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Cited by 1,114Pharmacology and Obesity TreatmentDiabetes Treatment and ManagementBariatric Surgery and Outcomes

Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial

Open access
Wadden, Thomas A., Bailey, Timothy S., Billings, Liana K., Davies, Melanie, Frias, Juan P., Koroleva, Anna, Lingvay, Ildiko, O’Neil, Patrick M. +5 more·2021·JAMA
DOI 10.1001/jama.2021.1831PMC PMC7905697
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Abstract

Importance: Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches. Objective: To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity. Design, Setting, and Participants: Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30). Interventions: Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks. Main Outcomes and Measures: The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight. Results: Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants. Conclusions and Relevance: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03611582.

Integrity signals

Registry

Crossref · 10.1001/jama.2021.1831

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

8 of 24 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Interpretationown data

    The addition of semaglutide to intensive behavioral therapy may help patients achieve more than the average 5% to 10% reduction in body weight typically produced by behavioral interventions at 6 to 12 months.

    “The present findings suggest that the addition of semaglutide to intensive behavioral therapy may help patients achieve more than the average 5% to 10% reduction in body weight typically produced by behavioral interventions at 6 to 12 months.1,21”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] 1. Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society. Circulation. 2014;129(25)(suppl 2):S102-S138. doi:10. 1161/01.cir.0000437739.71477.ee source
    • cites [21] 21. Webb VL, Wadden TA. Intensive lifestyle intervention for obesity: principles, practices, and results. Gastroenterology. 2017;152(7):1752-1764. doi:10.1053/j.gastro.2017.01.045 source
  • Findingown data

    At week 68, C-reactive protein levels had improved with semaglutide relative to placebo.

    “At week 68, levels of C-reactive protein and lipids had improved with semaglutide relative to placebo, with the exception of high-density lipoprotein cholesterol (Table 2 and eTable 1 in Supplement 1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    A higher proportion of participants in the semaglutide vs placebo group achieved weight loss of at least 10% of baseline weight (75.3% vs 27.0%; P < .001).

    “A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001).”
    Quote in the paperSubstantial claim
  • Findingown data

    A higher proportion of participants in the semaglutide vs placebo group achieved weight loss of at least 15% of baseline weight (55.8% vs 13.2%; P < .001).

    “A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001).”
    Quote in the paperSubstantial claim
  • Findingown data

    Semaglutide was associated with improvement vs placebo in diastolic blood pressure at week 68.

    “Semaglutide was associated with improvements vs placebo in BMI and diastolic blood pressure at week 68 (Table 2 and eTable 1 in Supplement 1).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 29
  • May combine two claims. 18
  • The quote only partly states this claim. 1

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

    Premisecitation

    Weight loss can be increased by an additional 3 to 5 percentage points by including a low-calorie (1000-1200 kcal/d) portion-controlled diet composed of liquid shakes, meal bars, and prepared meals.

    “Weight loss can be increased by an additional 3 to 5 percentage points by including a low-calorie (1000-1200 kcal/d) portion-controlled diet composed of liquid shakes, meal bars, and prepared meals.2,3”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [2] 2. Heymsfield SB, van Mierlo CA, van der Knaap HC, Heo M, Frier HI. Weight management using a meal replacement strategy: meta and pooling analysis from six studies. Int J Obes Relat Metab Disord. 2003;27(5):537-549. doi:10.1038/sj.ijo. 0802258 source
    • cites [3] 3. Wadden TA, Foster GD, Sarwer DB, et al. Dieting and the development of eating disorders in obese women: results of a randomized controlled trial. Am J Clin Nutr. 2004;80(3):560-568. doi:10.1093/ ajcn/80.3.560 source

      The weight-results passage (page unavailable) reports 12.1% weight loss in the meal-replacement group versus 7.8% with a conventional-food diet at week 20—an additional 4.3 percentage points in obese women. The Meal replacement section (page unavailable) describes a 1000 kcal/day plan of liquid servings and an evening meal, not a 1000–1200 kcal/day plan including meal bars; the difference in weight loss was no longer significant at week 40. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Once-daily liraglutide, 3.0 mg, added approximately 3 to 5 percentage points of additional weight loss to intensive behavioral therapy compared with behavioral therapy alone.

    “Once-daily liraglutide, 3.0 mg, a glucagon-like peptide 1 receptor agonist approved for weight management, added approximately 3 to 5 percentage points of additional weight loss to intensive behavioral therapy compared with behavioral therapy alone.9,10”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [9] 9. Wadden TA, Walsh OA, Berkowitz RI, et al. Intensive behavioral therapy for obesity combined with liraglutide 3.0 mg: a randomized controlled trial. Obesity (Silver Spring). 2019;27(1):75-86. doi: 10.1002/oby.22359 source
    • cites [10] 10. Wadden TA, Tronieri JS, Sugimoto D, et al. Liraglutide 3.0 mg and intensive behavioral therapy (IBT) for obesity in primary care: the SCALE IBT randomized controlled trial. Obesity (Silver Spring). 2020;28(3):529-536. doi:10.1002/oby.22726 source

  • May combine two claims.

    Premisecitation

    A 20-week clinical study of participants with obesity found that treatment with once-weekly semaglutide, 2.4 mg, compared with placebo reduced self-reported hunger and food cravings and decreased energy intake during an ad libitum lunch by 35%.

    “A 20-week clinical study of participants with obe-sity found that treatment with once-weekly semaglutide, 2.4 mg, compared with placebo reduced self-reported hunger and food cravings and decreased energy intake during an ad libitum lunch by 35%.27”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] 27. 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 source

  • May combine two claims.

    Premisecitation

    Larger-than-expected reductions in resting and nonresting energy expenditure that occur with weight loss (ie, metabolic adaptation), compensatory changes in other homeostatic regulators of body weight, and patients' behavioral fatigue in adhering to diet and activity recommendations may contribute to the 5% to 10% weight reduction plateau observed with behavioral therapy.

    “Larger-than-expected reductions in resting and nonresting energy expenditure that occur with weight loss (ie, metabolic adaptation), compensatory changes in other homeostatic regulators of body weight, and patients' behavioral fatigue in adhering to diet and activity recommendations may contribute to the 5% to 10% weight reduction plateau observed with behavioral therapy.[23][24][25]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [23] 23. 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
    • cites [24] 24. Heckman BW, Mathew AR, Carpenter MJ. Treatment burden and treatment fatigue as barriers to health. Curr Opin Psychol. 2015;5:31-36. doi:10. 1016/j.copsyc.2015.03.004 source

      The Chronic Disease and Health Behaviors section says treatment burden can reduce adherence to behavioral interventions, supporting the proposed role of behavioral fatigue. But Potential Applications says treatment fatigue had not been applied to obesity and does not link it to a 5%–10% weight-loss plateau. The paper does not address the sentence’s metabolic mechanisms, which appear alongside other citations. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [25] 25. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-1604. doi:10.1056/NEJMoa1105816 source

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

    Premisecitation

    Preclinical studies suggest that weight loss with semaglutide results from its effects on glucagon-like peptide 1 receptors that mediate direct and indirect effects on the brain areas involved in regulation of appetite, including in the hypothalamus and hindbrain, ultimately leading to reduced energy intake.

    “Preclinical studies suggest that weight loss with semaglutide results from its effects on glucagon-like peptide 1 receptors that mediate direct and indirect effects on the brain areas involved in regulation of appetite, including in the hypothalamus and hindbrain, ultimately leading to reduced energy intake.26”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] 26. 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

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

    Study design and conductcitation

    Two estimands were used to address different scientific questions.

    “Two estimands were used to address different scientific questions, as described elsewhere.17,18”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [17] 17. Food and Drug Administration. E9(R1) statistical principles for clinical trials: addendum: estimands and sensitivity analysis in clinical trials. Accessed October 22, 2020. https://www.fda.gov/media/ 108698/download

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

    • cites [18] 18. Wharton S, Astrup A, Endahl L, et al. Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data. Int J Obes (Lond). Published online January 18, 2021. doi: 10.1038/s41366-020-00733-x source

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

    Findingown data

    At week 68, the estimated change in pulse from baseline was 3.1/min for semaglutide vs 2.1/min for placebo (trial product estimand difference, 1.0/min [95% CI, -0.7 to 2.6]).

    “At week 68, the estimated change in pulse from baseline was 3.1/min for semaglutide vs 2.1/min for placebo (trial product estimand difference, 1.0/min [95% CI, -0.7 to 2.6]) (eTable 2 in Supplement 1).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: All randomized participants remained receiving randomized treatment for the duration of the trial and did not receive rescue intervention.

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

    Findingown data

    From baseline to week 68, the SF-36 physical component summary score improved similarly in both groups.

    “From baseline to week 68, SF-36 physical component summary score improved similarly in both groups, whereas the mental component summary score favored semaglutide (Table 2; eTable 1 and eFigure 7 in Supplement 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    At any given time during the study, the proportion of participants who experienced vomiting was less than 5% in both treatment groups.

    “At any given time during the study, the proportion of participants who experienced vomiting was less than 5% in both treatment groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proportion of participants experiencing nausea with semaglutide peaked at approximately 25% at week 20 and declined thereafter, remaining at approximately 15% for the duration of the study.

    “The proportion of participants experiencing nausea with semaglutide peaked at approximately 25% at week 20 and declined thereafter, remaining at approximately 15% for the duration of the study.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    No deaths were reported during the study.

    “No deaths were reported during the study.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Malignant neoplasms were reported in 3 semaglutide-treated participants (0.7%) and 1 placebo-treated participant (0.5%).

    “Malignant neoplasms were reported in 3 semaglutide-treated participants (0.7%; basal cell carcinoma, breast cancer, and papillary thyroid cancer) and 1 placebo-treated participant (0.5%; invasive lobular breast carcinoma).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were no cases of acute pancreatitis, medullary thyroid carcinoma, or pancreatic cancer in either group.

    “There were no cases of acute pancreatitis, medullary thyroid carcinoma, or pancreatic cancer in either group.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    At the follow-up visit at week 75 after the off-treatment period, mean pulse had neared the baseline level.

    “At the follow-up visit (week 75) after the offtreatment period, mean pulse had neared the baseline level.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    From baseline to week 68, the SF-36 mental component summary score favored semaglutide.

    “From baseline to week 68, SF-36 physical component summary score improved similarly in both groups, whereas the mental component summary score favored semaglutide (Table 2; eTable 1 and eFigure 7 in Supplement 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    More participants discontinued treatment due to adverse events in the semaglutide group (5.9%) than in the placebo group (2.9%), mainly because of gastrointestinal events.

    “More participants discontinued treatment due to adverse events in the semaglutide group (5.9%) compared with placebo (2.9%), mainly because of gastrointestinal events (Table 3).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    At week 68, the change in SF-36 physical functioning score was 2.4 for semaglutide and 1.6 for placebo, a difference of 0.8 (95% CI, -0.2 to 1.9; P=.12).

    “SF-36 physical functioning score d | 2.4 | 1.6 | 0.8 (-0.2 to 1.9) | | .12”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Gastrointestinal disorders leading to treatment discontinuation occurred in 3.4% of semaglutide-treated participants compared with 0% of placebo-treated participants.

    “Gastrointestinal disorders | 14 (3.4) | 20 | 3.8 | 0 | |”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At week 68, the change in SF-36 mental component summary score was -0.8 for semaglutide and -2.9 for placebo, a difference of 2.1 (95% CI, 0.5 to 3.6; P=.011).

    “Mental component summary score | -0.8 | -2.9 | 2.1 (0.5 to 3.6) | | .011”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    A sample size of 600 participants was calculated to provide power of 86% for the 7 end points in the hierarchic testing procedure, with greater than 99% power for the co-primary end points.

    “A sample size of 600 participants was calculated to provide power of 86% for the 7 end points in the hierarchic testing procedure, with greater than 99% power for the co-primary end points”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    STEP 3 was a 68-week, randomized, double-blind, placebo-controlled, multicenter study conducted at 41 sites in the US from August 2018 to April 2020.

    “STEP 3 was a 68-week, randomized, double-blind, placebocontrolled, multicenter study conducted at 41 sites in the US from August 2018 to April 2020.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Observed benefits of weight loss might have been larger if participants had been selected because of having elevated risk factors (eg, hypertension, hyperlipidemia), which they were not in the present study.

    “Observed benefits of weight loss might have been larger if participants had been selected because of having elevated risk factors (eg, hypertension, hyperlipidemia), which they were not in the present study.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Larger weight losses (eg, ≥10%) are desired because they produce greater improvements in several obesity-related cardiometabolic risk factors and diseases, including type 2 diabetes, hypertension, and sleep apnea.

    “Larger weight losses (eg, ≥10%) are desired because they produce greater improvements in several obesityrelated cardiometabolic risk factors and diseases, including type 2 diabetes, hypertension, and sleep apnea.[4][5][6][7][8]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4][5][6][7][8]

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

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

    Study design and conductown data

    Participants were randomized 2:1 with a blocking schema (block size of 9) via an interactive web-response system to once-weekly subcutaneous semaglutide, 2.4 mg, or visually identical placebo for 68 weeks.

    “Participants were randomized 2:1 with a blocking schema (block size of 9) via an interactive web-response system to onceweekly subcutaneous semaglutide, 2.4 mg, or visually identical placebo for 68 weeks”
    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 long-acting glucagon-like peptide 1 receptor agonist approved for the treatment of type 2 diabetes at once-weekly doses of up to 1.0 mg, which reduces body weight by approximately 6% by 1 year in these patients.

    “Subcutaneous semaglutide is a long-acting glucagon-like peptide 1 receptor agonist approved for the treatment of type 2 diabetes at once-weekly doses of up to 1.0 mg, 11 which reduces body weight by approximately 6% by 1 year in these patients.12,13”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] 11. Food and Drug Administration. Ozempic (semaglutide) injection, for subcutaneous use [prescribing information]. Accessed September 25, 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.

    • cites [12] 12. Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care. 2018;41(2): 258-266. doi:10.2337/dc17-0417 source
    • cites [13] 13. Ahrén B, Masmiquel L, Kumar H, et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5(5):341-354. doi:10.1016/S2213- 8587(17)30092-X source

  • May combine two claims.

    Interpretationreasoning

    The larger proportions of participants treated with semaglutide compared with placebo who achieved categorical weight losses of at least 10%, 15%, or 20% translated into greater improvements in waist circumference, blood pressure, glycated hemoglobin level, C-reactive protein level, and several lipid parameters.

    “The larger proportions of participants treated with semaglutide compared with placebo who achieved categorical weight losses of at least 10%, 15%, or 20% translated into greater improvements in waist circumference, blood pressure, glycated hemoglobin level, C-reactive protein level, and several lipid parameters.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Efficacy end points were analyzed with the full analysis set (all participants randomly assigned to a treatment group regardless of whether they initiated treatment), and adverse event end points were analyzed with the safety analysis set (all randomized participants exposed to at least 1 dose of randomized treatment).

    “Efficacy end points were analyzed with the full analysis set (ie, all participants randomly assigned to a treatment group regardless of whether they initiated treatment), and adverse event end points were analyzed with the safety analysis set (ie, all randomized participants exposed to at least 1 dose of randomized treatment).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The superiority of subcutaneous semaglutide to placebo for the primary and secondary confirmatory end points was assessed in hierarchic order, with superiority at a significance level of 5% required before testing of subsequent end points in the hierarchy.

    “The superiority of subcutaneous semaglutide to placebo for the primary and secondary confirmatory end points was assessed in hierarchic order, with superiority at a significance level of 5% required before testing of subsequent end points in the hierarchy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Overall, 567 participants (92.8%) completed the trial, and 505 (82.7%) completed the trial in the on-treatment period.

    “Overall, 567 participants (92.8%) completed the trial, and 505 (82.7%) completed the trial in the on-treatment period (Figure 1).”
    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

    In the semaglutide group, 12 participants were lost to follow-up by week 38, and in the placebo group, 5 were lost to follow-up by week 25.

    “In the semaglutide group, 12 were lost to follow-up by week 38, and in the placebo group, 5 were lost to follow-up by week 25.”
    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 was conducted according to consensus ethical principles derived from guidelines, including the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice Guideline, and applicable local laws and regulations.

    “The study was conducted according to consensus ethical principles derived from guidelines, including the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice Guideline, and applicable local laws and regulations.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Missing data were imputed with a multiple imputation approach; missing body weight measurements were imputed by sampling from available measurements at week 68 from participants receiving randomized treatment in the relevant randomized treatment group; missing values were multiply imputed (×1000).

    “Missing data were imputed with a multiple imputation approach, similar to that described by McEvoy.19 Missing body weight measurements were imputed by sampling from available measurements at week 68 from participants receiving randomized treatment in the relevant randomized treatment group.Missing values were multiply imputed (× 1000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 19. McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 2016;26(1): 30-36. doi:10.1080/10543406.2015.1094814 source

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

    Study design and conductnone given

    All participants provided written informed consent.

    “All participants provided written informed consent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the STEP 1 trial, semaglutide 2.4 mg resulted in a 14.9% reduction in baseline body weight at 68 weeks, compared with 2.4% for placebo, both with the same less-intensive lifestyle intervention.

    “Participants in STEP 1 lost 14.9% of baseline weight with semaglutide at 68 weeks, compared with 2.4% for placebo plus the same lifestyle intervention.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] 31. Wilding JPH, Batterham RL, Calanna S, et al; the STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. Published February 10, 2021. doi:10.1056/ NEJMoa2032183

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The primary hierarchic statistical analyses were based on the treatment policy estimand (similar to an intention-to-treat analysis), which quantified the average treatment effect among all randomized participants, regardless of adherence to treatment or initiation of rescue interventions.

    “The primary hierarchic statistical analyses were based on the treatment policy es-timand (similar to an intention-to-treat analysis), which quantified the average treatment effect among all randomized participants, regardless of adherence to treatment or initiation of rescue interventions (ie, antiobesity medications or bariatric surgery).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The trial was relatively brief and did not address whether semaglutide-treated participants would sustain their 16% weight reduction if they continued to receive the medication past 68 weeks.

    “Second, this was a relatively brief trial, which did not address whether semaglutide-treated participants would sustain their 16% weight reduction if they continued to receive the medication past 68 weeks.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The proportion of participants permanently discontinuing trial product was similar between treatment groups (semaglutide, 16.7%; placebo, 18.6%).

    “The proportion of participants permanently discontinuing trial product was similar between treatment groups (semaglutide, 16.7%; placebo, 18.6%) (eFigure 2 in Supplement 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The trial could not identify the separate contributions to weight loss of intensive behavioral therapy and the initial low-calorie diet in the placebo group, nor determine the relative benefit of combining either of these enhanced interventions with semaglutide.

    “First, it could not identify the separate contributions to weight loss of intensive behavioral therapy and the initial low-calorie diet in the placebo group or, as previously indicated, determine the relative benefit of combining either of these enhanced interventions with semaglutide.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The protocol and amendments were approved by institutional review boards or independent ethics committees at each study site.

    “The protocol and amendments (available in Supplement 2) were approved by institutional review boards or independent ethics committees at each study site.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    A total of 5.6% of participants were lost to follow-up.

    “A total of 5.6% of participants were lost to follow-up.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Selected adverse events (eg, cardiovascular events, acute pancreatitis) and deaths were reviewed by an independent external event adjudication committee.

    “Selected adverse events (eg, cardiovascular events, acute pancreatitis) and deaths were reviewed by an independent external event adjudication committee.”
    Quote in the paperNot a substantial claim
41 of 41

  • The authors state this as an assumption.

    All randomized participants remained receiving randomized treatment for the duration of the trial and did not receive rescue intervention.

    “The trial product estimand quantified the average treatment effect in all randomized participants, assuming they remained receiving randomized treatment for the duration of the trial (and without rescue intervention).”

  • The paper relies on this without support.

    The STEP 1 and STEP 3 trial populations and lifestyle interventions are sufficiently comparable to allow an indirect comparison of weight loss outcomes.

    “These findings suggest that the inclusion of intensive behavioral therapy plus an 8-week low-calorie diet ultimately may not contribute significant additional weight loss beyond that achieved by semaglutide and less-intensive lifestyle intervention.”
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?

  • 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 [754]

    The Abstract describes one 68-week trial of semaglutide 2.4 mg versus placebo, not three 56-week liraglutide trials. It reports weight changes of −16.0% and −5.7%, respectively, rather than the claimed ranges. The Introduction mentions liraglutide but does not report the claimed results. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In the SURMOUNT-3 trial, individuals who received tirzepatide after a comprehensive 12-week lifestyle intervention achieved a mean 25% weight reduction, compared to 4.8% in the placebo group.

    “In the SURMOUNT‐3 trial, individuals who received tirzepatide after a comprehensive 12‐week lifestyle intervention achieved a mean 25% weight reduction, compared to 4.8% in the placebo group [178]”

    From Nutritional priorities to support <scp>GLP</scp> ‐1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society (2025) · cites this paper as [178]

    The Abstract (page not supplied) identifies this as the STEP 3 trial of semaglutide, not SURMOUNT-3 or a tirzepatide trial. It reports an initial 8-week low-calorie diet and mean weight changes at week 68 of −16.0% with semaglutide versus −5.7% with placebo, rather than 25% versus 4.8%. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In the SURMOUNT 3 trial, tirzepatide 10 or 15 mg/week started after 12 weeks of intensive lifestyle intervention produced a 25% reduction from baseline (vs. 4.8% with intensive lifestyle intervention alone).

    “whereas in the SURMOUNT 3 trial, tirzepatide 10 or 15 mg/week started after 12 weeks of intensive lifestyle intervention produced a 25% reduction from baseline (vs. 4.8% with intensive lifestyle intervention alone) [178].”

    From Nutritional priorities to support <scp>GLP</scp> ‐1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society (2025) · cites this paper as [178]

    The Abstract identifies this as the STEP 3 trial of semaglutide 2.4 mg versus placebo, both alongside intensive behavioral therapy and an initial low-calorie diet. It reports mean weight changes of −16.0% versus −5.7% at week 68, not the claimed SURMOUNT 3 tirzepatide comparison or 25% versus 4.8%. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In clinical trials of liraglutide 3 mg, the incidence of cholelithiasis was greater than with placebo.

    “In clinical trials of liraglutide 3 mg, the incidence of cholelithiasis was greater than placebo.741,754”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [754]

    Table 3 (Adverse Events; page unavailable) reports more cholelithiasis with semaglutide 2.4 mg than with placebo (3.2% vs 1.0%). The paper mentions liraglutide 3 mg in its introduction, but the cited comparison is for semaglutide, not liraglutide; it therefore does not support the claim about liraglutide trials. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Intensive lifestyle interventions may provide small additional weight loss benefit to the new obesity pharmacotherapies.

    “As the new obesity pharmacotherapies will lead up to 15–25% mean WL, intensive lifestyle interventions may provide small additional WL benefit to these treatments [11, 106].”

    From What is the pipeline for future medications for obesity? (2025) · cites this paper as [106]

    The discussion (section labeled Adverse Events; page unavailable) compares semaglutide results with a less-intensive lifestyle program and suggests that adding intensive behavioral therapy and a low-calorie diet may not yield significant additional weight loss. This is consistent with at most a small possible benefit, but the paper does not establish that benefit or extend the finding to new obesity pharmacotherapies generally. The Limitations section says the trial could not determine the relative benefit of those added interventions. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

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

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

  • Lost-to-follow-up percentage conflicts with participant flow

    Minor

    The participant-flow figure lists 18 semaglutide and 7 placebo participants lost to follow-up. That is 25 of 611 randomized participants, or 4.1%, not 5.6%.

1 of 1

Cites

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Authors
Wadden, T. A., Bailey, T. S., Billings, L. K., Davies, M., Frias, J. P., Koroleva, A., Lingvay, I., O’Neil, P. M., Rubino, D. M., Skovgaard, D., Wallenstein, S. O. R., Garvey, W. T., & STEP 3 Investigators
Affiliations
  • University of Pennsylvania (US)
  • AMCR Institute (US)
  • Endeavor Health (US)
  • University of Leicester (GB)
  • National Research Institute, Los Angeles, California
  • Novo Nordisk (Denmark) (DK)
  • The University of Texas Southwestern Medical Center (US)
  • Weight Management Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston
  • Washington Center for Weight Management and Research (US)
  • University of Alabama at Birmingham (US)
Corresponding author
Wadden, Thomas A.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2021-04-13
Volume
325
Issue
14
Pages
1403
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2021.1831
PMC
PMC7905697
OpenAlex
W3129305070
Cited by
1,114
References
33
Citations by year
2026: 237 · 2025: 287 · 2024: 222 · 2023: 147 · 2022: 132 · 2021: 85
FWCI
85.54
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079626)
Topics
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
Keywords
semaglutide, obesity, overweight, weight loss, hypocaloric diet, GLP-1 receptor agonists, pharmacotherapy, adjunctive therapy, comorbid obesity, cardiometabolic risk factors, weight regain after weight loss
MeSH terms
Semaglutide, Adult, Combined Modality Therapy, Diet, Reducing, Double-Blind Method, Glucagon-Like Peptides, Female, Humans, Injections, Subcutaneous, Male, Middle Aged, Obesity, Weight Loss, Cognitive Behavioral Therapy, Anti-Obesity Agents, Overweight, Glucagon-Like Peptide 1

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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

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