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

STEP 4 is the maintenance-design counterpart to STEP 1 and the cleanest randomized evidence on what happens when semaglutide stops. The trial enrolled 902 adults with overweight or obesity who first underwent a 20-week open-label run-in on semaglutide 2.4 mg weekly with lifestyle intervention; 803 participants who completed the run-in (achieving a mean 10.6% body-weight reduction) were then re-randomized 2:1 to continue semaglutide or switch to placebo for 48 additional weeks. From week 20 to week 68, the continued-semaglutide arm lost an additional 7.9% of body weight, while the switched-to-placebo arm regained 6.9% — a 14.8-percentage-point difference. Approximately 40% of participants on continued semaglutide reached a cumulative ≥20% body-weight loss across the full 68-week period, magnitudes previously confined to bariatric-surgery cohorts. Cardiometabolic markers (waist circumference, lipids, blood pressure, glycemic measures) tracked the weight pattern: improvements maintained on semaglutide, reversal toward baseline on placebo. The trial design is the regulatory-grade evidence behind the FDA's approach to chronic weight management as a chronic indication.

The randomization happens at week 20, not at baseline — meaning the trial reports a maintenance comparison among completers rather than an intention-to-treat comparison from the start of treatment. Participants who could not tolerate the run-in are not represented in the maintenance analysis, which biases the comparison toward the tolerable-population effect. The 48-week maintenance window is long for an obesity trial but short relative to the chronic-therapy framing of GLP-1 indications; the question of how the trajectory looks beyond two years is partially addressed by STEP 5 (two-year data) but not by this trial. The 6.9% regain in the placebo arm is consistent with the 11.6-point regain observed in the STEP 1 extension (Wilding et al. 2022), which followed participants for a full year off-treatment rather than 48 weeks; together the two papers anchor the discontinuation-rebound conversation. Industry sponsorship by Novo Nordisk is disclosed.