STEP-4 (withdrawal trial)

STEP 4 answered the question every patient eventually asks: what happens if I stop? It is a withdrawal trial, and its design is the point. All 902 participants started on semaglutide and spent 20 weeks titrating up to 2.4 mg weekly. The 803 who reached that maintenance dose — having already lost an average of 10.6% of their body weight during the run-in — were then randomly assigned, two to one, either to keep taking semaglutide or to switch to placebo for 48 more weeks. Both groups kept the lifestyle program.

The split was stark. From week 20 to week 68, the group that continued lost a further 7.9% of body weight. The group switched to placebo gained 6.9% back — a 14.8-percentage-point gap. Waist circumference, systolic blood pressure and self-reported physical functioning all moved in the same direction. Rubino and colleagues published it in JAMA in April 2021.

In practical terms: a person who weighed 107 kg at randomization and had already dropped about 11 kg during the run-in would, on average, lose roughly another 8 kg by staying on the drug, or regain roughly 7 kg by stopping. The lifestyle program alone did not hold the loss.

That is why clinicians describe obesity pharmacotherapy as chronic treatment rather than a course you finish. The common confusion is reading regain as personal failure. It is the expected physiology: appetite signaling returns to its pre-treatment setting once the drug clears, and the body defends its former weight. Nothing about the regain says the patient did something wrong.

Worth asking your clinician: what the plan is if coverage lapses or supply runs short, whether a lower maintenance dose is an option instead of stopping outright, and what a realistic taper looks like if you do need to come off. Our STEP 4 deep dive covers the design in detail, STEP 1 covers the initial weight-loss trial, and the titration planner maps the dose ladder you would be restarting.