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Original Investigation
March 23, 2021

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

Author Affiliations
  • 1Washington Center for Weight Management, Arlington, Virginia
  • 2Endocrinology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • 3Diabetes Research Centre, University of Leicester, Leicester, England
  • 4NIHR Leicester Biomedical Research Centre, Leicester General Hospital, Leicester, England
  • 5Novo Nordisk A/S, Søborg, Denmark
  • 6Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge
  • 7Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas
  • 8Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
  • 9Dallas Diabetes Research Center at Medical City, Dallas, Texas
  • 10Department of Endocrinology and Nutrition, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Faculty of Medicine, Universidad Complutense, Madrid, Spain
  • 11Department of Endocrinology and Metabolic Diseases, Kantonsspital Olten, Olten, Switzerland
  • 12Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 13Internal Medicine Department and Obesity Clinic, Hasharon Hospital–Rabin Medical Center, Petach-Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
JAMA. 2021;325(14):1414-1425. doi:10.1001/jama.2021.3224
Visual Abstract. Effect of Continued Semaglutide Treatment vs Placebo on Weight Loss Maintenance in Overweight or Obesity
Effect of Continued Semaglutide Treatment vs Placebo on Weight Loss Maintenance in Overweight or Obesity
Audio Clinical Review (43:35)
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Key Points

Question  What effect does continued treatment with 2.4 mg of subcutaneous semaglutide have on the maintenance of body weight loss in adults with overweight or obesity without diabetes?

Findings  In this randomized clinical trial of adults with overweight or obesity, 803 participants completed a 20-week run-in of weekly treatment with subcutaneous semaglutide, 2.4 mg, with a mean weight loss of 10.6%, and were randomized to continued treatment with subcutaneous semaglutide vs placebo for an additional 48 weeks. At the end of this time, mean weight change was −7.9% vs +6.9%, respectively, a difference that was statistically significant.

Meaning  Among adults with overweight or obesity completing a 20-week run-in period, maintaining treatment with subcutaneous semaglutide compared with switching to placebo resulted in continued weight loss.

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

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