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

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 &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 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