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Cited by 22Pharmacology and Obesity TreatmentDiabetes Treatment and ManagementRegulation of Appetite and Obesity

Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial

Open access
Aronne, Louis J., Horn, Deborah B., le Roux, Carel W., Chao, Ariana M., Ho, Wayne, Halpern, Bruno, Griffin, Ryan, Xie, Cathy +6 more·2026·Nature Medicine
DOI 10.1038/s41591-026-04386-7PMC PMC13375559
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Abstract

Incretins have improved the management of obesity and its related complications, but maintaining these health benefits requires ongoing administration, which can be challenging. Orforglipron, a once-daily oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated weight loss efficacy, improvements in cardiometabolic risk factors, and safety generally similar to injectable GLP-1 receptor agonists. Here this double-blind, placebo-controlled trial randomized participants previously treated with tirzepatide (cohort 1: N = 205) or semaglutide (cohort 2: N = 171) during the SURMOUNT-5 study to orforglipron once daily or placebo. Cohort 1 participants who achieved body weight plateau maintained a model-based estimate (MBE) of 74.7% (s.e.m. 4.05) of body weight reduction with orforglipron compared with an MBE of 49.2% (s.e.m. 3.92) with placebo, resulting in an estimated treatment difference of MBE 25.5% (95% confidence interval 14.5 to 36.5); P < 0.001; treatment-regimen estimand) at week 52. Cohort 2 participants who achieved body weight plateau maintained an MBE of 79.3% (s.e.m. 4.42) of body weight reduction with orforglipron compared with an MBE of 37.6% (s.e.m. 7.46) with placebo, resulting in an estimated treatment difference of MBE 41.7 (95% confidence interval 24.4 to 59.0); P < 0.001; treatment-regimen estimand) at week 52. All key secondary endpoints were met. The most common adverse events were gastrointestinal effects, which were mostly mild to moderate in severity. These data demonstrate orforglipron’s potential as a globally scalable option for minimizing weight changes after injectable therapy. Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial’s 1-year duration. ClinicalTrials.gov registration: NCT06584916 .

AI snapshot

Written from the paper’s full text.

TL;DR

In the phase 3b ATTAIN-MAINTAIN trial, switching to once-daily oral orforglipron after 72 weeks of tirzepatide or semaglutide maintained a greater proportion of prior body weight reduction than placebo at week 52 in both cohorts. Orforglipron was generally well tolerated, with gastrointestinal adverse events most common and mostly mild to moderate.

Key findings

  • Cohort 1 (prior tirzepatide; N = 205 randomized): participants who achieved body weight plateau maintained a model-based estimate (MBE) of 74.7% (s.e.m. 4.05) of body weight reduction with orforglipron versus 49.2% (s.e.m. 3.92) with placebo; estimated treatment difference 25.5% (95% CI 14.5–36.5), P < 0.001 at week 52.
  • Cohort 2 (prior semaglutide; N = 171 randomized): plateau participants maintained an MBE of 79.3% (s.e.m. 4.42) versus 37.6% (s.e.m. 7.46) with placebo; estimated treatment difference 41.7 (95% CI 24.4–59.0), P < 0.001 at week 52.
  • Key secondary endpoints were met; for example, ≥80% maintenance in plateau participants was 43.7% versus 16.4% in cohort 1 (risk difference 27.3, 95% CI 14.1–40.6; P < 0.001) and 55.0% versus 6.9% in cohort 2 (risk difference 48.1, 95% CI 35.6–60.5; P < 0.001).
  • Safety: most common AEs were gastrointestinal (nausea, constipation, vomiting, diarrhea), mostly mild to moderate; study drug discontinuations due to AEs were 4.8%–7.3% with orforglipron MTD; SAEs were reported in <2% of the total group, and one death in the cohort 2 orforglipron group was not considered related to study treatment.

Methods

  • Design: two phase 3b randomized, double-blind, placebo-controlled cohorts at 29 US sites; participants had completed SURMOUNT-5 with ≥5% weight reduction at week 72 on tirzepatide (cohort 1) or semaglutide (cohort 2), without diabetes. Randomized 3:2 to once-daily orforglipron 36 mg or MTD versus placebo, stratified by plateau status, sex, and percent weight loss (<20%, ≥20%). Placebo participants with ≥50% weight regain from week 24 could receive rescue orforglipron.
  • Primary endpoint: percent maintenance of SURMOUNT-5 body weight reduction in participants who achieved body weight plateau, defined as the ratio of total weight loss from SURMOUNT-5 start to ATTAIN-MAINTAIN week 52 over total weight loss from SURMOUNT-5 start to ATTAIN-MAINTAIN baseline. Primary estimand was modified treatment-regimen; efficacy estimand was supportive.
  • Analysis: continuous endpoints used ANCOVA (modified treatment-regimen) or MMRM (efficacy estimand); binary endpoints used logistic regression; safety used SAS-Before Rescue. Sample size: 150 per cohort to provide ~90% power to detect a 10% treatment difference.

Limitations

  • Stated: no comparator arm continuing injectable obesity-management medication; 1-year trial duration; sites only in the USA and a predominantly white population; rescue orforglipron after week 24 prevents pure placebo-versus-treatment comparison after week 24.
  • Stated/evident: only 25 (31.3%) cohort 1 and 12 (18.2%) cohort 2 placebo participants completed week 52 without active therapy, limiting precision and generalizability of placebo comparisons, especially in cohort 2; the paper notes high variability in the maintenance endpoint due to limited sample size.
  • Evident from text: participants with diabetes were excluded, so findings may not generalize to people with obesity and type 2 diabetes.

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

Integrity signals

Registry

Crossref · 10.1038/s41591-026-04386-7

Cites

16 of 16 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

12 of 14 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Weight regain after discontinuing weight loss interventions, regardless of modality of weight loss, has been demonstrated.

    “Weight regain after discontinuing weight loss interventions, regardless of modality of weight loss, has been demonstrated”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Aronne, L. J. et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 331, 38–48 (2024). source

      The Results report substantial weight regain after tirzepatide withdrawal, and the Discussion says trials across several medication classes found regain after pharmacotherapy stopped. The Introduction says sustaining weight loss from lifestyle-based caloric restriction is challenging, but the supplied passages do not demonstrate regain after discontinuing interventions regardless of modality. Page numbers are not provided in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [4] Group AfHiDS. Association of weight loss maintenance and weight regain on 4-year changes in CVD risk factors: the action for health in diabetes (Look AHEAD) clinical trial. Diabetes Care 39, 1345–1355 (2016). source

      The Abstract (page unavailable) says weight regain is common after behavioral treatment, even with ongoing treatment contact. The Intervention section (page unavailable) describes a lifestyle intervention; the paper does not establish regain specifically after discontinuation or regardless of weight-loss modality. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Persistence with existing injectable obesity management medications (OMMs) remains a barrier to weight loss maintenance.

    “persistence with existing injectable obesity management medications (OMMs) remains a barrier to weight loss maintenance2.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] Gasoyan, H., Pfoh, E. R., Schulte, R., Le, P. & Rothberg, M. B. Early- and later-stage persistence with antiobesity medications: a retrospective cohort study. Obesity 32, 486–493 (2024). source
  • Premisecitation

    Literature suggests that aligning with patients' preferences of attributes in treatment modalities increases the likelihood of patients persisting on therapy.

    “Literature suggests that aligning with patients’ preferences of attributes in treatment modalities increases the likelihood of patients persisting on therapy10,11.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Losi, S. et al. The role of patient preferences in adherence to treatment in chronic disease: a narrative review. Drug Target Insights 15, 13 (2021). source
    • cites [11] Craig, H. et al. Factors that determine patients considering medication for the disease of obesity: an IMI2 SOPHIA study. Int. J. Obesity 49, 397–401 (2025). source

      The Discussion (page unavailable) reports that treatment attributes and patients’ preferences influence treatment choices, and it discusses beliefs that affect medication adherence. It does not establish that matching treatment attributes to preferences increases the likelihood of patients persisting on therapy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    During the weight maintenance phase, weight regain can occur secondary to decreased energy expenditure and increased energy efficiency, which together result in a net decrease in caloric needs.

    “During the weight maintenance phase, weight regain can occur secondary to decreased energy expenditure and increased energy efficiency, which together result in a net decrease in caloric needs5–8.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [5] Rosenbaum, M. & Foster, G. Differential mechanisms affecting weight loss and weight loss maintenance. Nat. Metab. 5, 1266–1274 (2023). source
    • cites [6] Hall, K. D. & Kahan, S. Maintenance of lost weight and long-term management of obesity. Med. Clin. 102, 183–197 (2018). source

      The “Physiological responses to weight loss” section (page unavailable) reports declining energy expenditure after weight loss, and “Weight regain versus maintenance” says that preventing regain requires sustained effort against ongoing metabolic slowing and increased appetite. The copy does not identify increased energy efficiency as a separate contributor to reduced caloric needs; it also emphasizes increased appetite as an important driver of regain. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [7] Aronne, L. J. et al. Describing the weight-reduced state: physiology, behavior, and interventions. Obesity 29, S9–S24 (2021). source
    • cites [8] Theodorakis, N., Kreouzi, M., Pappas, A. & Nikolaou, M. Beyond calories: individual metabolic and hormonal adaptations driving variability in weight management—a state-of-the-art narrative review. Int. J. Mol. Sci. 25, 13438 (2024). source
  • Findingown data

    In cohort 1, the mean body weight (MBE) at week 52 was 95.9 kg with orforglipron.

    “For these participants, the mean body weight (MBE) at week 52 was 95.9 kg (s.e.m. 0.91) with orforglipron (Fig. 2c).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 32

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

    Premisecitation

    The doses of orforglipron capsule formulation (1, 3, 6, 12, 24, 36 mg) are equivalent to tablet doses of 0.8, 2.5, 5.5, 9, 14.5, 17.2 mg, respectively, which are approved in the USA.

    “the doses have been shown as the equivalent to tablet doses of 0.8, 2.5, 5.5, 9, 14.5 and 17.2 mg, respectively, which are approved in the USA13.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Ma, X. et al. Pharmacokinetic bioequivalence of orforglipron tablets and capsules in healthy participants with obesity or overweight. Diabetes Obes. Metab. https://doi.org/10.1111/dom.70783 (2026). source

      The Methods (Study Design) list the six capsule doses and their corresponding tablet doses, and the Results (Pharmacokinetics) report bioequivalence for all six pairs. No passage in our copy says the tablet doses are approved in the USA; the paper’s references to FDA guidance concern study design, not approval. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The approach of stopping medication after intentional weight loss can lead to weight cycling and loss of improvements in cardiometabolic health such as increased insulin resistance or blood pressure, as is seen when individuals stop therapy in other chronic diseases such as hypertension and dyslipidemia.

    “The approach of stopping medication after intentional weight loss can lead to weight cycling and loss of improvements in cardiometabolic health such as increased insulin resistance or blood pressure, as is seen when individuals stop therapy in other chronic diseases such as hypertension and dyslipidemia3,15,16.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [3] Aronne, L. J. et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 331, 38–48 (2024). 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
    • cites [15] Wilding, J. P. et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes. Metab. 24, 1553–1564 (2022). source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [16] Rubino, D. et al. 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 325, 1414–1425 (2021). source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In cohort 1 at 24 weeks, participants had a mean MBE body weight reduction of −19.0% from the beginning of SURMOUNT-5, with a mean MBE body weight of 93.4 kg.

    “Participants in cohort 1 at 24 weeks, before rescue therapy eligibility per study protocol, had a mean MBE body weight reduction of −19.0% (s.e.m. 0.68) from the beginning of SURMOUNT-5, with a mean MBE body weight of 93.4 kg (s.e.m. 0.79).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SAEs were reported by three participants in the orforglipron group in cohort 1 and one participant each in the orforglipron and placebo group in cohort 2, accounting for <2% of the total group.

    “SAEs were reported by three participants in the orforglipron group in cohort 1 and one participant each in the orforglipron and placebo group in cohort 2, accounting for <2% of the total group (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 1, participants randomized only to orforglipron had a mean baseline waist circumference of 120.8 cm in SURMOUNT-5, and at the start of ATTAIN-MAINTAIN had a mean waist circumference of 100.3 cm, a decrease of 20.5 cm.

    “Participants in cohort 1 randomized only to orforglipron in ATTAIN-MAINTAIN had a mean baseline waist circumference of 120.8 cm (s.e.m. 1.48) in SURMOUNT-5. At the start of the ATTAIN-MAINTAIN study, they had a mean waist circumference of 100.3 cm (s.e.m. 1.50) with a decrease in mean waist circumference of 20.5 cm (s.e.m. 0.95)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 2, participants had a mean MBE body weight reduction of 15.1% and absolute body weight reduction of 17.1 kg from the beginning of SURMOUNT-5 to the end of ATTAIN-MAINTAIN.

    “Participants in cohort 2 had a mean MBE body weight reduction of 15.1% (s.e.m. 0.67) (Fig. 3a) and absolute body weight reduction of 17.1 kg (Fig. 3b) from the beginning of SURMOUNT-5 to the end of ATTAIN-MAINTAIN.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In cohort 2, participants randomized only to orforglipron had a mean baseline waist circumference of 119.1 cm in SURMOUNT-5, and at the start of ATTAIN-MAINTAIN had a waist circumference of 103.4 cm, a decrease of 15.6 cm.

    “Participants in cohort 2 randomized only to orforglipron in ATTAIN-MAINTAIN had a mean baseline waist circumference of 119.1 cm (s.e.m. 1.77) in SURMOUNT-5. At the start of the ATTAIN-MAINTAIN study, they had a waist circumference of 103.4 (s.e.m. 1.83) cm with a decrease in mean waist circumference of 15.6 (s.e.m. 1.09) cm”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In those randomized to the orforglipron group, two participants in cohort 1 and one participant in cohort 2 were escalated from a dose of 24 mg to 36 mg of orforglipron.

    “In those randomized to the orforglipron group, two participants in cohort 1 and one participant in cohort 2 were escalated from a dose of 24 mg to 36 mg of orforglipron.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 2 at 24 weeks, participants had a mean MBE body weight reduction of 16.3% from the beginning of SURMOUNT-5, with a mean MBE body weight of 94.5 kg.

    “Participants in cohort 2 at 24 weeks, before rescue therapy eligibility per study protocol, had a mean MBE body weight reduction of 16.3% (s.e.m. 0.56) from the beginning of SURMOUNT-5, with a mean MBE body weight of 94.5 kg (s.e.m. 0.68).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among participants treated with orforglipron in cohort 1, four participants had increased ALT levels ≥3 times the upper limit of normal; one participant in cohort 2 and one participant in the placebo group for both cohorts 1 and 2 experienced this elevation in ALT.

    “Among the participants treated with orforglipron in cohort 1, four participants had increased ALT levels greater than or equal to three times the upper limit of normal (ULN) and one participant in cohort 2 and one participant in the placebo group for both cohorts 1 and 2 experienced this elevation in ALT (Extended Data Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 1, participants had a mean MBE body weight reduction of 16.8% and absolute body weight reduction of 19.6 kg from the beginning of SURMOUNT-5 to the end of ATTAIN-MAINTAIN.

    “Participants in cohort 1 had a mean MBE body weight reduction of 16.8% (s.e.m. 0.76) (Fig. 2a) and absolute body weight reduction of 19.6 kg (s.e.m. 0.91) (Fig. 2b) from the beginning of SURMOUNT-5 to the end of ATTAIN-MAINTAIN.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mean absolute change in weight from week 0 to 52 in ATTAIN-MAINTAIN was approximately 5 kg (5%) in cohort 1 and 1 kg (1%) in cohort 2.

    “Participants treated with orforglipron demonstrated average reductions in body weight from week 0 to 52 in ATTAIN-MAINTAIN of approximately 5 kg (5%) in cohort 1 and 1 kg (1%) in cohort 2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In cohort 2, participants subsequently randomized to orforglipron had a mean baseline A1c of 5.6% at the beginning of SURMOUNT-5, which improved to 5.2% at the beginning of ATTAIN-MAINTAIN, and remained at 5.2% at 52 weeks.

    “in cohort 2 participants subsequently randomized to orforglipron had a mean baseline A1c of 5.6% at the beginning of SURMOUNT-5. At the beginning of ATTAIN-MAINTAIN, after weight reduction with injectables, the A1c improved to a mean of 5.2%. At 52 weeks, the mean A1c remained at 5.2% and retained the improvements in this marker after switching to oral orforglipron.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 2, participants randomized only to orforglipron had a mean baseline body weight of 113.5 kg in SURMOUNT-5, and at the start of ATTAIN-MAINTAIN had a baseline body weight of 95.0 kg, a reduction of 16.5%.

    “participants in cohort 2 randomized only to orforglipron in ATTAIN-MAINTAIN had a mean baseline body weight of 113.5 kg (s.e.m. 2.64) in SURMOUNT-5. At the start of the ATTAIN-MAINTAIN study, they had a baseline body weight of 95.0 kg (s.e.m. 2.51) with a reduction of 16.5% (s.e.m. 0.81).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    One death was reported in the orforglipron group in cohort 2 and was not considered related to the study treatment.

    “One death was reported in the orforglipron group in cohort 2 and was not considered related to the study treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proportion of participants reporting any adverse events (AEs) and the number of reported serious adverse events (SAEs) were similar between arms.

    “The proportion of participants reporting any adverse events (AEs) and the number of reported serious adverse events (SAEs) were similar between arms”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Most GI AEs were mild to moderate in severity, and there were no dose de-escalations within the first 4 weeks when transitioning from injectable therapy directly to 12 mg of orforglipron.

    “Most GI AEs were mild to moderate in severity, and there were no dose de-escalations within the first 4 weeks when transitioning from injectable therapy directly to 12 mg of orforglipron”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The transition from injectable therapy directly to 12 mg of orforglipron was generally well tolerated, with fewer than 5% of participants experiencing gastrointestinal AEs and no participants requiring a dose de-escalation in both cohort 1 and cohort 2 during the first 4 weeks of the trial.

    “This transition was generally well tolerated, with fewer than 5% of participants experiencing gastrointestinal AEs and no participants requiring a dose de-escalation in both cohort 1 and cohort 2 during the first 4 weeks of the trial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In both cohorts 1 and 2, two participants receiving orforglipron had increased AST levels ≥3 times the upper limit of normal; in the placebo group, one participant in cohort 2 experienced this elevation.

    “In both cohorts 1 and 2, two participants receiving orforglipron had increased AST levels greater than or equal to three times the ULN. In the placebo group, one participant in cohort 2 experienced this elevation (Extended Data Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 2, 55.0% of orforglipron-treated participants maintained ≥80% of body weight reduction versus 6.9% with placebo, with a risk difference of 48.1 (95% CI 35.6 to 60.5), P < 0.001.

    “55.0% (s.e.m. 5.08) of those treated with orforglipron maintained ≥80% of the body weight reduction achieved during SURMOUNT-5, compared with 6.9% (s.e.m. 3.77) with placebo, corresponding to a risk difference of 48.1 (95% CI 35.6 to 60.5; P < 0.001)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Participants treated with orforglipron demonstrated significant and clinically meaningful maintenance of body weight reduction achieved with injectable therapy compared with placebo, with 75% and 79% in the orforglipron group versus 49% and 38% in the placebo group in cohorts 1 and 2, respectively.

    “In ATTAIN-MAINTAIN, participants treated with orforglipron demonstrated significant and clinically meaningful maintenance of body weight reduction achieved with injectable therapy compared with placebo, with 75% and 79% in the orforglipron group versus 49% and 38% in the placebo group in cohorts 1 and 2, respectively.”
    • Also stated in: § Discussion · plain
      “A key finding of this trial is that participants were better able to maintain the majority of weight loss achieved with injectable therapy when switched to orforglipron compared with placebo.”
    • Also stated in: § Discussion · plain
      “Once-daily orforglipron minimized weight changes after body weight reduction achieved with tirzepatide or semaglutide for people living with obesity without type 2 diabetes.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Of participants experiencing AST/ALT elevations, one participant in cohort 2 receiving placebo also experienced an increase of twice the upper limit of normal for total bilirubin.

    “Of the participants experiencing these aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations, one participant in cohort 2 receiving placebo also experienced an increase of twice the ULN for total bilirubin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 1, participants subsequently randomized to orforglipron had a mean baseline HbA1c of 5.6% at the beginning of SURMOUNT-5, which improved to 5.2% at the beginning of ATTAIN-MAINTAIN, and remained at 5.2% at 52 weeks.

    “in cohort 1, participants subsequently randomized to orforglipron had a mean baseline HbA1c of 5.6% at the beginning of SURMOUNT-5. At the beginning of ATTAIN-MAINTAIN, after weight reduction with injectables, the HbA1c improved to a mean of 5.2%. At 52 weeks, the mean HbA1c remained at 5.2% and retained the improvements in this marker after switching to oral orforglipron.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In cohort 1, participants randomized only to orforglipron had a mean baseline body weight of 115.8 kg in SURMOUNT-5, and at the start of ATTAIN-MAINTAIN had a baseline body weight of 90.9 kg, a reduction of 21.5%.

    “participants in cohort 1 randomized only to orforglipron in ATTAIN-MAINTAIN had a mean baseline body weight of 115.8 kg (s.e.m. 2.23) in SURMOUNT-5. At the start of the ATTAIN-MAINTAIN study, they had a baseline body weight of 90.9 kg (s.e.m. 2.12) with a reduction of 21.5% (s.e.m. 0.83).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    A blind, independent, external committee adjudicated all deaths, pancreatic AEs and cardiovascular events.

    “A blind, independent, external committee adjudicated all deaths, pancreatic AEs and cardiovascular events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Trial limitations include study sites located only in the USA and a predominantly white study population.

    “Trial limitations include study sites located only in the USA and a predominantly white study population, although the study includes a more representative US population with a higher Black or African American and Hispanic or Latino population.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Randomization was stratified by achievement of plateau at week 72 in SURMOUNT-5, sex and percent weight loss at week 72 of SURMOUNT-5 (<20%, ≥20%).

    “Randomization was stratified by achievement of plateau at week 72 in SURMOUNT-5, sex and percent weight loss at week 72 of SURMOUNT-5 (<20%, ≥20%).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The completed trial is registered on ClinicalTrials.gov (NCT06584916).

    “The completed trial is registered on ClinicalTrials.gov (NCT06584916).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The sample size of 150 participants per cohort was estimated to ensure 118 participants reached a plateau in body weight, providing approximately 90% power to detect a 10% treatment difference for the primary endpoint, assuming a 20% discontinuation rate and a common standard deviation of 14%, using a two-group t-test with a 5% two-sided significance level.

    “We estimated that a sample size of 150 participants was required for each cohort to ensure that 118 participants reached a plateau in body weight. This sample size provides approximately 90% power to detect a 10% treatment difference for the primary endpoint. This calculation assumed a 20% discontinuation rate and a common standard deviation of 14%, utilizing a two-group t-test with a 5% two-sided”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Study investigators, site staff, clinical monitors and participants were blinded to the study intervention until study completion.

    “Study investigators, site staff, clinical monitors and participants were blinded to the study intervention until study completion.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Participants were randomized in a 3:2 ratio to receive once-daily orforglipron or placebo, using a computer-generated random sequence from a Lilly interactive web response system.

    “Participants were randomized in a 3:2 ratio to receive once-daily orforglipron (36 mg or MTD of 24 or 36 mg), or placebo, using a computer-generated random sequence from a Lilly interactive web response system.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The trial was double-blind, randomized, and placebo-controlled.

    “Here this double-blind, placebo-controlled trial randomized participants”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The trial was conducted in compliance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonization.

    “The trial was conducted in compliance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonization.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    ATTAIN-MAINTAIN consisted of two phase 3b randomized, double-blind, placebo-controlled cohorts conducted at 29 sites in the USA.

    “ATTAIN-MAINTAIN consisted of two phase 3b randomized, double-blind, placebo-controlled cohorts conducted at 29 sites in the USA.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The trial protocol was approved by the Advarra central institutional review board.

    “The trial protocol was approved by the Advarra central institutional review board.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial's 1-year duration.

    “Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial’s 1-year duration.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Trial strengths include inclusion of healthy lifestyle counseling throughout the trial.

    “Trial strengths include the randomized, controlled study design, inclusion of healthy lifestyle counseling throughout the trial, and use of rescue orforglipron in case of significant (≥50%) weight regain to limit the potential harm associated with weight regain, although this does not allow for pure placebo versus treatment comparison after week 24.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    As a nonpeptide oral therapy, orforglipron has the potential to eliminate some individual patient barriers to injectable therapy, can be taken without food or water restrictions and, if approved, can be globally scalable to meet the need for treatments worldwide.

    “As a nonpeptide oral therapy, orforglipron has the potential to eliminate some individual patient barriers to injectable therapy (for example, resistance to injection, increased challenges with traveling, cold chain distribution and so on), can be taken without food or water restrictions and, if approved, can be globally scalable to meet the need for treatments worldwide.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Orforglipron is a once-daily, nonpeptide GLP-1 receptor agonist currently under investigation for the treatment of obesity and type 2 diabetes.

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

    Premisecitation

    Obesity is a chronic, relapsing and treatable multifactorial disease.

    “Obesity is a chronic, relapsing and treatable multifactorial disease1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Nadolsky, K. et al. American Association of Clinical Endocrinology Consensus Statement: algorithm for the evaluation and treatment of adults with obesity/adiposity-based chronic disease–2025 update. Endocr. Pract. 31, 1351–1394 (2025). source

  • May combine two claims.

    Study design and conductown data

    Overall, 157 (76.6%) participants in cohort 1 and 137 (80.1%) participants in cohort 2 completed study treatment, and 176 (85.9%) completed the study in cohort 1 and 144 (84.2%) in cohort 2.

    “Overall, 157 (76.6%) participants in cohort 1 and 137 (80.1%) participants in cohort 2 completed study treatment, and 176 (85.9%) completed the study in cohort 1 and 144 (84.2%) in cohort 2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Trial limitations include the lack of a comparator arm that included continuing injectable OMM and a trial duration of 1 year.

    “Additional limitations were the lack of a comparator arm that included continuing injectable OMM and a trial duration of 1 year.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Trial strengths include the randomized, controlled study design.

    “Trial strengths include the randomized, controlled study design, inclusion of healthy lifestyle counseling throughout the trial, and use of rescue orforglipron in case of significant (≥50%) weight regain to limit the potential harm associated with weight regain, although this does not allow for pure placebo versus treatment comparison after week 24.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    Weight regain can be associated with negative overall health consequences, such as reversal of cardiometabolic improvement, impaired physical function and an increase in psychological burden.

    “Weight regain can be associated with negative overall health consequences, such as reversal of cardiometabolic improvement, impaired physical function (for example, increased pain) and an increase in psychological burden.”

  • The paper relies on this without support.

    Orforglipron is a once-daily, nonpeptide GLP-1 receptor agonist currently under investigation for the treatment of obesity and type 2 diabetes.

    “Orforglipron is a once-daily, nonpeptide GLP-1 receptor agonist (RA) currently under investigation for the treatment of obesity and type 2 diabetes.”

  • The paper relies on this without support.

    This is the initial clinical trial investigating the switch from injectable incretin-based therapy to an oral OMM for the maintenance of body weight reduction.

    “This is the initial clinical trial investigating the switch from injectable incretin-based therapy to an oral OMM for the maintenance of body weight reduction”

  • The authors state this as an assumption.

    The modified treatment-regimen estimand assumes that participants who had bariatric surgery or another weight loss procedure or took rescue orforglipron would not have received any additional improvement from their randomized study treatment.

    “This estimand also assumes that participants who had bariatric surgery or another weight loss procedure or took rescue orforglipron would not have received any additional improvement from their randomized study treatment.”

  • The authors state this as an assumption.

    The efficacy estimand assumes that participants had stayed on treatment, had not taken prohibited medications, had not had bariatric surgery or any other weight management procedures, and that participants who took rescue orforglipron would not have received any additional improvement from their randomized study treatment.

    “The efficacy estimand evaluated the treatment effect assuming that participants had stayed on treatment, had not taken prohibited medications, had not had bariatric surgery or any other weight management procedures and assuming that participants who took rescue orforglipron would not have received any additional improvement from their randomized study treatment.”
5 of 5

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.

  • Cohort 1 placebo weight-change sign conflicts with the reported treatment difference

    Major

    The reported changes of −16.5% with orforglipron and +12.6% with placebo differ by −29.1 percentage points, not the stated −3.9 points. A placebo change of −12.6% would produce the reported treatment difference.

    Reported -3.9 · recomputed -29.1

  • First-four-week gastrointestinal adverse-event rates contradict the discussion

    Major

    The Results report gastrointestinal adverse-event incidences of 10.5% and 9.5% in the first four weeks, whereas the Discussion says fewer than 5% of participants experienced gastrointestinal adverse events during that period.

  • Discussion calls weight regain a reduction

    Minor

    The Discussion describes an approximately 5 kg reduction during ATTAIN-MAINTAIN in cohort 1, but the Results give a starting weight of 90.9 kg and a week-52 weight of 95.9 kg-a gain of 5 kg.

3 of 3

Cites

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Cited by

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Related

Authors
Aronne, L. J., Horn, D. B., le Roux, C. W., Chao, A. M., Ho, W., Halpern, B., Griffin, R., Xie, C., Valderas, E. G., Lee, C. J., Ribeiro, A., Hyman, D. M., Glass, L., & Xavier, N.
Affiliations
  • Weill Cornell Medicine (US)
  • Johns Hopkins University (US)
  • University of Southern California (US)
  • Eli Lilly (United States) (US)
Corresponding author
Aronne, Louis J.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2026-05-13
Volume
32
Issue
7
Pages
2679-2687
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-026-04386-7
PMC
PMC13375559
OpenAlex
W7160964043
Semantic Scholar
45f984b46d073d8652d5b836b35c9227ea75cece
Cited by
22
References
16
Citations by year
2026: 22
FWCI
93.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Ulster University Research Portal (Ulster University) (acceptedVersion, cc-by)
Funders
Eli Lilly and Company
Topics
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
orforglipron, GLP-1 receptor agonists, obesity, weight maintenance, tirzepatide, semaglutide, model-based estimation, cardiometabolic risk, gastrointestinal adverse effects, oral GLP-1 receptor agonists
MeSH terms
Tirzepatide, Semaglutide, Adult, Double-Blind Method, Glucagon-Like Peptides, Female, Humans, Male, Middle Aged, Obesity, Oxadiazoles, Weight Loss, Fluorine Compounds

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 2026-10-30.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-30.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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