September 2, 2026 · 2 min read

Semaglutide: what the STEP 1 trial and its follow-ups reported

A research overview of semaglutide 2.4 mg, the GLP-1 receptor agonist, based on the STEP 1 randomized trial and later work on maintenance and withdrawal.

Semaglutide is a long-acting analogue of glucagon-like peptide 1 (GLP-1), the incretin hormone that signals fullness and helps coordinate insulin release. At a dose of 2.4 mg once weekly it has been studied for weight management in the STEP program of phase 3 trials. STEP 1 is the one most people mean when they cite a headline number.

STEP 1

STEP 1 enrolled 1,961 adults with a body-mass index of 30 or higher, or 27 or higher with at least one weight-related condition, and without diabetes. They were randomized 2:1 to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg or placebo, with lifestyle intervention in both groups. Mean weight change was -14.9% on semaglutide and -2.4% on placebo, a difference of 12.4 percentage points. In absolute terms that was -15.3 kg against -2.6 kg.

Mean body-weight change at week 68

Placebo-2.4%
Semaglutide 2.4 mg-14.9%

Primary estimand (effects regardless of treatment discontinuation) in STEP 1, 1,961 adults without diabetes (Wilding et al., N Engl J Med 2021).

How many people reached each target

Responder rates tell the same story in a different way. At 68 weeks, 86.4% of the semaglutide group had lost 5% or more, 69.1% had lost 10% or more and 50.5% had lost 15% or more. In the placebo group those figures were 31.5%, 12.0% and 4.9%.

Participants reaching each weight-loss target at week 68

Placebo
Semaglutide 2.4 mg

5% or more

31.5% Placebo
86.4% Semaglutide 2.4 mg

10% or more

12% Placebo
69.1% Semaglutide 2.4 mg

15% or more

4.9% Placebo
50.5% Semaglutide 2.4 mg

Share of participants with a weight reduction of at least the stated percentage in STEP 1 (Wilding et al., N Engl J Med 2021).

What happens after

Two follow-up papers address the question of what comes next. The STEP 1 extension examined weight regain and cardiometabolic effects after withdrawal of semaglutide, and its title makes the finding plain: weight returned after stopping. STEP 4 was designed differently, randomizing people who had already been on semaglutide to continue it or switch to placebo, to test weight loss maintenance.

Both are good illustrations of a general point in obesity pharmacology. A weight change measured on drug and a change that lasts after drug are different outcomes, and trials need to measure both.