Trial summary

STEP 4: what happens when semaglutide stops

By David Chen·Editor

Every other trial on this site measures what the drug does while it is being taken. This one measured what happens when it is not — and it is the trial most relevant to a price, because a price is a monthly commitment.

Participants

803 randomized

Duration

68 weeks

Comparator

A switch to placebo after the run-in

Published

JAMA, 2021

Registration

NCT03548987

PubMed

PMID 33755728

Why this trial exists

A weight-loss result at 68 weeks answers a narrower question than most readers are asking. The question underneath “how much will I lose” is usually “and what happens if I stop” — because stopping is what a monthly bill eventually forces for a lot of people. STEP 4 is the trial designed to answer exactly that, by taking the drug away from people who were already responding to it.

Who was in the trial

Adults with a body mass index of at least 30 — or 27 with at least one weight-related comorbidity — and without diabetes, who had already reached the 2.4 mg maintenance dose during a 20-week run-in.

This is a selected group, and the selection is the point: everyone randomized had already tolerated semaglutide and climbed to the 2.4 mg maintenance dose during the run-in. 902 people entered that run-in and 803 of them — 89.0% — reached the dose and were randomized. The result below therefore describes people for whom the drug was already working, not people starting from scratch.

How it was run

Randomized, double-blind, 68-week phase 3a withdrawal study at 73 sites in 10 countries. After the run-in, participants were randomized 2:1 to 48 further weeks of semaglutide or a switch to placebo, plus lifestyle intervention in both groups.

Percent change in body weight from week 20 to week 68.

Note where the clock starts. The primary endpoint is measured from week 20 — the end of the run-in — not from the beginning. The 10.6% the average participant had already lost is the baseline the figures below move from, not part of them.

What it found

The two groups moved in opposite directions. Those who continued semaglutide lost a further 7.9% over the next 48 weeks; those switched to placebo regained 6.9%. The difference is -14.8 percentage points, with a 95% confidence interval of -16.0 to -13.5 and P<.001.

Waist circumference, systolic blood pressure and SF-36 physical functioning all improved with continued semaglutide relative to placebo — by 9.7 cm, 3.9 mm Hg and 2.5 points respectively, all with P<.001. 98.0% of participants completed the trial.

What it does not say

It does not say the regain continues to a starting weight, because the trial stopped at week 68. It does not describe people who stop after a shorter course, or who taper rather than switch abruptly, or who stop because they could not tolerate the drug — everyone here had already tolerated it. And it tested the approved product, not a compounded preparation.

What this means for a price

It changes what a monthly figure is measuring. If the result is held only while the drug is taken, then the honest comparison between two sellers is not one month against one month but a year against a year — which is why every price on this site is restated as a true calendar month first, and why the running total exists at all.

It also makes the sellers charging a large sum up front worth reading twice. A twelve-month prepayment and a trial showing regain after withdrawal are two halves of the same question, and what prepaying really costs works through the arithmetic.