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Cited by 33Liver Disease Diagnosis and TreatmentDiabetes Treatment and ManagementPharmacology and Obesity Treatment

Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD

Open access
Moolla, Ahmad, Poolman, Toryn, Othonos, Nantia, Dong, Jiawen, Smith, Kieran, Cornfield, Thomas, White, Sarah, Ray, David W. +7 more·2025·JHEP Reports
DOI 10.1016/j.jhepr.2025.101363PMC PMC12060445
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Abstract

Background & Aims: Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms may be important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal. Methods: lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA sequencing, circulating proteome, and stool microbiome analysis. Participants were randomised to lifestyle (∼500 kcal energy deficit) or GLP1-RA treatment for 12 weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12 weeks after treatment withdrawal. Results: Matched weight loss was achieved in both arms. Body composition changes, reductions in alanine aminotransferase, liver steatosis, and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids, and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12 weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23, and Flt3L were elevated, alongside dysregulated adipose gene expression. Conclusions: Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain. Impact and implications: Weight loss, through either lifestyle intervention or pharmacotherapy with GLP-1RA has an equally beneficial impact on the liver, and both strategies should be considered in the management of people with MASLD. GLP-1RA therapy may have additional benefits to improve glucose homeostasis even in the absence of pre-existing type 2 diabetes. Further research is needed to explore the differential impact of treatment withdrawal and the resultant metabolic consequences. Clinical Trials Registration: This study is registered at EudraCT (2016-002045-36).

AI snapshot

Written from the paper’s full text.

TL;DR

In adults with MASLD without type 2 diabetes, 12 weeks of lifestyle-induced and liraglutide-induced weight loss produced comparable reductions in liver fat and ALT, but liraglutide had additional metabolic benefits on glucose handling, fasting lipids, and de novo lipogenesis. After treatment withdrawal, liraglutide was associated with weight regain and changes in circulating cytokines and adipose gene expression, while liver benefits persisted.

Key findings

  • Matched weight loss was achieved in both arms: -4.7 ± 1.0 kg with lifestyle vs -5.2 ± 0.7 kg with liraglutide (p = 0.63), with similar reductions in ALT, MRS hepatic steatosis, and cT1.
  • GLP-1RA treatment, but not lifestyle, improved glucose handling and fasting lipids and significantly decreased DNL: fasting DNL fell from 15.2 ± 2.5% to 9.7 ± 1.9% and DNL AUC from 14.4 ± 2.1 to 10.2 ± 1.8 %.min in the liraglutide arm.
  • Twelve weeks after withdrawal, the liraglutide arm had weight regain of 1.3 ± 0.9 kg and significantly elevated circulating MMP-10, IL10RB, FGF-23, and Flt3L, alongside four differentially expressed adipose genes vs lifestyle; liver improvements persisted in both arms.
  • In mixed effects modelling, weight reduction was the only included variable significantly associated with reduction in MRS liver fat (p = 0.001).

Methods

  • Single-centre, open-label, prospective, randomised phase IIa trial in 29 participants with MASLD without type 2 diabetes who completed 12 weeks of either lifestyle intervention (~500 kcal/day deficit) or liraglutide titrated to 1.8 mg/day (2 participants reduced to 1.2 mg/day); 24 participants were followed 12 weeks after treatment withdrawal.
  • Metabolic phenotyping included DNL measurement using deuterated water, liver MRI/MRS, DXA body composition, subcutaneous adipose RNA sequencing, circulating proteomics, stool 16S microbiome analysis, and prolonged OGTT with adipose microdialysis in a subset (n = 18).
  • Primary outcome was change in hepatic steatosis by MRS from baseline to 12 weeks, powered to detect a 20% relative change; analyses used paired/unpaired tests or non-parametric equivalents, repeated measures ANOVA, and LIMMA for proteomics, with p < 0.05.

Limitations

  • The paper states the study was relatively small and short, had no placebo-treated comparator, did not include liver biopsy or fibrosis-specific non-invasive assessments, and enrolled only people without type 2 diabetes; lifestyle elements may have continued during washout despite formal withdrawal.
  • The text also makes evident that microdialysis was performed only in a subset (n = 18), microbiome analysis was compromised by limited sample numbers and required pooled analysis, and the open-label design could not blind participants or investigators.

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

Integrity signals

Registry

Crossref · 10.1016/j.jhepr.2025.101363

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 55 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Total weight loss was principally attributable to a reduction in total fat mass.

    “Total weight loss was principally attributable to a reduction in total fat mass”
    Quote in the paperNot a substantial claim
  • Findingown data

    HOMA-IR improved only in the lifestyle group.

    “HOMA-IR improved only in the lifestyle group”
    Quote in the paperNot a substantial claim
  • Findingown data

    Physical activity as assessed by IPAQ did not change in either arm.

    “Physical activity as assessed by IPAQ data did not change in either arm”
    Quote in the paperNot a substantial claim
  • Findingown data

    When adjusted for multiple comparisons, there were no significant changes in circulating proinflammatory cytokines levels after GLP-1RA treatment or lifestyle intervention.

    “When adjusted for multiple comparisons, there were no significant changes in circulating proinflammatory cytokines levels after GLP-1RA treatment or lifestyle intervention.”
    Quote in the paperNot a substantial claim
  • Findingown data

    After 12 weeks of intervention with either lifestyle or liraglutide, there remained no significant differences between the groups in microbiome.

    “After 12 weeks of intervention with either lifestyle or liraglutide, there remained no significant differences between the groups (Fig. S3).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 36

  • May combine two claims.

    Findingown data

    Percent fat mass and estimated visceral fat mass decreased in both groups, with no significant differences between arms.

    “Percent fat mass and estimated visceral fat mass decreased in both groups, and there were no significant differences between the two arms”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AUC glucose across the prolonged OGTT was reduced by GLP-1RA and not by lifestyle.

    “AUC glucose across the prolonged OGTT was reduced by GLP-1RA and not by lifestyle”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both lifestyle and liraglutide interventions achieved significant weight loss over 12 weeks.

    “Both interventions achieved significant weight loss”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Fasting NEFA levels decreased in both treatment groups but did not reach statistical significance.

    “Although fasting NEFA levels decreased in both treatment groups, this failed to reach statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Glycated haemoglobin decreased significantly in the GLP-1RA arm but not in the lifestyle arm.

    “Glycated haemoglobin decreased significantly in the GLP-1RA treatment arm, but not in those undergoing lifestyle intervention”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Following GLP-1RA withdrawal, weight increased by 1.3 ± 0.9 kg between end of treatment and 12 weeks post-treatment, with a significant increase in lean mass.

    “Following GLP1-RA withdrawal, weight increased by 1.3 ± 0.9 kg between the end of treatment and 12 weeks post-treatment, with a significant increase in lean mass (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the GLP-1RA treated group only, fasting triglycerides, total cholesterol, and non-HDL cholesterol all decreased.

    “In the GLP-1RA treated group only, fasting triglycerides, total cholesterol, and non-HDL cholesterol all decreased.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The baseline differences in total cholesterol and HDL cholesterol between the lifestyle and liraglutide groups did not confound the observed treatment differences in metabolic outcomes.

  • May combine two claims.

    Findingown data

    Lean mass did not change significantly in the lifestyle group but decreased in the GLP-1RA group.

    “lean mass did not change significantly in the lifestyle group but decreased in the GLP1-RA group”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ALT levels decreased in both treatment arms, with no significant differences between interventions.

    “ALT levels decreased in both treatment arms. There were no significant differences between the two interventions”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Diastolic blood pressure improved in the lifestyle group only and remained lower than the GLP-1RA group at 12 weeks.

    “diastolic blood pressure improved in the lifestyle group only, which remained lower than the GLP-1RA group at 12 weeks”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ninety-two proinflammatory cytokines were measured in serum samples from all participants, with no significant differences between groups at baseline.

    “Ninety-two proinflammatory cytokines were measured in serum samples from all participants and there were no significant differences between the two groups at baseline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both fasting DNL and DNL across the OGTT decreased in both arms, but only reached statistical significance in the GLP-1RA-treated group.

    “Although both fasting DNL and DNL measured across the prolonged OGTT decreased in both arms, this only reached statistical significance in the GLP-1RA-treated group”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At baseline, there were no significant differences in absolute or relative abundances of microbiome phyla, notably Bacteroidetes and Firmicutes, and the Firmicutes:Bacteroidetes ratio was similar in both groups.

    “At baseline, analysis of the 16S microbiome RNA sequencing demonstrated no significant differences in absolute or relative abundances of microbiome phyla, notably Bacteroidetes and Firmicutes. In addition, the Firmicutes:Bacteroidetes ratio was similar in both groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was a trend to increased abundance of Firmicutes and decreased Bacteroidetes after GLP-1RA withdrawal, with opposing effects in the lifestyle group, but these did not achieve statistical significance.

    “Although there was a trend to an increased abundance of Firmicutes and deceased Bacteroidetes after GLP-1RA withdrawal (with opposing effects in the lifestyle group), these did not achieve statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were no significant differences between treatment groups in ALT, hepatic steatosis, and cT1 during the washout phase.

    “there were no significant differences between treatment groups during this washout phase”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adipo-IR increased in both groups following treatment withdrawal but did not reach statistical significance.

    “although adipo-IR increased in both groups, it did not reach statistical significance”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    12 weeks after GLP-1RA withdrawal (but not lifestyle), adipose gene expression was dysregulated.

    “alongside dysregulated adipose gene expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Following intervention withdrawal, there was a trend towards increased Firmicutes and decreased Bacteroidetes, specifically following GLP-1RA (but not lifestyle) treatment.

    “following intervention withdrawal, we did observe a trend towards increased Firmicutes and decreased Bacteroidetes, specifically following GLP-1RA (but not lifestyle) treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    With either intervention, there were significant benefits both metabolically and specifically to the liver.

    “With either intervention, there were significant benefits both metabolically and specifically to the liver.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The cardioprotective impact of GLP-1RA therapy is established with several large cardiovascular outcome trials demonstrating clear benefits and suggest a class effect.

    “The cardioprotective impact of GLP-1RA therapy is now established with several large cardiovascular outcome trials demonstrating clear benefits and together strongly suggest a class effect of GLP-1RA therapy.11,12”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Bethel, 2018, Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis, Lancet Diabetes Endocrinol source

      Not checked in the free run.

    • cites [12] Yoshiji, 2022, Effects of glucagon-like peptide-1 receptor agonists on cardiovascular and renal outcomes: a meta-analysis and meta-regression analysis, Diabetes Obes Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Semaglutide achieved resolution of MASH in up to 59% of people and this was associated with a 13% reduction in weight.

    “More recently, semaglutide, a more potent GLP1-RA, has achieved resolution of MASH in up to 59% of people and this was associated with a 13% reduction in weight.16”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Newsome, 2021, A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study was a single-centre, open-label, prospective, randomised phase IIa clinical trial.

    “We conducted a single-centre, open-label, prospective, randomised phase IIa clinical trial”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In people with MASLD-cirrhosis, semaglutide failed to improve fibrosis, but was safe and well tolerated and conveyed significant metabolic improvements.

    “However, in people with MASLD-cirrhosis, it failed to improve fibrosis, but was safe and well tolerated and conveyed significant metabolic improvements (weight reduction, improved glucose control, and lipid profiles).17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Loomba, 2023, Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial, Lancet Gastroenterol Hepatol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Twenty-four participants (12 in each arm) were followed up at 24 weeks.

    “Twenty-four participants (n = 12 in both arms) were followed up at 24 weeks to evaluate the legacy effects of interventions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GLP-1RA therapy reduces appetite and promotes satiety, resulting in significant weight loss.

    “acting peripherally and centrally to reduce appetite and promote satiety resulting in significant weight loss.9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Ard, 2021, Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists, Adv Ther source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    In the liraglutide arm, 13/15 tolerated the highest dose (1.8 mg/day) and two required a dose reduction to 1.2 mg daily.

    “In the liraglutide treatment arm 13/15 people were able to tolerate the highest dose (1.8 mg/day) and two required a dose reduction to 1.2 mg daily.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    People with an established diagnosis of T2D were excluded to remove confounding effects of antidiabetic medications or altered glycaemic control.

    “People with an established diagnosis of T2D were excluded to remove any confounding effects of concomitant antidiabetic medications or alterations in glycaemic control.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GLP-1RA have important anti-inflammatory actions.

    “They also have important anti-inflammatory actions.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Bray, 2021, Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: a systematic review and meta-analysis of randomised controlled trials, Diabetes Obes Metab source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    At baseline, the lifestyle and liraglutide groups were well-matched except total cholesterol and HDL cholesterol were lower in the liraglutide group.

    “Both groups were well-matched at baseline, except for total cholesterol and HDL cholesterol which were lower in the liraglutide-treated group.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Participants were randomised using a random number block randomisation tool to lifestyle or liraglutide.

    “Participants were then randomised by members of the investigative team using a random number block randomisation tool to either a lifestyle intervention program provided by a commercial weight management organisation (Slimming World, Alfreton, UK) or to liraglutide treatment”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Treatment with pharmacotherapy for weight loss is often administered for a limited and defined time, and following cessation, weight regain is frequent.

    “Treatment with pharmacotherapy for weight loss is often administered for a limited and defined time, and following cessation, weight regain is frequent.20”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Wilding, 2022, Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension, Diabetes Obes Metab source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Twenty-nine participants (14 lifestyle, 15 liraglutide) completed the 12-week intervention.

    “Twenty-nine participants (n = 14 lifestyle, n = 15 liraglutide) completed the 12-week intervention required for evaluation of the primary study outcome.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    At baseline, no participants had impaired fasting glucose, but five of 29 had impaired glucose tolerance.

    “At baseline, no participants had impaired fasting glucose, but five of 29 had impaired glucose tolerance (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Microdialysis was only performed in a subset of participants (n=18) due to equipment availability.

    “Because of issues with equipment availability, microdialysis was only performed in a subset of participants (n = 18).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    These changes may have important implications for potential weight regain.

    “these may have important implications for potential weight regain”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    This might explain the rebound and the observed increase in DNL.

    “this might explain the rebound and the observed increase in DNL”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Both circulating and cerebrospinal fluid levels of IL-10RB are positively associated with BMI.

    “both circulating and cerebrospinal fluid levels are positively associated with BMI46,47”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Larsson, 2015, The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid, Cytokine source

      Not checked in the free run.

    • cites [47] Ponce-de-Leon, 2022, Novel associations between inflammation-related proteins and adiposity: a targeted proteomics approach across four population-based studies, Transl Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In those studies, immediately following treatment, the reductions in weight and liver fat content were similar.

    “Immediately following treatment, and similar to our observations, the reductions in weight and liver fat content were similar”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Khoo, 2019, Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease, Liver Int source

      Not checked in the free run.

    • cites [29] Khoo, 2017, Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: a pilot randomized trial, Diabetes Obes Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is evidence for decreasing aqueous humour levels of Flt3L after treatment for diabetic macular oedema using anti-VEGF therapy.

    “with evidence for decreasing aqueous humour levels after treatment for diabetic macular oedema using anti-VEGF therapy.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Mastropasqua, 2018, Relationship between aqueous humor cytokine level changes and retinal vascular changes after intravitreal aflibercept for diabetic macular edema, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In both situations, treatment withdrawal may lead to increased DNL that may fuel re-accumulation of hepatic TAG.

    “in both situations, treatment withdrawal may lead to increased DNL that may fuel re-accumulation of hepatic TAG.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Positive associations between circulating FGF-23 levels and hepatic steatosis, adiposity, and circulating hyperlipidaemia have been described.

    “Positive associations between circulating FGF-23 levels and hepatic steatosis, adiposity, and circulating hyperlipidaemia have been described42,43”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Hu, 2020, Association of serum fibroblast growth factor 23 levels with the presence and severity of hepatic steatosis is independent of sleep duration in patients with diabetes, Diabetes Metab Syndr Obes source

      Not checked in the free run.

    • cites [43] Hu, 2018, Associations of serum fibroblast growth factor 23 levels with obesity and visceral fat accumulation, Clin Nutr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Following weight loss intervention withdrawal, a differential impact on circulating FGF-23 levels could have a metabolic impact.

    “therefore following weight loss intervention withdrawal, a differential impact on circulating FGF-23 levels could have a metabolic impact.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A single study has reported lower circulating Flt3L levels in people with diabetic retinopathy compared with healthy control participants.

    “A single study has reported lower circulating levels in people with diabetic retinopathy (compared with healthy control participants),44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Hang, 2014, Multiplex bead array assay of plasma cytokines in type 2 diabetes mellitus with diabetic retinopathy, Mol Vis

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    It remains possible that the mechanisms underpinning these changes differ between treatment arms.

    “It remains possible that the mechanisms underpinning these changes differ between treatment arms”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    This is not a consistent finding in all studies.

    “although this is not a consistent finding in all studies.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Tang, 2015, Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes: a randomized trial, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In people with MASLD without T2D, matched weight loss through lifestyle or GLP-1RA has comparable effects on hepatic steatosis, but GLP-1RA treatment has additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL.

    “Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The baseline differences in total cholesterol and HDL cholesterol between the lifestyle and liraglutide groups did not confound the observed treatment differences in metabolic outcomes.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mice with genetic deletion of MMP-10 do not display a clear metabolic phenotype.

    “Although mice with genetic deletion to not display a clear metabolic phenotype,39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Kassim, 2007, Individual matrix metalloproteinases control distinct transcriptional responses in airway epithelial cells infected with Pseudomonas aeruginosa, Infect Immun source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain.

    “However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The elevated circulating proteins and dysregulated adipose gene expression after GLP-1RA withdrawal are causally related to weight regain.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It is possible that the additional benefit with GLP-1RA over and above weight loss could reflect improved glucose handling, decreasing substrate availability (glucose) for DNL.

    “It is possible that this additional benefit with GLP-1RA, over and above weight loss could reflect improved glucose handling, decreasing substrate availability (glucose) for DNL.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    There are changes in lipolytic function in adipose tissue, changes in lipid oxidation, alterations in circulating regulators of appetite, and emerging data suggesting that changes in the microbiome may play a role in the predisposition to weight regain.

    “There are changes in lipolytic function in adipose tissue36 alongside changes in lipid oxidation, alterations in circulating regulators of appetite37 as well as emerging data suggesting that changes in the microbiome may play a role in the predisposition to weight regain.38”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Kasher-Meron, 2019, Lipolysis defect in white adipose tissue and rapid weight regain, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

    • cites [37] van Baak, 2023, Obesity-induced and weight-loss-induced physiological factors affecting weight regain, Nat Rev Endocrinol source

      Not checked in the free run.

    • cites [38] Hjorth, 2020, Pretreatment Prevotella-to-Bacteroides ratio and markers of glucose metabolism as prognostic markers for dietary weight loss maintenance, Eur J Clin Nutr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MMP-10 has been implicated in the development of hepatocellular carcinoma.

    “MMP-10 has been implicated in the development of hepatocellular carcinoma.40,41”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] García-Irigoyen, 2015, Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis, Hepatology source

      Not checked in the free run.

    • cites [41] Sze, 2013, C-terminal truncated hepatitis B virus x protein is associated with metastasis and enhances invasiveness by C-Jun/matrix metalloproteinase protein 10 activation in hepatocellular carcinoma, Hepatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1RA improve cardiovascular and liver outcomes.

    “and also to improve cardiovascular and also liver outcomes.32,33”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Engström, 2024, Association of glucagon-like peptide-1 receptor agonists with serious liver events among patients with type 2 diabetes: a Scandinavian cohort study, Hepatology source

      Not checked in the free run.

    • cites [33] Krishnan, 2024, Cardiovascular and mortality outcomes with GLP-1 receptor agonists vs other glucose-lowering drugs in individuals with NAFLD and type 2 diabetes: a large population-based matched cohort study, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    There could be clinical implications for weight maintenance or regain.

    “there could be clinical implications for weight maintenance or regain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    This could explain differences in the propensity to weight regain and changes in metabolic variables measured at the end of the washout phase.

    “this could explain differences in the propensity to weight regain and changes in metabolic variables measured at the end of the washout phase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These differences might explain improvements in cardiovascular risk.

    “and perhaps explain improvements in cardiovascular risk”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    It is entirely plausible that elements of the lifestyle programme were continued by the participants during the washout phase.

    “it is entirely plausible that elements of the lifestyle programme were continued by the participants during the washout phase”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many studies have reported that an increased Firmicutes:Bacteroidetes ratio is associated with obesity.

    “many studies have reported that an increased Firmicutes:Bacteroidetes ratio (as we observed following GLP-1RA withdrawal) is associated with obesity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Crovesy, 2020, Profile of the gut microbiota of adults with obesity: a systematic review, Eur J Clin Nutr source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The study incorporated a dedicated washout period alongside deep metabolic phenotyping.

    “it incorporated a dedicated washout period (which is often omitted in clinical experimental studies) alongside deep metabolic phenotyping”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies have suggested that the impact of liraglutide on the microbiome may be modest in comparison with metformin.

    “some have suggested that the impact of liraglutide may be modest (in comparison with metformin),49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Ying, 2023, Therapeutic efficacy of liraglutide versus metformin in modulating the gut microbiota for treating type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease, Front Microbiol source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    The study was relatively small and of short duration.

    “Although this was a relatively small study over a short duration”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is evidence from rodent studies to suggest that GLP-1RA treatment can impact the microbiome.

    “There is evidence from rodent studies to suggest that GLP-1RA treatment can impact the microbiome,48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Liu, 2020, Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice, Life Sci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Others have demonstrated more robust effects of liraglutide on the microbiome.

    “others have demonstrated more robust effects.50”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Shang, 2021, Liraglutide-induced structural modulation of the gut microbiota in patients with type 2 diabetes mellitus, PeerJ source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Genetic inhibition of CAMK2 signalling specifically in adipose tissue improves adipose insulin sensitivity and glucose tolerance.

    “genetic inhibition of CAMK2 signalling specifically in adipose tissue (through conditional genetic deletion of other CAM2K subunits, delta and gamma) improves adipose insulin sensitivity and glucose tolerance53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Dai, 2021, Adipocyte CAMK2 deficiency improves obesity-associated glucose intolerance, Mol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    This may have implications for future weight regain in this group.

    “and this may have implications for future weight regain in this group.51”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    This could be off-set by the impact of treatment withdrawal.

    “but this could be off-set by the impact of treatment withdrawal.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In people with MASLD, altered natural killer cell expression of Siglec-7 associated with compromised NK cell function has been described.

    “in people with MASLD, altered natural killer cell expression of Siglec-7 (Sialic acid-binding immunoglobulin-like lectin-7), that is associated with compromised NK cell function has been described.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Sakamoto, 2021, Increased frequency of dysfunctional Siglec-7, Front Immunol

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    This may contribute to the rebound effects observed after GLP-1RA withdrawal.

    “and this may contribute to the rebound effects that we observed after GLP-1RA withdrawal.”
    Quote in the paperNot a substantial claim
67 of 67

  • The paper relies on this without support.

    The baseline differences in total cholesterol and HDL cholesterol between the lifestyle and liraglutide groups did not confound the observed treatment differences in metabolic outcomes.

    “Both groups were well-matched at baseline, except for total cholesterol and HDL cholesterol which were lower in the liraglutide-treated group.”

  • The paper relies on this without support.

    The elevated circulating proteins and dysregulated adipose gene expression after GLP-1RA withdrawal are causally related to weight regain.

    “However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain.”

  • The paper relies on this without support.

    Very few studies have tried to directly compare the impact of GLP-1RA therapy with matched weight loss.

    “To date, very few studies have tried to directly compare the impact of GLP-1RA therapy with matched weight loss.”

  • The paper relies on this without support.

    Dedicated cardiovascular outcome studies in people with MASLD treated with GLP-1RA have not been performed.

    “accepting that a dedicated cardiovascular outcome studies in people with MASLD, treated with GLP-1RA have not been performed”

  • The paper relies on this without support.

    GLP-1 has a well-established role to regulate glucose-sensitive insulin secretion from the pancreatic islet.

    “GLP-1 has a well-established role to regulate glucose-sensitive insulin secretion from the pancreatic islet”

  • The paper relies on this without support.

    GLP-1 receptors are expressed in extra-pancreatic tissues.

    “but GLP-1 receptors are also expressed in extra-pancreatic tissues”

  • The paper relies on this without support.

    Weight regain occurs after all weight loss interventions.

    “It is often overlooked in clinical studies and occurs after all weight loss interventions.”

  • The paper relies on this without support.

    Mechanisms of weight loss differ across all interventions.

    “In the same way that mechanisms of weight loss differ across all interventions (as does their relative efficacy)”

  • The paper relies on this without support.

    The mechanisms that contribute to weight regain are multiple and complex.

    “The mechanisms that contribute to weight regain are multiple and complex.”

  • The paper relies on this without support.

    MMP-10 is highly expressed in epithelial cells.

    “MMP-10 (stomelysin-2) is highly expressed in epithelial cells.”

  • The paper relies on this without support.

    FGF-23 is principally regarded as a bone-derived regulator of phosphate and vitamin D homeostasis.

    “FGF-23 is principally regarded as a bone-derived regulator of phosphate and vitamin D homeostasis.”

  • The paper relies on this without support.

    Flt3L has complex immune regulatory functions.

    “Flt3L has complex immune regulatory functions”

  • The paper relies on this without support.

    The role of IL-10RB in regulating metabolic phenotype is largely unknown.

    “Similarly, the role of IL-10RB in regulating metabolic phenotype is largely unknown.”

  • The paper relies on this without support.

    Clinical studies of GLP-1RA impact on the microbiome are sparse.

    “but clinical studies are sparse”

  • The paper relies on this without support.

    In studies published to date, the specific impact of weight loss, as distinct from effects on blood glucose control, cannot be disentangled.

    “However, in the studies published to date, the specific impact of weight loss, as distinct from effects on blood glucose control, cannot be disentangled.”

  • The paper relies on this without support.

    Most of the identified DEGs have not been examined in the context of MASLD.

    “Most of the identified DEGs have not been examined in the context of MASLD”

  • The paper relies on this without support.

    Liver biopsy continues to be the gold standard assessment of MASLD stage and severity (including MASH and fibrosis).

    “which continues to be the gold standard assessment of MASLD stage and severity (including MASH and fibrosis)”
17 of 17

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?

  • Evidence from a recent randomised controlled trial that directly compared liraglutide with a BWMP supports the conclusion of faster weight regain after WMM compared with BWMPs.

    “However, evidence from a recent randomised controlled trial that directly compared liraglutide with a BWMP supports our conclusion of faster weight regain after WMM compared with BWMPs.37”

    From Weight regain after cessation of medication for weight management: systematic review and meta-analysis (2026) · cites this paper as [37]

    The Results section (‘Impact of treatment withdrawal’; page unavailable) reports weight gain of 1.3 ± 0.9 kg in the liraglutide arm over 12 weeks, versus a further 0.4 ± 1.0 kg reduction in the lifestyle arm. That direction supports the citing sentence, but the paper says the between-arm difference in weight change was not statistically significant, so it does not establish faster regain after liraglutide. (LLM, conf=0.88)

    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.

  • Impaired glucose tolerance is shown before, not after, GLP-1RA withdrawal

    Minor

    The text says impaired glucose tolerance recurred following withdrawal, but Table 3 reports one affected participant at the end of treatment and none 12 weeks after withdrawal.

  • Fibrosis assessments are said to be absent but appear in the tables

    Minor

    The discussion says non-invasive assessments to measure fibrosis were not included, whereas Tables 1 and 3 report FIB-4 and NAFLD fibrosis scores under a heading identifying them as non-invasive markers of liver fibrosis.

  • Tables disagree on impaired glucose tolerance at 12 weeks

    Minor

    Table 1 reports no impaired glucose tolerance among the 15 GLP-1RA participants at 12 weeks. Table 3 reports one among the 12 followed-up GLP-1RA participants at the same end-of-treatment visit.

3 of 3

Cites

Flagged first, then by citations

2 of the 54 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Sakamoto, 2021, Increased frequency of dysfunctional Siglec-7, Front Immunol, 12

Cited by

Sorted by citations

Related

Authors
Moolla, A., Poolman, T., Othonos, N., Dong, J., Smith, K., Cornfield, T., White, S., Ray, D. W., Mouchti, S., Mózes, F. E., Thomaides-Brears, H., Neubauer, S., Cobbold, J. F., Hodson, L., & Tomlinson, J. W.
Affiliations
  • Churchill Hospital (GB)
  • Perspectum Ltd. (United Kingdom) (GB)
  • John Radcliffe Hospital (GB)
  • University of Oxford (GB)
Corresponding author
Tomlinson, Jeremy W.
ORCID
Venue
JHEP Reports
Publisher
Elsevier BV
Published
2025-05
Volume
7
Issue
5
Pages
101363
ISSN
2589-5559 (ISSN-L)
DOI
10.1016/j.jhepr.2025.101363
PMC
PMC12060445
OpenAlex
W4407763278
Semantic Scholar
e532e1077ffd6fc947ecdf7e12291d793b852be0
Cited by
33
References
54
Citations by year
2026: 23 · 2025: 10
FWCI
22.87
Type
journal article
Language
en
Open access
Licence
Locations
  • JHEP Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Wellcome Trust (221805/Z/20/Z)
  • British Heart Foundation (FS/SBSRF/21/31013, FS/15/56/31645)
  • NIHR Oxford Biomedical Research Centre (NIHR203316)
  • UK Research and Innovation Medical Research Council (MR/V034049/1, MR/P011462/1, MR/W019000/1)
  • National Institute for Health and Care Research
  • Royal Society
  • University of Oxford
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
non-alcoholic fatty liver disease, GLP-1 receptor agonists, liraglutide, weight regain, treatment withdrawal, hepatic steatosis, lipogenesis, glucose homeostasis, circulating proteome, adipose tissue gene expression, gut microbiota, fibroblast growth factor 23, MMP-10, IL10RB, Flt3L

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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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