People who stopped semaglutide after 20 weeks regained most of their lost weight, while those who continued lost even more — a 14.8 percentage point difference.
14.8 percentage point differenceContinuing semaglutide vs stopping produced a 14.8 percentage point difference in body weight change over 48 weeks — the clearest evidence that stopping means regaining
What the researchers found
After an initial 20-week period where all participants lost an average of 10.6% body weight on semaglutide 2.4 mg, those who continued semaglutide lost an additional 7.9% body weight over 48 more weeks, while those switched to placebo regained 6.9%. The net difference was a staggering 14.8 percentage points between continuing and stopping the drug.
Beyond weight, continuing semaglutide also produced significant improvements in waist circumference (-9.7 cm vs placebo), systolic blood pressure (-3.9 mmHg vs placebo), and physical functioning scores. By the end of the full 68-week period, people who stayed on semaglutide had lost a total of approximately 17.4% of their starting body weight.
Gastrointestinal side effects occurred in 49.1% of those continuing semaglutide vs 26.1% on placebo, but dropout rates due to adverse events were similar (2.4% vs 2.2%). Study completion was remarkably high at 98%.
Why it matters
This is one of the most important studies in the semaglutide weight loss program because it definitively answers the question: what happens when you stop? The answer is clear — weight comes back. This has major implications for how patients and doctors approach GLP-1 therapy, confirming that semaglutide for obesity is likely a long-term or lifelong treatment rather than a short-term intervention. It also demonstrates that continuing treatment produces ongoing benefits beyond just weight loss.
The numbers in context
n=803 randomized · 10.6% weight loss in run-in · -7.9% continued vs +6.9% placebo (weeks 20-68) · 14.8 percentage point difference · p<0.001 · -9.7 cm waist difference · -3.9 mmHg systolic BP · 98% trial completion · 73 sites, 10 countries
How the study worked
This was a randomized, double-blind, phase 3a withdrawal trial (STEP 4) conducted at 73 sites in 10 countries. All 902 participants first received semaglutide 2.4 mg weekly for 20 weeks (16 weeks dose escalation + 4 weeks maintenance). Then 803 participants who reached the maintenance dose were randomized 2:1 to either continue semaglutide (n=535) or switch to placebo (n=268) for 48 more weeks. Both groups received lifestyle intervention throughout. Primary endpoint was percent body weight change from week 20 to week 68.
Who was studied
803 adults with overweight or obesity (BMI ≥30, or ≥27 with comorbidities) without diabetes, across 73 sites in 10 countries; mean age 46, 79% women
What this study cannot tell us
The study excluded people with diabetes, so results may not fully apply to that population. The 20-week run-in means participants who couldn't tolerate semaglutide were already filtered out before randomization. The placebo group's weight regain demonstrates drug dependence for weight maintenance, raising questions about lifelong treatment costs and sustainability.
How to read the evidence
This is a strong-grade study: a phase 3a randomized, double-blind, placebo-controlled trial published in JAMA, conducted across 73 sites in 10 countries with 98% completion rate. The withdrawal design directly answers the clinically critical question of what happens when treatment stops.
When this study was published
Published in 2021, this was one of the four pivotal STEP trials that led to semaglutide 2.4 mg (Wegovy) approval for weight management. The findings remain highly relevant as millions of patients now face the question of whether to continue or stop GLP-1 therapy.
The bigger picture
STEP 4 was a pivotal study in reshaping how the medical community and public think about GLP-1 weight loss drugs. By showing that weight regain begins almost immediately after stopping semaglutide, it established that obesity treatment with these drugs requires ongoing use — similar to blood pressure or cholesterol medications. This finding has fueled the debate about long-term costs, insurance coverage, and whether lifelong injectable therapy is sustainable for the millions of people with obesity.
Questions still open
- Is there a lower maintenance dose of semaglutide that could prevent weight regain while reducing side effects and costs?
- Can lifestyle changes made during semaglutide treatment be enough to maintain some weight loss after stopping the drug?
- What are the effects of decades-long semaglutide use that a 68-week trial can't capture?
Common questions
How much weight do people regain after stopping semaglutide?
Does this mean semaglutide is a lifelong medication?
Read the original research
Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.
JAMA, 325(14), 1414-1425
Citation
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. (2021). Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.. JAMA, 325(14), 1414-1425. https://doi.org/10.1001/jama.2021.3224