STEP 4 trial finds stopping weekly semaglutide leads to weight regain

Adults with overweight or obesity who kept taking weekly semaglutide 2.4 mg after reaching the maintenance dose continued to lose weight, while those switched to a placebo regained it, according to the STEP 4 randomized withdrawal trial published in JAMA ^[1][2].

The trial was built to answer a question the drug's earlier studies had not: what happens when treatment stops. It enrolled 902 adults without diabetes at 73 sites in 10 countries between June 2018 and March 2020. Everyone received weekly injections of semaglutide during a 20-week run-in — 16 weeks of dose escalation plus 4 weeks at the 2.4 mg maintenance dose — and averaged a 10.6% loss of body weight by the end of that period ^[2].

Of those, 803 participants (89.0%) reached the 2.4 mg dose and were randomly assigned 2:1 either to continue semaglutide (535 people) or to switch to placebo (268 people) for 48 more weeks. Both groups continued a lifestyle intervention ^[2]. Participants averaged 46 years old, 79% were women, and mean body weight at randomization was 107.2 kg. To qualify, people needed a body mass index of at least 30, or at least 27 with one or more weight-related conditions ^[2].

From week 20 to week 68, the continued-semaglutide group lost an additional 7.9% of body weight, while the placebo group gained 6.9%, a difference of 14.8 percentage points (95% CI, −16.0 to −13.5; P < .001) ^[2]. The regain in the placebo group amounted to roughly two-thirds of the weight those participants had lost during the run-in.

The three confirmatory secondary measures split the same way. Waist circumference fell 9.7 cm more with continued semaglutide (95% CI, −10.9 to −8.5 cm), systolic blood pressure was 3.9 mm Hg lower (95% CI, −5.8 to −2.0 mm Hg), and scores on a physical-functioning questionnaire were 2.5 points higher (95% CI, 1.6 to 3.3), with all results significant at P < .001 ^[2].

Gastrointestinal events were reported by 49.1% of participants who continued semaglutide versus 26.1% of those on placebo. Discontinuation because of adverse events was similar in the two groups: 2.4% with continued semaglutide and 2.2% with placebo. Overall, 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment ^[2].

Why it matters for patients

The trial addresses a practical question that comes up when people consider stopping a GLP-1 medication: whether the weight loss holds. In this study, it did not hold for the group that stopped. People who switched to placebo regained weight on average, and their waist circumference, systolic blood pressure and self-reported physical functioning moved in the less favorable direction along with it. The people who stayed on the drug continued losing weight during the same 48 weeks ^[2].

Two features of the design are worth noting. Everyone in the trial received lifestyle support in addition to their assigned treatment, so the difference between groups reflects the drug rather than a difference in diet or activity counseling ^[2]. And the study enrolled adults with overweight or obesity but without diabetes, so the results may not describe people with type 2 diabetes ^[2].

What the trial does not answer is what happens after week 68. Whether weight regain levels off over longer periods, what occurs if treatment is restarted, and how these results apply to other GLP-1 or dual-agonist medications have not been established by this study ^[2]. The trial is registered as NCT03548987 ^[2].