Reading the incretin obesity trials: estimands, comparators and what happens after stopping

STEP 1 (semaglutide) and SURMOUNT-1 (tirzepatide) are the trials most often cited in metabolism threads. They are large, placebo-controlled and published in full, which makes them good material for practising careful reading. This thread is about how to read them, not about doses or use.

• Design: STEP 1 randomised 1,961 adults over 68 weeks; SURMOUNT-1 randomised 2,539 adults over 72 weeks. Both arms in each trial received lifestyle intervention, so the comparison is drug plus lifestyle versus placebo plus lifestyle.
• Estimands: each paper reports an effect "regardless of adherence" (treatment-policy or treatment-regimen) and an effect "if everyone stayed on treatment". The second is larger. Say which one you are quoting.
• Population: participants had obesity or overweight with a weight-related condition, and the trials excluded several groups. Check the eligibility criteria before generalising.
• Adverse events and discontinuation: read the safety tables, not just the abstract; gastrointestinal events were the most common reason for stopping.
• After stopping: the STEP 1 extension followed participants after treatment ended and found that most of the lost weight, around two thirds, was regained within a year.

Reply with a specific figure or table from one of these papers and what you think it does or does not show.

Sources

1. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989–1002. doi:10.1056/NEJMoa2032183
2. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205–216. doi:10.1056/NEJMoa2206038
3. Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 2022;24(8):1553–1564. doi:10.1111/dom.14725