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Cited by 1,444Pharmacology and Obesity TreatmentDiabetes Treatment and ManagementRegulation of Appetite and Obesity

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial

Open access
Rubino, Domenica, Abrahamsson, Niclas, Davies, Melanie, Hesse, Dan, Greenway, Frank L., Jensen, Camilla, Lingvay, Ildiko, Mosenzon, Ofri +80 more·2021·JAMA
DOI 10.1001/jama.2021.3224PMC PMC7988425
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Abstract

Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Design, Setting, and Participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main Outcomes and Measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). Conclusions and Relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03548987.

Integrity signals

Registry

Crossref · 10.1001/jama.2021.3224

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Systolic blood pressure change from week 20 to week 68 differed by -3.9 mm Hg (95% CI, -5.8 to -2.0 mm Hg) between continued semaglutide and placebo.

    “systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg])”
    Quote in the paperNot a substantial claim
  • Findingown data

    Discontinuation because of adverse events occurred in similar proportions with continued semaglutide (2.4%) and placebo (2.2%).

    “similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).”
    Quote in the paperNot a substantial claim
  • Findingown data

    There was no change in diastolic blood pressure in either treatment group from week 20 to week 68.

    “with no change in diastolic blood pressure in either treatment group”
    Quote in the paperNot a substantial claim
  • Findingown data

    Gastrointestinal events were reported in 41.9% of continued semaglutide participants and 26.1% of placebo participants.

    “Gastrointestinal events were reported in 41.9% of participants who continued subcutaneous semaglutide vs 26.1% with placebo”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among the 803 participants randomized after the 20-week run-in, mean weight loss during run-in was 10.6%.

    “Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized”
    Quote in the paperNot a substantial claim
  • May combine two claims. 47
  • Classified as probably not a substantial claim. 39
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    From week 20 to week 68, mean body weight change was -7.9% with continued semaglutide and +6.9% with placebo.

    “With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo”
    Quote in the paperSubstantial claim

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

    Findingown data

    Of 504 continued semaglutide participants who completed treatment, 89.5% received 2.4 mg at week 68, 4.0% received 1.7 mg, 2.8% received less than 1.7 mg, and data were missing for 3.8%.

    “Of the 504 participants who continued semaglutide and completed treatment, 89.5% received 2.4 mg at week 68, 4.0% received 1.7 mg, and 2.8% received less than 1.7 mg; data were missing for 3.8%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During the 20-week run-in, reductions occurred in waist circumference, BMI, systolic and diastolic blood pressure, hemoglobin A1c, and fasting plasma glucose, and lipid profiles improved.

    “This was accompanied by reductions in waist circumference, BMI, systolic and diastolic blood pressure, hemoglobin A 1c , and fasting plasma glucose and improvements in lipid profiles”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Among randomized participants, 787 (98.0%) completed the trial and 741 (92.3%) completed treatment.

    “787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Most randomized participants (64.8%) had 1 to 3 comorbidities, with dyslipidemia and hypertension most prevalent.

    “Most (64.8%) had 1 to 3 comorbidities, with dyslipidemia and hypertension most prevalent”
    Quote in the paperNot a substantial claim

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

    Findingown data

    One placebo-switched participant received rescue liraglutide during the randomized period, and no participants had bariatric surgery.

    “One participant who switched to placebo received rescue intervention (liraglutide) during the randomized period.No participants had bariatric surgery.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    During the 20-week run-in, mean body weight among participants who entered run-in declined by 10.6% to 96.1 kg.

    “During the 20-week run-in, mean body weight declined by 10.6% to 96.1 kg (Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Among participants not randomized at week 20 (n=99), mean body weight at week 0 was 103.6 kg, lower than in the randomized population; other characteristics were similar.

    “Among those not randomized at week 20 (n = 99 [11%]; Figure 1), mean body weight at week 0 (103.6 kg) was lower than in the randomized population; other characteristics were similar”
    Quote in the paperNot a substantial claim

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

    Findingown data

    At week 0, the 803 randomized participants had mean age 46.0 years, mean body weight 107.2 kg, mean BMI 38.4, and mean waist circumference 115.3 cm; 79.0% were female and 83.7% were White.

    “most were female (79.0%) and White (83.7%), with a mean age of 46.0 years, a mean body weight of 107.2 kg, a mean BMI of 38.4, and a mean waist circumference of 115.3 cm at week 0”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    From week 20 to week 68, systolic blood pressure remained stable with continued semaglutide and significantly increased with placebo.

    “From week 20 to week 68, systolic blood pressure remained stable with continued semaglutide and significantly increased with placebo”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Among randomized participants, 770 (95.9%) provided a body weight measurement at week 68.

    “770 (95.9%) provided a body weight measurement at week 68”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During the run-in period, 84.3% of participants reported adverse events, and gastrointestinal tract disorders were reported by 71.4%.

    “During the run-in period, 84.3% of participants reported adverse events, with gastrointestinal tract disorders reported by 71.4%”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Moderate acute pancreatitis was reported in 1 participant during run-in, who recovered during the study.

    “Moderate acute pancreatitis was reported in 1 participant (during run-in), who recovered during the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Observed proportions achieving at least 5%, 10%, 15%, and 20% body weight loss from week 0 to week 68 with continued semaglutide vs placebo were 88.7% vs 47.6%, 79.0% vs 20.4%, 63.7% vs 9.2%, and 39.6% vs 4.8%, respectively.

    “The observed proportions of participants achieving 5% or more, 10% or more, 15% or more, and 20% or more body weight loss from week 0 to week 68 with continued semaglutide vs placebo were 88.7% vs 47.6%, 79.0% vs 20.4%, 63.7% vs 9.2%, and 39.6% vs 4.8%, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During week 20 to week 68, continued semaglutide led to additional reductions in hemoglobin A1c and fasting plasma glucose and improvements in lipid profile vs placebo.

    “During week 20 to week 68, continued semaglutide led to additional reductions in hemoglobin A 1c and fasting plasma glucose and improvements in lipid profile vs placebo”
    Quote in the paperNot a substantial claim

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

    Findingown data

    One death was reported in each treatment group during the randomized period, each considered unrelated to study treatment.

    “One death was reported in each treatment group during the randomized period, each considered unrelated to study treatment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most gastrointestinal events were mild to moderate in severity, and the majority of participants recovered without treatment discontinuation.

    “Most gastrointestinal events were mild to moderate in severity, and the majority of participants recovered without treatment discontinuation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During run-in, 5.3% discontinued treatment because of adverse events, most of which were gastrointestinal tract disorders.

    “During the run-in, 5.3% of par-ticipants discontinued treatment because of adverse events, most of which were gastrointestinal tract disorders”
    Quote in the paperNot a substantial claim

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

    Findingown data

    During the randomized period, constipation occurred in 11.6% of participants continuing semaglutide and 6.3% of those switched to placebo.

    “Constipation | 62 (11.6) | 75 | 13.8 | 17 (6.3) | 19 | 7.1”
    Quote in the paperNot a substantial claim

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

    Findingown data

    During the randomized period, headache occurred in 7.7% of participants continuing semaglutide and 3.7% of those switched to placebo.

    “Headache | 41 (7.7) | 48 | 8.8 | 10 (3.7) | 10 | 3.8”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During weeks 20 to 68, the estimated mean change in body weight was -7.9% with continued semaglutide and +6.9% with placebo, a difference of -14.8% (95% CI, -16.0 to -13.5).

    “Body weight, % change | -7.9 (-8.6 to -7.2) | 6.9 (5.8 to 7.9) | -14.8 (-16.0 to -13.5) | <.001”
    Quote in the paperSubstantial claim

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

    Findingown data

    During the randomized period, acute pancreatitis occurred in 0 participants continuing semaglutide and 0 participants switched to placebo.

    “Acute pancreatitis | 0 | | | 0 | | |”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sustained weight loss of a similar magnitude to that observed in this trial has been linked to improvements in obesity-related complications, such as type 2 diabetes, with treatment guidelines recommending sustained weight loss of 5% to 15%.

    “Sustained weight loss of a similar magnitude to that observed in this trial has been linked to improvements in obesityrelated complications, [25][26][27] such as type 2 diabetes, 28 with treatment guidelines recommending sustained weight loss of 5% to 15% for people with these conditions.5,6”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [25] 25. Singh M, Lee J, Gupta N, et al. Weight loss can lead to resolution of gastroesophageal reflux disease symptoms: a prospective intervention trial. Obesity (Silver Spring). 2013;21(2):284-290. doi: 10.1002/oby.20279 source

      Not checked in the free run.

    • cites [26] 26. Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults: a review. JAMA. 2020;324(9): 879-887. doi:10.1001/jama.2020.12567 source

      Not checked in the free run.

    • cites [27] 27. Lean MEJ, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391(10120): 541-551. doi:10.1016/S0140-6736(17)33102-1 source

      Not checked in the free run.

    • cites [28] 28. Apovian CM, Garvey WT, Ryan DH. Challenging obesity: patient, provider, and expert perspectives on the roles of available and emerging nonsurgical therapies. Obesity (Silver Spring). 2015;23(suppl 2): S1-S26. doi:10.1002/oby.21140 source

      Not checked in the free run.

    • cites [5] 5. Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22(suppl 3):1-203. doi:10.4158/ EP161365.GL source

      Not checked in the free run.

    • cites [6] 6. Yumuk V, Tsigos C, Fried M, et al; Obesity Management Task Force of the European Association for the Study of Obesity. European guidelines for obesity management in adults. Obes Facts. 2015;8(6):402-424. doi:10.1159/000442721 source

      Not checked in the free run.

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

    Premisereasoning

    Well-tolerated new therapies that can produce substantial, sustained weight loss when used long term are needed.

    “Well-tolerated new therapies that can produce substantial, sustained weight loss, when used long term, are therefore needed.7,10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] 7. Bray GA, Frühbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016;387(10031): 1947-1956. doi:10.1016/S0140-6736(16)00271-3 source

      Not checked in the free run.

    • cites [10] 10. Kushner RF, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring). 2020;28(6):1050-1061. doi:10.1002/oby. 22794 source

      Not checked in the free run.

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

    Study design and conductcitation

    The sample size calculation included assumed differences between treatment groups of 8.7 percentage points in body weight change, 5.8 cm in waist circumference change, 4 mm Hg in systolic blood pressure change, and 3.9 points in SF-36 physical functioning score change, based on data from the phase 2 trial.

    “The calculation included assumed differences between treatment groups of 8.7 percentage points in body weight change, 5.8 cm in waist circumference change, 4 mm Hg in systolic blood pressure change, and 3.9 points in SF-36 physical functioning score change, based on data from the phase 2 trial of semaglutide for obesity.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] 14. O'Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392(10148):637-649. doi:10.1016/ S0140-6736(18)31773-2 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In continued semaglutide participants, run-in weight loss was sustained and continued, reached a plateau at week 60 to week 68, and resulted in an estimated 17.4% reduction over the entire trial.

    “In those who continued semaglutide after randomization, weight loss achieved during the run-in period not only was sustained but continued, reaching a plateau at week 60 to week 68 and ultimately resulting in an estimated reduction of 17.4% over the entire trial.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Continuous end points for the trial product estimand were assessed using a mixed model for repeated measurements with randomized treatment as a factor and baseline (week 20) end point value as a covariate, nested within visit, with an unstructured covariance matrix.

    “Continuous end points were assessed using a mixed model for repeated measurements (MMRM), with randomized treatment as a factor and baseline (week 20) end point value as a covariate, 10 all nested within visit.An unstructured covariance matrix for measurements within the same participant was used.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] 10. Kushner RF, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring). 2020;28(6):1050-1061. doi:10.1002/oby. 22794 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 conductnone given

    Results are reported for the treatment policy estimand unless stated otherwise, and exploratory data and run-in data are summarized by descriptive statistics only.

    “Results are reported for the treatment policy estimand unless stated otherwise.Exploratory data and data from the run-in period (weeks 0-20) are summarized by descriptive statistics only.”
    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 conductown data

    Participants were randomized in a 2:1 ratio using a blocking schema (block size 6) in a double-blind manner via an interactive web-based response system.

    “Participants receiving semaglutide, 2.4 mg, at week 20 were randomized in a 2:1 ratio using a blocking schema (block size of 6) in a double-blind manner, via an interactive web-based response system”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Subcutaneous semaglutide is a GLP-1 receptor agonist approved for treatment of type 2 diabetes at doses of 1.0 mg or less once weekly.

    “Subcutaneous semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes at doses of 1.0 mg or less once weekly.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] 11. US Food and Drug Administration. Ozempic (semaglutide): prescribing information. Revised January 2020. Accessed July 22, 2020. https:// www.accessdata.fda.gov/drugsatfda_docs/label/ 2020/209637s003lbl.pdf

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Weekly administration was proposed to be more clinically convenient and was supported by a tolerability trial and pharmacokinetic modeling.

    “Proposed to be more clinically convenient, weekly administration was supported by a tolerability trial and pharmacokinetic modeling.10,15”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] 10. Kushner RF, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring). 2020;28(6):1050-1061. doi:10.1002/oby. 22794 source

      Not checked in the free run.

    • cites [15] 15. Lingvay I, Desouza CV, Lalic KS, et al. A 26-week randomized controlled trial of semaglutide once daily versus liraglutide and placebo in patients with type 2 diabetes suboptimally controlled on diet and exercise with or without metformin. Diabetes Care. 2018;41(9):1926-1937. doi:10.2337/dc17-2381 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Continuous end points were analyzed using analysis of covariance with randomized treatment as a factor and baseline (week 20) end point value as a covariate.

    “Continuous end points were analyzed using analysis of covariance, with randomized treatment as a factor and baseline (week 20) end point value as a covariate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The significant and sustained weight loss with continued semaglutide was accompanied by sustained improvement in waist circumference, lipid profiles, and glucose metabolism, all cardiometabolic risk factors.

    “The significant and sustained weight loss demonstrated with continued semaglutide in this study was accompanied by sustained improvement in waist circumference, lipid profiles, and glucose metabolism, all of which are cardiometabolic risk factors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    These results emphasize the chronicity of obesity and the need for treatments that can maintain and maximize weight loss.

    “These results emphasize the chronicity of obesity and the need for treatments that can maintain and maximize weight loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    With liraglutide 3.0 mg/d, weight losses of 10% or more and 15% or more were achieved by 33% and 14%, respectively, among people treated for 56 weeks.

    “with the GLP-1 receptor agonist liraglutide, at a 3.0-mg/d dosage, which is approved for weight management, weight losses of 10% or more and 15% or more were achieved by 33% and 14%, respectively, among people treated for 56 weeks.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] 30. Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443-1451. doi:10.1038/ijo.2013.120 source

      Not checked in the free run.

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

    Study design and conductreasoning

    A post hoc mixed-effects regression analysis of the primary end point was performed with study site as a random effect to account for the multicenter study design.

    “To account for the multicenter study design, a post hoc mixed-effects regression analysis of the primary end point was performed, with study site as a random effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Continued semaglutide produced significantly better outcomes for waist circumference, systolic blood pressure, and SF-36 physical functioning scores than placebo.

    “Continued semaglutide also produced significantly better outcomes for waist circumference, systolic blood pressure, and SF-36 physical functioning scores vs placebo.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Cardiovascular events, acute pancreatitis events, and deaths were reviewed by an independent external event adjudication committee.

    “Cardiovascular events, acute pancreatitis events, and deaths were reviewed by an independent external event adjudication committee.”
    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 conductcitation

    The study was conducted according to the ICH Good Clinical Practice Guideline and the Declaration of Helsinki, and all participants provided written informed consent.

    “The study was conducted according to the International Council for Harmonisation Good Clinical Practice Guideline and the Declaration of Helsinki 16 ; all participants provided written informed consent.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] 16. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    The finding that 40% of continued semaglutide participants lost an additional 10% body weight supports its use for long-term treatment of obesity.

    “supporting its use for long-term treatment of obesity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Weight loss with liraglutide in clinical trials was of lesser magnitude and appeared to plateau earlier (at 20 or 40 weeks) than with semaglutide in the present trial (at 60-68 weeks).

    “weight loss with liraglutide in clinical trials was of lesser magnitude and appeared to plateau earlier (at 20 weeks 31 or 40 weeks 30 ) than with semaglutide in the present trial (at 60-68 weeks).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] 31. Hellström PM. GLP-1 analogue liraglutide as adjunct treatment in diabetes type 2 after failed bariatric/metabolic surgery. Ann Transl Med. 2019;7 (suppl 6):S240. doi:10.21037/atm.2019.08.94 source

      Not checked in the free run.

    • cites [30] 30. Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443-1451. doi:10.1038/ijo.2013.120 source

      Not checked in the free run.

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

    Interpretationreasoning

    Given the modest efficacy of currently approved pharmacotherapies, semaglutide may offer the potential to bridge the gap between behavioral and pharmacological options and bariatric surgery, which is currently considered the most effective and reliable intervention available for weight management.

    “Given the modest efficacy of currently approved pharmacotherapies, [7][8][9] semaglutide may offer the potential to bridge the gap between behavioral and pharmacological options and bariatric surgery, which is currently considered the most effective and reliable intervention available for weight management.6,27,32”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [7] 7. Bray GA, Frühbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016;387(10031): 1947-1956. doi:10.1016/S0140-6736(16)00271-3 source

      Not checked in the free run.

    • cites [8] 8. Bessesen DH, Van Gaal LF. Progress and challenges in anti-obesity pharmacotherapy. Lancet Diabetes Endocrinol. 2018;6(3):237-248. doi:10. 1016/S2213-8587(17)30236-X source

      Not checked in the free run.

    • cites [9] 9. Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016; 315(22):2424-2434. doi:10.1001/jama.2016.7602 source

      Not checked in the free run.

    • cites [6] 6. Yumuk V, Tsigos C, Fried M, et al; Obesity Management Task Force of the European Association for the Study of Obesity. European guidelines for obesity management in adults. Obes Facts. 2015;8(6):402-424. doi:10.1159/000442721 source

      Not checked in the free run.

    • cites [27] 27. Lean MEJ, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391(10120): 541-551. doi:10.1016/S0140-6736(17)33102-1 source

      Not checked in the free run.

    • cites [32] 32. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012; 366(17):1567-1576. doi:10.1056/NEJMoa1200225 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Premisecitation

    Sustained weight loss of 5% to 15% is advised to improve many conditions associated with overweight/obesity, with adjunctive pharmacotherapy recommended to help achieve this goal.

    “Sustained weight loss of 5% to 15% is advised to improve many conditions associated with overweight/obesity, with adjunctive pharmacotherapy recommended to help achieve this goal.5,6”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] 5. Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22(suppl 3):1-203. doi:10.4158/ EP161365.GL source

      Not checked in the free run.

    • cites [6] 6. Yumuk V, Tsigos C, Fried M, et al; Obesity Management Task Force of the European Association for the Study of Obesity. European guidelines for obesity management in adults. Obes Facts. 2015;8(6):402-424. doi:10.1159/000442721 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In this trial, adults with overweight or obesity who continued once-weekly subcutaneous semaglutide 2.4 mg had ongoing and persistent weight loss, whereas those who switched to placebo gained weight.

    “adults with obesity/overweight who continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, had ongoing and persistent weight loss vs participants who switched to placebo, who gained weight.”
    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 sample size calculation assumed a 5% permanent discontinuation rate from week 20 to week 68 and available data for 60% of these participants at week 68.

    “assuming a 5% permanent discontinuation rate from week 20 to week 68 and available data for 60% of these participants at week 68”
    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 conductown data

    The trial was a 68-week randomized, double-blind, placebo-controlled withdrawal study conducted at 73 sites in 10 countries.

    “This trial was a 68-week, randomized, double-blind, placebocontrolled withdrawal study conducted at 73 sites in 10 countries”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The 2.4 mg dose is greater than currently approved for type 2 diabetes and was chosen based on a phase 2 clinical trial in which greater weight loss was seen with once-daily semaglutide 0.4 mg (equal to 2.8 mg/wk) vs current approved medical therapy.

    “This dose, which is greater than what is currently approved for type 2 diabetes, was chosen based on a phase 2 clinical trial, in which greater weight loss was seen with once-daily semaglutide, 0.4 mg (equal to 2.8 mg/wk), vs current approved medical therapy.14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] 14. O'Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392(10148):637-649. doi:10.1016/ S0140-6736(18)31773-2 source

      Not checked in the free run.

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

    Premisecitation

    Once-weekly subcutaneous semaglutide 2.4 mg is being investigated for treatment of overweight/obesity in the global phase 3 STEP program.

    “Onceweekly subcutaneous semaglutide, 2.4 mg, is being investigated for the treatment of overweight/obesity in the global phase 3 Semaglutide Treatment Effect in People With Obesity (STEP) program.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] 10. Kushner RF, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring). 2020;28(6):1050-1061. doi:10.1002/oby. 22794 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Short-term treatment (3-6 months) fails to produce long-term health benefits, while several agents also have safety concerns.

    “Short-term treatment (3-6 months) fails to produce long-term health benefits, 5 while several agents also have safety concerns.[7][8][9]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [5] 5. Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22(suppl 3):1-203. doi:10.4158/ EP161365.GL source

      Not checked in the free run.

    • cites [7] 7. Bray GA, Frühbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016;387(10031): 1947-1956. doi:10.1016/S0140-6736(16)00271-3 source

      Not checked in the free run.

    • cites [8] 8. Bessesen DH, Van Gaal LF. Progress and challenges in anti-obesity pharmacotherapy. Lancet Diabetes Endocrinol. 2018;6(3):237-248. doi:10. 1016/S2213-8587(17)30236-X source

      Not checked in the free run.

    • cites [9] 9. Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016; 315(22):2424-2434. doi:10.1001/jama.2016.7602 source

      Not checked in the free run.

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

    Premisecitation

    Maintaining long-term weight loss is challenging because of metabolic adaptation and difficulty adhering to lifestyle interventions, with weight regain often following weight loss.

    “Maintaining long-term weight loss is challenging because of metabolic adaptation 2 and the difficulty of adhering to lifestyle interventions, 3 with weight regain often following weight loss.4”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] 2. Leibel RL, Seeley RJ, Darsow T, Berg EG, Smith SR, Ratner R. Biologic responses to weight loss and weight regain: report from an American Diabetes Association research symposium. Diabetes. 2015; 64(7):2299-2309. doi:10.2337/db15-0004 source

      Not checked in the free run.

    • cites [3] 3. Lemstra M, Bird Y, Nwankwo C, Rogers M, Moraros J. Weight loss intervention adherence and factors promoting adherence: a meta-analysis. Patient Prefer Adherence. 2016;10:1547-1559. doi: 10.2147/PPA.S103649 source

      Not checked in the free run.

    • cites [4] 4. Kroeger CM, Hoddy KK, Varady KA. Impact of weight regain on metabolic disease risk: a review of human trials. J Obes. 2014;2014:614519. doi:10. 1155/2014/614519 source

      Not checked in the free run.

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

    Premisecitation

    Weight loss with semaglutide is believed to stem from improved appetite control and consequent reduced energy intake via effects in the hypothalamus and area postrema of the brain.

    “Weight loss with semaglutide is believed to stem from improved appetite control, and consequent reduced energy intake, via effects in the hypothalamus and area postrema of the brain. 12,13”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] 12. Friedrichsen M, Breitschaft A, Tadayon S, Wizert A, Skovgaard D. The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diabetes Obes Metab. 2021;23(3):754-762. doi:10. 1111/dom.14280

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [13] 13. Gabery S, Salinas CG, Paulsen SJ, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020;5(6): e133429. doi:10.1172/jci.insight.133429 source

      Not checked in the free run.

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

    Study design and conductnone given

    Participants eligible for randomization at week 20 had to have attained the target maintenance dose of semaglutide (2.4 mg once weekly) by week 16 and continued taking this dose until week 20.

    “Participants eligible for randomization at week 20 had to have attained the target maintenance dose of semaglutide (2.4 mg once weekly) by week 16 and have continued taking this dose until week 20.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Missing data were imputed using a multiple imputation approach from week 68 measurements from participants in the same treatment group; 1000 complete data sets were generated and combined using the Rubin formula.

    “A multiple imputation approach 21 was used in which missing data were imputed from week 68 measurements from participants in the same treatment group.One thousand complete data sets were generated and analyzed, and the results were combined using the Rubin formula 22”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] 21. Little RJA, Rubin DB. Statistical Analysis With Missing Data. John Wiley & Sons; 1987.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [22] 22. Sjöström L, Rissanen A, Andersen T, et al; European Multicentre Orlistat Study Group. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet. 1998;352(9123):167-172. doi:10.1016/S0140-6736(97)11509-4 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 conductnone given

    Two further estimands (tertiary and quaternary) addressing treatment effects between week 0 and week 68 were included; the tertiary was identical to the primary treatment policy estimand and the quaternary was identical to the secondary trial product estimand except week 20 values were replaced by week 0 values.

    “Two further estimands (the tertiary and quaternary estimands) addressing treatment effects between week 0 and week 68 were also included.The tertiary estimand was identical to the primary treatment policy estimand, and the quaternary estimand was identical to the secondary trial product estimand, except values at week 20 (baseline) were replaced by those at week 0 (start of run-in) in the respect”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    To reduce the possible influence of semaglutide's long half-life on adverse event reporting, adverse events were counted only during the randomized period if they began after randomization.

    “To lessen any potential effect of the long half-life of semaglutide on adverse event reporting, adverse events were counted only during the randomized period if onset was after randomization.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Because of potential type I error due to multiple comparisons, findings for supportive secondary end points should be interpreted as exploratory.

    “Because of the potential for type I error due to multiple comparisons, findings for analyses of supportive secondary end points should be interpreted as exploratory.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The run-in period and trial setting likely produced a study population that was more tolerant of semaglutide and more adherent to medication than a typical clinical population.

    “The run-in period, as well as the trial setting, likely resulted in a study population who was both more tolerant of semaglutide and more adherent to medication use than would be the case in a typical setting.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The study did not assess adherence to lifestyle interventions.

    “Second, there was no assessment of adherence to lifestyle interventions.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study used a blinded design.

    “Additional strengths of the study include the large sample size, blinded design, and high rates of treatment regimen and trial completion.”
    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

    All results from statistical analyses were accompanied by 2-sided 95% confidence intervals and corresponding P values, with statistical significance defined as P < .05.

    “All results from statistical analyses were accompanied by 2-sided 95% confidence intervals and corresponding P values (statistical significance defined as P < .05).”
    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 conductown data

    For analysis of participants who gained weight, a mixed model for repeated measurements with baseline body weight as covariate was used to classify weight gain, and this classification was analyzed using logistic regression.

    “For the analysis of participants who gained weight, the MMRM (with baseline body weight in kilograms as the covariate) was used to classify participants according to whether they gained weight or not.This classification was then analyzed using logistic regression, with the same factor and covariate as the MMRM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The withdrawal design can introduce selection bias and favorable carryover effects into the randomized period.

    “Third, while the withdrawal design is a strength, it can also result in selection bias and favorable carryover effects to the randomized period, potentially resulting in overestimation of weight loss with continued semaglutide compared with what would be expected in a typical individual.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The high treatment and trial completion rates were probably due to several factors: efforts to retain participants, selecting a population that tolerated semaglutide during run-in, and including people who had previously tried to lose weight and were therefore likely motivated to stay in the trial after run-in weight loss.

    “The high treatment and trial completion rates were likely a result of multiple factors, including a focus on participant retention, selection of a population who could tolerate semaglutide during run-in, and inclusion of participants who had previously attempted to lose weight and so were likely motivated to continue in the trial following weight loss in the run-in period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study had high rates of completion of the treatment regimen and of the trial.

    “Additional strengths of the study include the large sample size, blinded design, and high rates of treatment regimen and trial completion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The safety and tolerability profile of semaglutide 2.4 mg/week in this trial matched that seen in a phase 2 obesity study, in type 2 diabetes trials using lower doses, and with other GLP-1 receptor agonists, with no new safety concerns.

    “Although a higher maintenance dosage of semaglutide (2.4 mg/wk) was used in this trial, the adverse event profile and tolerability were consistent with data from a phase 2 study in people with obesity 14 and semaglutide trials in patients with type 2 diabetes using lower maintenance dosages (up to 1.0 mg/wk), 34 as well as with that reported for other GLP-1 receptor agonists, 35 with no new concer”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] 14. O'Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392(10148):637-649. doi:10.1016/ S0140-6736(18)31773-2 source

      Not checked in the free run.

    • cites [34] 34. Trujillo J. Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes. J Clin Pharm Ther. 2020;45(suppl 1):43-60. doi:10.1111/ jcpt.13225

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [35] 35. US Food and Drug Administration. Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products: Guidance for Industry. Published March 2019. Accessed July 22, 2020. https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/enrichment- strategies-clinical-trials-support-approval-human- drugs-and-biological-products

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

65 of 65

  • The paper relies on this without support.

    Before this trial, the effect of continuing versus withdrawing semaglutide on weight loss maintenance in people with overweight or obesity was unknown.

    “The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.”

  • The authors state this as an assumption.

    For the trial product estimand, participants are assumed to have continued randomized treatment for the planned study duration without medication discontinuation or rescue interventions between week 20 and week 68.

    “The trial product estimand (the secondary estimand) quantified the average treatment effect modeled to assume participants continued taking randomized treatment for the planned study duration without medication discontinuation or rescue interventions between week 20 and week 68.”
2 of 2

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?

  • If incretin-based medications are stopped, bodyweight increases at about the same rate as it was lost.

    “If treatment with incretin-based medications is discontinued, bodyweight will increase at approximately the velocity as it had been lost with treatment.”

    From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [64]

    The Changes During the Run-in Period section reports 10.6% mean weight loss over 20 weeks, while the Results passage reports 6.9% mean weight regain over 48 weeks after participants switched from semaglutide to placebo (page numbers unavailable). Weight did increase after withdrawal, but its average rate of increase was substantially slower than its rate of loss. The trial also studied semaglutide specifically, not incretin-based medications generally. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • If treatment with incretin-based medications is discontinued, bodyweight will increase at approximately the same velocity as it had been lost with treatment.

    “If treatment with incretin-based medications is discontinued, bodyweight will increase at approximately the velocity as it had been lost with treatment. [64][65]5][66]”

    From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [64]

    The Changes During the Run-in Period section reports 10.6% mean weight loss over 20 weeks. The Changes Over the Entire Trial Period section reports that participants switched to placebo were still 5.0% below their starting weight at week 68—48 weeks after stopping semaglutide. They regained weight, but the reported changes imply a substantially slower average rate of regain than of initial loss, not approximately the same velocity. The cited trial also tested semaglutide specifically, not incretin-based medications generally. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In STEP trials, semaglutide 2.4 mg weekly produced a mean placebo-adjusted weight loss of 14.9% over 68 weeks in STEP 1 and up to 16.0% in STEP 4 with continued use.

    “In the semaglutide treatment effect in people (STEP) with obesity trials, semaglutide 2.4 mg weekly produced a mean placebo-adjusted weight loss of 14.9% over 68 weeks in STEP 1, and up to 16.0% in STEP 4 with continued use [6,8].”

    From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [8]

    The STEP 4 paper’s “Changes Over the Entire Trial Period” section reports a placebo-adjusted difference of 12.4 percentage points from week 0 to week 68, not 16.0. Its Abstract reports a 14.8-point difference for weeks 20–68 after the run-in. This citation is attached to the STEP 4 portion of a sentence that also cites a separate source for STEP 1; the STEP 4 result does not support the stated figure. (LLM, conf=0.89)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In three 56-week studies of people with obesity and dyslipidemia or hypertension, weight loss ranged from 6.2% to 8.0% with liraglutide 3 mg versus 0.2% to 2.9% with placebo.

    “In 3 studies of 56-week duration involving persons with obesity and dyslipidemia or hypertension, weight loss ranged from 6.2% to 8.0% with 3 mg liraglutide vs 0.2% to 2.9% with placebo.754–756”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [755]

    The Discussion (page unavailable) reports weight loss with 3.0 mg/day liraglutide after 56 weeks. It does not report three studies in people with obesity and dyslipidemia or hypertension, or the claimed 6.2%–8.0% and 0.2%–2.9% weight-loss ranges. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In STEP 4 and SURMOUNT 4, continuing semaglutide or tirzepatide was associated with additional weight loss and stopping was associated with weight regain and recidivism of health benefits.

    “For both semaglutide and tirzepatide, continuing the drug was associated with additional weight loss and stopping was associated with weight regain and recidivism of health benefits.”

    From New drugs for the treatment of obesity: do we need approaches to preserve muscle mass? (2025) · cites this paper as [23]

    The STEP 4 Discussion reports further weight loss with continued semaglutide and weight regain after switching to placebo. The Confirmatory and Supportive Secondary End Points section also reports worsening waist circumference and systolic blood pressure after the switch, consistent with loss of some health benefits. This paper studies semaglutide, not tirzepatide or SURMOUNT-4, so it cannot support the claim about both drugs. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Authors
Rubino, D., Abrahamsson, N., Davies, M., Hesse, D., Greenway, F. L., Jensen, C., Lingvay, I., Mosenzon, O., Rosenstock, J., Rubio, M. A., Rudofsky, G., Tadayon, S., Wadden, T. A., Dicker, D., STEP 4 Investigators, Friberg, M., Sjödin, A., Dicker, D., Segal, G., Mosenzon, O., Sabbah, M., Sofer, Y., Vishlitzky, V., Meesters, E. W., Serlie, M., van Bon, A., Cardoso, H., Freitas, P., Carneiro de Melo, P., Monteiro, M., Monteiro, M., Rodrigues, D., Badat, A., Joshi, P., Latiff, G., Mitha, E. A., Snyman, H. H., van Nieuwenhuizen, E., González Albarrán, O., Caixas, A., de al Cuesta, C., Garcia Luna, P. P., Morales Portillo, C., Mezquita Raya, P., Rubio, M. A., Abrahamsson, N., Hoffstedt, J., von Wowern, F., Uddman, E., Bach-Kliegel, B., Beuschlein, F., Bilz, S., Golay, A., Rudofsky, G., Strey, C., Fadieienko, G., Kosei, N., Tatarchuk, T., Velychko, V., Zinych, O., Aronoff, S. L., Bays, H. E., Brockmyre, A. P., Call, R. S., Crump, C., Desouza, C. V., Espinosa, V., Free, A. L., Gandy, W. H., Geller, S. A., Gottschlich, G. M., Greenway, F. L., Han-Conrad, L., Harper, W., Herman, L., Hewitt, M., Hollander, P., Kaster, S. R., Manessis, A., Martin, F. A., McNeill, R. E., Murray, A. V., Norwood, P. C., Reed, J. C. H., Rosenstock, J., Rubino, D. M., Schear, M. J., & Warren, M. L.
Affiliations
  • Washington Center for Weight Management and Research (US)
  • University of Leicester (GB)
  • Novo Nordisk (Denmark) (DK)
  • The University of Texas Southwestern Medical Center (US)
  • Universidad Complutense de Madrid (ES)
  • University of Pennsylvania (US)
  • for the STEP 4 Investigators
Corresponding author
Rubino, Domenica
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2021-04-13
Volume
325
Issue
14
Pages
1414
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2021.3224
PMC
PMC7988425
OpenAlex
W3138431202
Cited by
1,444
References
39
Citations by year
2026: 393 · 2025: 376 · 2024: 271 · 2023: 187 · 2022: 141 · 2021: 69 · 2020: 1
FWCI
97.49
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • Figshare (submittedVersion)
Funders
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Sanofi
  • University of Pennsylvania
  • Regeneron Pharmaceuticals
  • Hadassah Medical Organization
  • Jazz Pharmaceuticals
  • Intarcia Therapeutics
  • MannKind Corporation
  • Mylan
  • Novo Nordisk
  • Genentech
  • National Institute of General Medical Sciences (U54GM104940)
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
semaglutide, weight loss maintenance, obesity, overweight, GLP-1 receptor agonists, treatment withdrawal, lifestyle intervention, body weight, waist circumference, blood pressure, physical function, SF-36, body mass index, weight-related comorbidities, dose escalation, sustained weight loss, weight regain prevention, antipsychotic-induced weight gain
MeSH terms
Semaglutide, Adult, Blood Pressure, Double-Blind Method, Glucagon-Like Peptides, Female, Humans, Injections, Subcutaneous, Male, Middle Aged, Obesity, Weight Loss, Anti-Obesity Agents, Overweight, Glucagon-Like Peptide 1, Waist Circumference

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-30.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-30.

Statistics and arithmetic are recomputed, not judged.

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