Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.
Level 2 - randomized trial
Randomized, double-blind, placebo-controlled trial
PubMed 33755728 · doi:10.1001/jama.2021.3224
What was done
A randomized, double-blind, 68-week phase 3a withdrawal trial (STEP 4) conducted across 73 sites in 10 countries evaluated semaglutide for weight maintenance. Adults with overweight or obesity (BMI ≥30, or ≥27 with ≥1 weight-related comorbidity) without diabetes underwent a 20-week open-label run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. The 803 participants who reached the target maintenance dose were randomized 2:1 to 48 weeks of continued subcutaneous semaglutide 2.4 mg weekly (n=535) or switch to placebo (n=268), both combined with lifestyle intervention. The primary endpoint was percent change in body weight from week 20 to week 68.
What was found
Participants lost a mean of 10.6% body weight during the 20-week run-in. From week 20 to 68, continued semaglutide led to an additional mean weight change of -7.9% versus +6.9% with switch to placebo (difference: -14.8 percentage points [95% CI, -16.0 to -13.5]; P < .001). Continued semaglutide also showed greater improvements in waist circumference (difference: -9.7 cm [95% CI, -10.9 to -8.5]), systolic blood pressure (difference: -3.9 mm Hg [95% CI, -5.8 to -2.0]), and SF-36 physical functioning score (difference: 2.5 [95% CI, 1.6 to 3.3]; all P < .001). Gastrointestinal adverse events occurred in 49.1% with semaglutide versus 26.1% with placebo, though discontinuation rates due to adverse events were similar (2.4% vs 2.2%).
Why it matters
This trial demonstrates that chronic treatment with semaglutide is required to sustain weight loss; discontinuation results in rapid weight regain despite ongoing lifestyle intervention.
Limits
The randomized withdrawal design selectively enrolled responders who successfully tolerated titration to 2.4 mg/week during run-in (89.0% of initial cohort), limiting applicability to non-responders or those intolerant to dose escalation. The study population was predominantly female (79%) and excluded individuals with diabetes.