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Original Investigation
February 24, 2021

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

Author Affiliations
  • 1Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 2AMCR Institute, Escondido, California
  • 3Department of Medicine, NorthShore University HealthSystem/University of Chicago Pritzker School of Medicine, Skokie, Illinois
  • 4Diabetes Research Centre, University of Leicester, Leicester, United Kingdom
  • 5NIHR Leicester Biomedical Research Centre, Leicester General Hospital, Leicester, United Kingdom
  • 6National Research Institute, Los Angeles, California
  • 7Novo Nordisk A/S, Søborg, Denmark
  • 8Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas
  • 9Weight Management Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston
  • 10Washington Center for Weight Management and Research, Arlington, Virginia
  • 11Department of Nutrition Sciences, University of Alabama at Birmingham
JAMA. 2021;325(14):1403-1413. doi:10.1001/jama.2021.1831
Visual Abstract. Semaglutide Plus Intensive Behavioral Therapy and Weight Loss in Overweight Adults
Semaglutide Plus Intensive Behavioral Therapy and Weight Loss in Overweight Adults
Audio Clinical Review (43:35)
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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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