Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity
Authors: Rubino Domenica , Abrahamsson Niclas , Davies Melanie , Hesse Dan , Greenway Frank L. , Jensen Camilla , Lingvay Ildiko , Mosenzon Ofri , Rosenstock Julio , Rubio Miguel A. , Rudofsky Gottfried , Tadayon Sayeh , Wadden Thomas A. , Dicker Dror ,   STEP 4 Investigators, Friberg Mette , Sjödin Anders , Dicker Dror , Segal Gabriella , Mosenzon Ofri , Sabbah Muhammad , Sofer Yael , Vishlitzky Victor , Meesters Eelco W. , Serlie Mirelle , van Bon Arianne , Cardoso Helena , Freitas Paula , Carneiro de Melo Pedro , Monteiro Margarida , Monteiro Mariana , Rodrigues Dírcea , Badat Aysha , Joshi Pankaj , Latiff Gulam , Mitha Essack A. , Snyman Hans H. , van Nieuwenhuizen Elane , González Albarrán Olga , Caixas Assumpta , de al Cuesta Carmen , Garcia Luna Pedro Pablo , Morales Portillo Cristobal , Mezquita Raya Pedro , Rubio Miguel Angel , Abrahamsson Niclas , Hoffstedt Johan , von Wowern Fredrik , Uddman Erik , Bach-Kliegel Birgit , Beuschlein Felix , Bilz Stefan , Golay Alain , Rudofsky Gottfried , Strey Christopher , Fadieienko Galyna , Kosei Nataliia , Tatarchuk Tetiana , Velychko Valentyna , Zinych Olesya , Aronoff Stephen L. , Bays Harold E. , Brockmyre Andrew P. , Call Robert S. , Crump Charles , Desouza Cyrus V. , Espinosa Valerie , Free Almena L. , Gandy Winston H. , Geller Steven A. , Gottschlich Gregory M. , Greenway Frank L. , Han-Conrad Laurie , Harper Wayne , Herman Lee , Hewitt Mitzie , Hollander Priscilla , Kaster Steven R. , Manessis Anastasios , Martin Frederick A. , McNeill Robert E. , Murray Alexander V. , Norwood Paul C. , Reed John C.H. , Rosenstock Julio , Rubino Domenica M. , Schear Martin J. , Warren Mark L. 
Published: March 2021

ImportanceThe 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.ObjectiveTo 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 ParticipantsRandomized, 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.InterventionsA 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 MeasuresThe 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]).ResultsAmong 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 &amp;lt; .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 &amp;lt; .001). Gastrointestinal events were reported in 41.9% 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT03548987