the exercise group (1.8% or 1.4 kg) and the liraglutide group (1.6% or 2.0 kg).

    “Better results in the combined group were also found in terms of fat loss, with a reduction of 3.5% (À4.7 kg), approximately twice the decrease in the exercise group (À1.8% or À1.4 kg) and the Lira group (À1.6% or À2.0 kg) (77).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] Lundgren, 2021, Healthy weight loss maintenance with exercise, liraglutide, or both combined, N Engl J Med source

      The Body Weight and Body-Fat Percentage section reports a greater reduction in body-fat percentage with the combination than with either treatment alone, and the Discussion says fat-mass loss was approximately twice that of the single treatments. Our copy does not report the cited group-specific figures of 3.5%, 1.8%, and 1.6%, or the corresponding kilogram losses; its reported percentage-point figures are treatment comparisons, not those values. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a previous study, initial 20-week semaglutide 2.4 mg reduced body weight by 10.6% (11.1 kg); continued semaglutide to 68 weeks produced an additional 7.9% (7.1 kg) reduction, while discontinuation at 20 weeks led to regain of 6.9% (6.1 kg).

    “an initial 20-week Sema (2.4 mg) administration reduced body weight by 10.6% (À11.1 kg) (82).Thereafter, an additional body weight reduction of 7.9% (À7.1 kg) was reported for those maintained on Sema treatment until 68 weeks, whereas the group that discontinued treatment at 20 weeks demonstrated body weight regain of 6.9% (6.1 kg) (82).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [82] Rubino, 2021, Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial, JAMA source

  • May combine two claims.

    Premisecitation

    An overview of 12 systematic reviews and meta-analyses reported that exercise training with or without diet produced significant weight and fat mass losses but no net increase in lean mass; resistance training reduced lean mass loss by 0.8 kg compared with diet only.

    “An overview of 12 systematic reviews and meta-analyses summarizing the impact of exercise training (with or without diet) on body composition during weight loss reported significant weight (À1.5 to 3.5 kg) and fat mass (À1.3 to 2.6 kg) losses in response to exercise training (68) but no net increase in LM.However, RT reduced the loss in LM by 0.8 kg in comparison with diet only.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [68] Bellicha, 2021, Effect of exercise training on weight loss, body composition changes, and weight maintenance in adults with overweight or obesity: an overview of 12 systematic reviews and 149 studies, Obes Rev source

  • May combine two claims.

    Premisecitation

    Muscle mass is highly metabolically active, and muscle loss is linked to decreased metabolic rate.

    “muscle mass is highly metabolically active, with muscle loss linked to decreased metabolic rate (84).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [84] Christoffersen, 2022, Beyond appetite regulation: targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss, Obesity (Silver Spring) source

  • May combine two claims.

    Study design and conductcitation

    The Lundgren study was not designed to evaluate combining exercise and incretin treatment as the primary weight loss therapy, and its exercise intervention involved endurance training rather than resistance training.

    “It was not designed to evaluate the effects of combining exercise and incretin treatment as the primary weight loss therapy.It is also relevant that the exercise intervention involved ET rather than RT and that Sema and Tz have much”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] Lundgren, 2021, Healthy weight loss maintenance with exercise, liraglutide, or both combined, N Engl J Med source

  • May combine two claims.

    Premisecitation

    Another systematic review and meta-analysis concluded that adding resistance training to diet attenuated loss of lean mass by 93.5%, with an absolute difference of approximately 1 kg; similar reductions in fat mass and body weight occurred between resistance-training-with-diet and diet-alone groups.

    “Another systematic review and meta-analysis, which summarized six articles regarding the impact of RT on diet-induced loss in LM mass, concluded that adding RT to diet attenuated the loss of LM by 93.5%, with an absolute difference in LM of approximately 1 kg.Similar reductions in fat mass and body weight were reported between RT-with-diet and diet-alone groups (69) (Fig. 4).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [69] Sardeli, 2018, Resistance training prevents muscle loss induced by caloric restriction in obese elderly individuals: a systematic review and meta-analysis, Nutrients source

  • May combine two claims.

    Premisecitation

    In middle-aged individuals with obesity, 68 weeks of semaglutide therapy induced mean weight loss of 17.3% (18.3 kg) versus 2% (2.1 kg) with placebo, but 52 weeks after therapy, participants regained 67% (12.2 kg) of their lost weight.

    “a recent report indicated that, in middle-aged (49 ± 12 years) individuals with obesity (BMI $30 kg/m 2 ) (81), 68 weeks of Sema therapy induced mean weight loss of 17.3% (À18.3 kg) vs. 2% (À2.1 kg) for placebo, but 52 weeks after therapy, participants had regained 67% (112.2 kg) of their lost weight.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [81] Wilding, 2022, Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension, Diabetes Obes Metab source

  • May combine two claims.

    Findingnone given

    Weight loss from incretin therapy is mainly fat, but a substantial portion is lean or muscle mass.

    “However, it is germane that while the weight loss is primarily fat, a considerable amount is lean or muscle mass.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Liraglutide, semaglutide, tirzepatide, and retatrutide are incretin agonist peptides that induce 15-24% weight loss in adults with overweight or obesity and also improve blood pressure, cholesterol, blood glucose, and insulin.

    “Liraglutide and semaglutide (GLP-1RA), tirzepatide (GLP-1 and GIP receptor dual agonist), and retatrutide (GLP-1, GIP, and glucagon receptor triple agonist) are peptides with incretin agonist activity that induce $ $ $ $15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Supervised resistance exercise training lasting more than 10 weeks can produce large increases in lean mass, about 3 kg, and strength, about 25%, in men and women.

    “Studies indicate that supervised resistance exercise training interventions with a duration >10 weeks can elicit large increases in lean mass ($ $ $ $3 kg) and strength ($ $ $ $25%) in men and women.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Maintaining muscle mass and function as people age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality.

    “Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    These incretin agents cause rapid and significant lean mass loss of about 10% or 6 kg, comparable to a decade or more of aging.

    “However, these agents also cause rapid and significant loss of lean mass ($ $ $ $10% or $ $ $ $6 kg), comparable to a decade or more of aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    GLP-1 receptor agonists cause substantial weight loss in randomized trials, and this effect may be enhanced when combined with GIP receptor agonists.

    “Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight loss in randomized trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Incretin therapies produce substantial weight loss, and a portion of that loss is lean mass, roughly 10% or 6 kg, which is similar to a decade or more of aging.

    “Incretin therapies induce significant weight loss, part of which is lean mass ($10% or $6 kg), comparable to a decade or more of aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Compensation for lean mass loss is effective using resistance training, but overcompensation, meaning an increase in mass rather than prevention of loss, does not typically occur.

    “This suggests that compensation for LM loss is effective using RT, but overcompensation (i.e., increase in mass rather than prevention of loss) does not typically occur.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Based on well-established effects on lean mass in obesity, sarcopenia, and type 2 diabetes, it is plausible that resistance training would mitigate lean mass loss, and perhaps promote greater fat mass loss, in participants administered incretin therapy.

    “Based on well-established effects on LM in obesity, sarcopenia, and type 2 diabetes, it is plausible that RT would mitigate LM loss, and perhaps promote greater fat mass loss, in participants administered incretin therapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mechanisms by which resistance exercise preserves lean mass in obesity, sarcopenia, and type 2 diabetes are similar enough to those in patients receiving incretin therapy for the effects to translate.

  • May combine two claims.

    Premisecitation

    In 94 premenopausal women with overweight after 1 year of dietary intervention, resistance training improved fat-free mass (0.3 kg or 0.6%), whereas endurance training and no exercise reduced fat-free mass.

    “In 94 premenopausal women (35 ± 6.2 years) who were overweight (BMI 27-30 kg/m 2 ), after 1 year of dietary intervention, RT improved fat-free mass (10.3 kg, or 0.6%), whereas ET (À1.0 kg or À2.2%) and no exercise training (À1.5 kg or À3.1%) reduced fat-free mass (61).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Hunter, 2008, Resistance training conserves fat-free mass and resting energy expenditure following weight loss, Obesity (Silver Spring) source

  • May combine two claims.

    Interpretationreasoning

    The absolute magnitude of resistance training impact on lean mass mitigation depends on factors such as protein supplementation and whether lean mass loss is induced by diet (about 1-kg effect) or disease (more than 1-kg effect).

    “The absolute magnitude of RT impact in terms of LM mitigation depends upon factors such as whether the exercise is combined with protein supplementation or whether the LM loss is induced by diet ($1-kg effect) or disease (>1-kg effect).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In healthy untrained men, quadriceps cross-sectional area increased 6% after 21 weeks of resistance training, while endurance training induced a 2% increase.

    “In healthy untrained men (n = 38, age 37 ± 7 years), the cross-sectional area of the quadriceps femoris increased by 6% after 21 weeks of RT, while endurance training (ET) (e.g., cycling) induced a modest increase of 2% (56).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Mikkola, 2012, Neuromuscular and cardiovascular adaptations during concurrent strength and endurance training in untrained men, Int J Sports Med source

  • May combine two claims.

    Premisecitation

    In an RT study of individuals aged 70 years or older with presarcopenia, there were no significant differences between males and females in lean mass, but only males significantly improved strength.

    “an RT study of individuals ($70 years) with presarcopenia (based on appendicular LM index) observed no significant differences between males and females in LM but that only males significantly improved their strength (64).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Vikberg, 2019, Effects of resistance training on functional strength and muscle mass in 70-year-old individuals with pre-sarcopenia: a randomized controlled trial, J Am Med Dir Assoc source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The authors propose that resistance training may be a key intervention that, when performed with incretin treatment, could improve body composition and provide additional health benefits.

    “we propose that RT may be a key intervention that, when performed in conjunction with incretin treatment, could improve body composition and provide additional health benefits.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mechanisms by which resistance exercise preserves lean mass in obesity, sarcopenia, and type 2 diabetes are similar enough to those in patients receiving incretin therapy for the effects to translate.
    • Rests on an assumption: Resistance exercise training can be feasibly and safely adopted by patients receiving incretin therapy.

  • May combine two claims.

    Interpretationcitation

    Collectively, evidence supports resistance training as an effective approach to increase or maintain lean mass or at least mitigate the decrease in lean mass associated with diet interventions.

    “Collectively, this evidence supports RT as an effective approach to increase or maintain LM or at least mitigate the decrease of LM associated with diet interventions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Larger improvements in lean mass after resistance training have been reported in younger adults than older adults, although both groups benefited.

    “Larger improvements in LM have been reported after RT in younger (11.7 kg, 95% CI 1.0-2.4kg) compared with older adults (10.9 kg, 95% CI 0.8-1.1 kg), although both groups benefited (62).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Lopez, 2022, Moderators of resistance training effects in overweight and obese adults: a systematic review and meta-analysis, Med Sci Sports Exerc source

  • May combine two claims.

    Premisecitation

    Incretin pharmacotherapies are very effective for inducing weight loss, but weight is rapidly regained on cessation of energy intake restriction, and this also appears true of incretin therapies.

    “While incretin pharmacotherapies are very effective for inducing weight loss, extensive diet literature indicates that weight is rapidly regained on cessation of energy intake restriction (80).This also appears to be true of incretin therapies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Machado, 2022, Understanding weight regain after a nutritional weight loss intervention: systematic review and meta-analysis, Clin Nutr ESPEN source
34 of 34

  • The paper relies on this without support.

    The mechanisms by which resistance exercise preserves lean mass in obesity, sarcopenia, and type 2 diabetes are similar enough to those in patients receiving incretin therapy for the effects to translate.

    “Based on well-established effects on LM in obesity, sarcopenia, and type 2 diabetes, it is plausible that RT would mitigate LM loss, and perhaps promote greater fat mass loss, in participants administered incretin therapy.”

  • The paper relies on this without support.

    Resistance exercise training can be feasibly and safely adopted by patients receiving incretin therapy.

    “We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy to optimize changes in body composition by preserving lean mass while achieving fat loss.”

  • The authors state this as an assumption.

    Incretin therapies produce an average weight loss of about 17%.

    “Here, we assume that incretin therapies induce an average of $17% weight loss (combined data from Wilding et al. [17] and Jastreboff et al. [20])”

  • The paper relies on this without support.

    Lean mass is highly metabolically active.

    “LM is highly metabolically active, so its retention during incretin therapy may also result in less fat regain after treatment cessation.”

  • The paper relies on this without support.

    Resistance training increases skeletal muscle mass and strength and prevents muscle loss caused by dieting and disease.

    “RT increases skeletal muscle mass and strength and prevents muscle loss that results from dieting and disease.”

  • The paper relies on this without support.

    Exercise is nonpharmacological, has multiple health benefits, and has evidence of effectiveness in other contexts.

    “However, exercise is nonpharmacological and has multiple health benefits, and there is evidence for its effectiveness as an intervention in other contexts.”

  • The paper relies on this without support.

    Effective loss of excess weight conveys multiple health benefits, including reduced cardiovascular risk.

    “In summary, effective loss of excess weight conveys multiple health benefits, including a reduction in cardiovascular risk.”

  • The paper relies on this without support.

    In the Australian health care system, exercise provision for type 2 diabetes yields total well-being benefits of about $8,000 per person treated at a cost of $580.

    “it was calculated that total well-being benefits amounted to $8,000 per person treated, while the cost of exercise provision was $580.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The degree of weight loss with incretin therapies is associated with a well-documented decline in lean mass and bone mineral density.

    “the well-documented decline in lean mass and BMD associated with that degree of weight loss must be considered.”

    From The Benefits of Exercise Training in Combination With Weight Loss Therapies (2025) · cites this paper as [43]

    The section ‘Impact of Incretin Therapies Compared With Other Forms of Muscle Loss’ reports substantial lean-mass loss with semaglutide and tirzepatide. The passages from our copy do not document a decline in bone mineral density (BMD) with incretin-associated weight loss, so that part of the claim is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Exercise and targeted nutritional intakes have been proposed to influence body composition outcomes during treatment with incretin-based medications, although these practices have been minimally examined in this context.

    “Among other factors, exercise and targeted nutritional intakes have been proposed to influence body composition outcomes during treatment with incretin-based medications, although these practices have been minimally examined in this context.7,12,13”

    From Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series (2025) · cites this paper as [12]

    The Abstract proposes tailored resistance exercise during incretin therapy to preserve lean mass, and the exercise-training section says definitive combination studies are lacking. The passages do not propose targeted nutritional intakes for body composition during incretin treatment or establish how extensively those practices have been studied. Page numbers were not available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • GLP-1RA benefits are accompanied by concerns about side effects, cost, long-term sustainability, and loss of lean mass, which may be mitigated by concurrent exercise.

    “However, these benefits are accompanied by concerns about side effects, cost, long-term sustainability and, above all, the loss of lean mass, which may be mitigated by concurrent exercise (16–20).”

    From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [17]

    The Impact of Incretin Therapy on Body Weight section reports gastrointestinal side effects, and the Abstract reports lean-mass loss and proposes resistance exercise to preserve it. The section on rebound weight gain after incretin therapy documents substantial regain after treatment stops, supporting a concern about long-term maintenance. The copy does not identify the cost of GLP-1RA treatment as a concern; its cost discussion in the Conclusions concerns obesity and exercise provision instead. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Combining GLP-1RAs with exercise may yield additive or synergistic effects on weight loss and metabolic syndrome severity as well as on oxidative stress and inflammation.

    “Recent randomized controlled trials and meta-analyses suggest that combining GLP-1RAs with exercise may yield additive or synergistic effects on weight loss and metabolic syndrome severity as well as on oxidative stress and inflammation.”

    From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [17]

    The section ‘Can Exercise Training Preserve LM and Function in Individuals Taking Incretin Therapy?’ (page unavailable) reports greater weight loss with liraglutide plus exercise than with liraglutide alone after an initial low-calorie diet. It does not report combination effects on metabolic syndrome severity, oxidative stress, or inflammation; it also cautions that the study tested weight-loss maintenance rather than the combination as primary weight-loss therapy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • GLP-1RAs generally produce greater short-term weight loss than exercise alone, but exercise is superior for maintaining lean mass and cardiorespiratory fitness.

    “Direct comparisons reveal that GLP-1RAs generally produce greater short-term weight loss than exercise alone, but exercise is superior for maintaining lean mass and cardiorespiratory fitness (16, 17, 19).”

    From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [17]

    In “Can Exercise Training Preserve LM and Function in Individuals Taking Incretin Therapy?” (page not provided), the paper reports that, after an initial low-calorie diet, the liraglutide-only group lost 0.7% body weight over 12 months while the exercise-only group gained 2%; exercise also increased lean mass more than liraglutide. This supports the direction of the weight and lean-mass comparisons in that specific maintenance study, but not a general claim about short-term weight loss. The passages found do not compare cardiorespiratory fitness between exercise and GLP-1RAs. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Fat-loss percentages differ between the text and Table 1

    Minor

    For the same liraglutide-and-exercise study, the text gives fat-loss percentages of 3.5%, 1.8%, and 1.6% for the combination, exercise-only, and liraglutide-only groups. Table 1 gives 12.1%, 3.8%, and 5.3%, respectively, while reporting the same kilogram losses.

1 of 1

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Authors
Locatelli, J. C., Costa, J. G., Haynes, A., Naylor, L. H., Fegan, P. G., Yeap, B. B., & Green, D. J.
Affiliations
  • The University of Western Australia (AU)
  • Curtin University (AU)
Corresponding author
  • Yeap, Bu B.
  • Green, Daniel J.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2024-04-30
Volume
47
Issue
10
Pages
1718-1730
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dci23-0100
OpenAlex
W4396515179
Cited by
152
References
94
Citations by year
2026: 67 · 2025: 72 · 2024: 13
FWCI
9.49
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/journals/pages/license (vor)
Locations
  • Diabetes Care (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
Funders
  • National Health and Medical Research Council (APP1080914)
  • Western Australian State Government (Research Excellence Award)
Topics
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
obesity, weight loss, resistance training, lean mass preservation, body composition, sarcopenia, frailty, GLP-1 receptor agonists, GIP receptor agonist, tirzepatide, liraglutide, semaglutide, retatrutide, muscle mass, weight regain, hypocaloric diet
MeSH terms
Liraglutide, Body Composition, Humans, Obesity, Weight Loss, Incretins, Resistance Training

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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