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

Educational Objective
To learn whether semaglutide may be effective for weight management in patients with obesity.
1 Credit CME
Key Points

Question  In adults with overweight or obesity without diabetes, what effect does once-weekly subcutaneous semaglutide, 2.4 mg, have on body weight when added to intensive behavioral therapy with an initial low-calorie diet?

Findings  In this randomized clinical trial that included 611 adults with overweight or obesity, 68 weeks’ treatment with once-weekly subcutaneous semaglutide vs placebo, combined with intensive behavioral therapy (and a low-calorie diet for the initial 8 weeks), resulted in reductions in body weight of 16.0% vs 5.7%, respectively; the difference was statistically significant.

Meaning  When used as an adjunct to intensive behavioral therapy and initial low-calorie diet, once-weekly subcutaneous semaglutide produced significantly greater weight loss than placebo during 68 weeks in adults with overweight or obesity.

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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Thomas A. Wadden, PhD, Perelman School of Medicine at the University of Pennsylvania, 3535 Market St, Ste 3027, Philadelphia, PA 19104 (wadden@pennmedicine.upenn.edu).

Accepted for Publication: February 4, 2021.

Published Online: February 24, 2021. doi:10.1001/jama.2021.1831

Author Contributions: Drs Wadden and Garvey had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors had access to the trial results, and reviewed and approved the final version of the manuscript for publication.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wadden, Billings, Koroleva, O'Neil, Rubino, Skovgaard, Garvey.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Skovgaard, Wallenstein.

Administrative, technical, or material support: Wadden, Rubino, Skovgaard.

Supervision: Wadden, Bailey, Koroleva, Skovgaard.

Conflict of Interest Disclosures: Dr Wadden reports receiving grants from Novo Nordisk (from grant support to the University of Pennsylvania) and personal fees from Novo Nordisk for service on a scientific advisory board during the conduct of the study, as well as personal fees from WW International (formerly Weight Watchers) for service on a scientific advisory board outside the submitted work. Dr Bailey reports receiving grants, personal fees, and nonfinancial support (writing assistance) from Novo Nordisk during the conduct of the study. Dr Billings reports receiving personal fees from Novo Nordisk, Sanofi, and Eli Lilly outside the submitted work. Dr Davies is co-funded by the NIHR Leicester Biomedical Research Centre and reports receiving consulting fees from Novo Nordisk; advisory board member, speaker, and consulting fees from Sanofi-Aventis, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Janssen; advisory board fees from Lexicon, Servier, and Gilead Sciences Ltd; speaker fees from Napp Pharmaceuticals; and grants from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca, and Janssen outside the submitted work. Dr Frias reports receiving research support grants from Novo Nordisk during the conduct of the study; grants and personal fees from Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Sanofi; and grants from Janssen and Pfizer outside the submitted work. Dr Koroleva reports being an employee of Novo Nordisk A/S and holding shares in the company. Dr Lingvay reports receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly and Company, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind Corporation, Target Pharma, Valeritas, and Zealand Pharma; advisory board fees from Boehringer Ingelheim and Sanofi US Services; grant support, paid to UT Southwestern, from Merck; grant support, paid to her institution, from Mylan Pharmaceuticals and Pfizer; grant support, paid to UT Southwestern; and advisory board fees, consulting fees, and travel support from Novo Nordisk. Dr O'Neil reports receiving grants from Novo Nordisk during the conduct of the study; grants from Epitomee Medical, Eli Lilly, and WW International; and personal fees from Robard, Gedeon Richter, WebMD, and Novo Nordisk outside the submitted work. Dr Rubino reports receiving writing assistance from Novo Nordisk during the conduct of the study; serving as a clinical investigator for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and reports owning Novo Nordisk shares of stock outside the submitted work. Dr Skovgaard reports spousal employment at Novo Nordisk. Dr Wallenstein reports receiving personal fees from Novo Nordisk during the conduct of the study and outside the submitted work. Dr Garvey reports receiving grants from Novo Nordisk; serving as site principal investigator for the clinical trial, which was sponsored by his university during the conduct of the study; receiving grants from Lexicon and Pfizer outside the submitted work; and serving as an ad hoc consultant on advisory committees for Jazz Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, and Pfizer. In each instance, he received no financial compensation, nor was there a financial relationship. No other disclosures were reported.

Funding/Support: This trial was funded by Novo Nordisk A/S.

Role of the Funders/Sponsors: Representatives of the sponsor (Novo Nordisk A/S) were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Data were gathered by the site investigators, and the sponsor performed study site oversight, data collation, and analysis. A medical writer (Nicola Beadle, PhD, of Axis, a division of Spirit Medical Communications Group Ltd, funded by the sponsor) assisted with drafting the manuscript, under the direction of the authors. The sponsor did not have the right to veto publication or to control the decision regarding to which journal the manuscript was submitted. These decisions resided with the authors.

Group Information: A list of the STEP 3 Investigators appears in eAppendix 1 in Supplement 1.

Meeting Presentation: Presented at the 38th annual meeting of the Obesity Society, November 5, 2020.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank all participants, investigators, and trial staff who were involved in the conduct of the trial, as well as Jena Tronieri, PhD, at the Perelman School of Medicine at the University of Pennsylvania, who was compensated by Novo Nordisk to supervise the delivery of intensive behavioral therapy by registered dietitians at the study sites. We also thank Lisa von Huth Smith, PhD (an employee of Novo Nordisk A/S) for review of and input to aspects related to patient-reported outcomes in the manuscript.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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