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

Washington Center for Weight Management, Arlington, Virginia. Endocrinology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Diabetes Research Centre, University of Leicester, Leicester, England. NIHR Leicester Biomedical Research Centre, Leicester General Hospital, Leicester, England. Novo Nordisk A/S, Søborg, Denmark. Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge. Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas. Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. Dallas Diabetes Research Center at Medical City, Dallas, Texas. Department 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. Department of Endocrinology and Metabolic Diseases, Kantonsspital Olten, Olten, Switzerland. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Internal Medicine Department and Obesity Clinic, Hasharon Hospital-Rabin Medical Center, Petach-Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

JAMA. 2021;(14):1414-1425
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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.

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