Stopping a GLP-1: what happened in the trials that stopped it on purpose
Four randomized trials have withdrawn a GLP-1 on purpose and watched what happened. The clearest number comes from the STEP 1 extension: participants who had lost 17.3% of their weight over 68 weeks regained 11.6 percentage points of it in the year after the drug and the lifestyle program both stopped, finishing 5.6% below where they started. That's roughly two-thirds of the loss coming back, and the trial's own authors say so.
What this comes down to
- STEP 1 extension, 327 participants: 17.3% lost by week 68, 11.6 percentage points regained by week 120, a net 5.6% against 0.1% for placebo. Cardiometabolic improvements reverted toward baseline.
- STEP 4, 803 randomized after a 20-week run-in: continuing semaglutide produced a further -7.9% while switching to placebo produced +6.9%, a 14.8-point gap.
- SURMOUNT-4, 670 randomized after a 36-week lead-in: -5.5% continuing tirzepatide against +14.0% on placebo, and 89.5% versus 16.6% keeping at least 80% of the weight they had lost.
- SURMOUNT-MAINTAIN, published June 2026, tested a middle option: dropping to 5 mg held -16.6% at week 112 against -21.9% on the maximum tolerated dose and -9.9% on placebo.
STEP 1 extension: stop everything, wait a year
STEP 1 randomized 1,961 adults to 68 weeks of semaglutide 2.4 mg or placebo alongside a lifestyle intervention, and reported a mean weight change of -14.9% against -2.4%[1]. At week 68 everything stopped — the drug and the lifestyle program both — and an off-treatment extension followed 327 of the completers for another year.
In that subset, weight loss to week 68 had been 17.3% on semaglutide and 2.0% on placebo. By week 120, semaglutide participants had regained 11.6 percentage points and placebo participants 1.9, leaving net losses of 5.6% and 0.1% from baseline[2]. The cardiometabolic improvements seen to week 68 reverted toward baseline for most variables. The authors' conclusion is that the findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain the improvements.
The three trials that randomized the stopping
An extension watches what people do. A randomized withdrawal trial assigns it, which is a stronger design, and it's the reason these three carry more weight than the first.
| Trial | Design | Continuing | Switched to placebo |
|---|---|---|---|
| STEP 4, semaglutide | 803 randomized 2:1 after a 20-week run-in; weeks 20 to 68 | -7.9% | +6.9% |
| SURMOUNT-4, tirzepatide | 670 randomized 1:1 after a 36-week lead-in; weeks 36 to 88 | -5.5% | +14.0% |
| SURMOUNT-MAINTAIN, tirzepatide | 378 randomized 3:3:2 after a 60-week lead-in; change from baseline to week 112 | -21.9% at maximum tolerated dose, -16.6% at 5 mg | -9.9% |
Randomized withdrawal and maintenance trials of GLP-1 drugs, as reported in each paper
STEP 4 randomized 803 people who had reached the 2.4 mg maintenance dose during a 20-week run-in, in which they lost a mean 10.6%. Over the next 48 weeks, continuing produced a further -7.9% and switching to placebo produced +6.9%, a difference of 14.8 percentage points[3]. Waist circumference, systolic blood pressure and physical functioning scores all favored continuing.
SURMOUNT-4 ran a 36-week open-label lead-in during which 783 people lost a mean 20.9%, then randomized 670 of them to continue tirzepatide or switch to placebo for 52 weeks. From week 36 to week 88, weight changed -5.5% on tirzepatide and +14.0% on placebo, a 19.4-point difference, and 89.5% of the tirzepatide group kept at least 80% of their lead-in loss against 16.6% on placebo[4].
The newest trial asked whether there is a middle option
SURMOUNT-MAINTAIN, published in June 2026, is the first of these to test something other than all or nothing. After a 60-week open-label weight-loss period at the maximum tolerated dose, 378 adults were randomized 3:3:2 to continue at that dose, drop to 5 mg, or switch to placebo for 52 more weeks[5]. At week 112, change from baseline was -21.9% at the maximum tolerated dose, -16.6% at 5 mg and -9.9% on placebo, with all three comparisons at p below 0.0001.
The rescue numbers are the ones that make the shape of it obvious. Participants could receive rescue tirzepatide from week 84 if they regained more than half of what they had lost. Eleven of 138 at the maximum tolerated dose needed it, 35 of 142 at 5 mg, and 60 of 90 on placebo. The trial's own interpretation is that reducing to 5 mg might provide a valuable alternative to discontinuation, with the caveat that individual response varies.
The 5 mg arm above is a licensed strength of an approved product, reached after 60 weeks at a higher one, inside a randomized trial with rescue therapy available. That's a different thing from a compounded program sold as a microdose from the start, which hasn't been tested this way. The distinction is drawn out in the microdosing article.
PubMed, via the E-utilities API
(semaglutide[tiab] OR tirzepatide[tiab]) AND ("randomized withdrawal"[tiab] OR "randomised withdrawal"[tiab] OR "weight maintenance"[tiab] OR "maintenance of weight"[tiab] OR "bodyweight reduction"[tiab]) AND "randomized controlled trial"[pt] AND "humans"[mh]Returned 12. Positive control — semaglutide or tirzepatide, identical filter with no maintenance term — returned 413 through the identical filter in the same session.
Twelve of 413. The four described on this page are the ones designed around stopping or maintaining; the rest of the twelve match the filter through a phrase in a title rather than through that design. This is a well-answered question by the standards of this field, which is unusual and worth saying.
What this does to the price you are comparing
Every one of these trials points the same way: the effect lasts while the drug does. That turns a GLP-1 from a course of treatment into a subscription, and it means the number that matters isn't the first month but the twelfth. A first-month rate that renews higher is a different product from the one advertised, which is a pattern worth recognizing, and a membership fee that recurs beside the medication is its own charge. The calculator exists to hold those apart, because the sellers' own pages generally don't.
None of them reports what the regained weight was made of. The body-composition work that exists was done during weight loss, not during regain, which leaves an obvious question unanswered — and it is the question people ask most often about stopping. What was measured on the way down is in the lean mass article.
The trials also stopped the drug abruptly by design, which is what a trial has to do and not necessarily what happens in practice. Anything about tapering belongs to a prescriber; we can only report that no randomized trial in this set tested one. The reactions that make people want to stop in the first place are tabulated in the side-effect article, and what has been tested against the commonest of them is in the nausea article.
Questions people actually ask
How much weight do you regain after stopping semaglutide?
In the STEP 1 extension, 327 participants who had lost 17.3% of their weight regained 11.6 percentage points in the year after the drug and the lifestyle program both stopped, finishing 5.6% below baseline. In STEP 4, people switched to placebo gained 6.9% over the following 48 weeks while those who continued lost a further 7.9%.
Do you have to take a GLP-1 forever?
That's a decision for a patient and a prescriber, and nobody here holds a medical license. What the trials show is that the weight and the cardiometabolic improvements both move back toward baseline when the drug stops, and that the trials' own authors describe ongoing treatment as required to maintain those improvements.
Does a lower dose work for maintenance?
SURMOUNT-MAINTAIN is the first randomized test of that. Dropping to 5 mg held a 16.6% reduction from baseline at week 112 against 21.9% at the maximum tolerated dose and 9.9% on placebo, and 25% of the 5 mg group needed rescue therapy for regain against 8% at the higher dose and 67% on placebo.
Is the regained weight the same as the weight you lost?
None of the four withdrawal trials measured the composition of the regained weight. The body-composition substudies that exist were run during weight loss rather than during regain, so the honest answer is that it hasn't been measured in these trials either way.
Sources
Every source here was fetched and read for this article, with the identifier taken off the record that came back and the claim it supports written down beside it. All of it was read in September 2026, the same session the rest of this page draws on.
- 1.Once-Weekly Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine, 2021. PMID 33567185 · doi:10.1056/NEJMoa2032183The 68-week parent trial: 1,961 adults randomized 2:1 to semaglutide 2.4 mg or placebo plus a lifestyle intervention, with a mean body weight change of -14.9% against -2.4%, an estimated treatment difference of -12.4 percentage points.
- 2.Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, Obesity and Metabolism, 2022. PMID 35441470 · doi:10.1111/dom.14725The off-treatment extension of 327 STEP 1 completers: mean weight loss of 17.3% on semaglutide and 2.0% on placebo to week 68; regain of 11.6 and 1.9 percentage points by week 120; net losses of 5.6% and 0.1% from week 0; cardiometabolic improvements reverting toward baseline; and the authors' conclusion that ongoing treatment is required to maintain improvements.
- 3.Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA, 2021. PMID 33755728 · doi:10.1001/jama.2021.3224803 participants randomized 2:1 after a 20-week run-in in which they lost a mean 10.6%; body weight change from week 20 to week 68 of -7.9% with continued semaglutide against +6.9% on placebo, a difference of 14.8 percentage points; and improvements in waist circumference, systolic blood pressure and physical functioning favoring continuation.
- 4.Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA, 2024. PMID 38078870 · doi:10.1001/jama.2023.24945A 36-week open-label lead-in producing a mean 20.9% weight reduction in 783 participants, 670 of whom were randomized 1:1 for 52 weeks; mean percent weight change from week 36 to week 88 of -5.5% with tirzepatide against +14.0% with placebo, a difference of -19.4 percentage points; 89.5% against 16.6% maintaining at least 80% of the lead-in weight loss; and overall reductions from week 0 to 88 of 25.3% and 9.9%.
- 5.Tirzepatide for maintenance of bodyweight reduction in people with obesity in the USA (SURMOUNT-MAINTAIN): a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet, 2026. PMID 42119587 · doi:10.1016/S0140-6736(26)00656-2A 112-week phase 3b trial with a 60-week open-label weight-loss period and a 52-week double-blind maintenance period; 378 participants randomized 3:3:2 to continue at the maximum tolerated dose, reduce to 5 mg, or switch to placebo; model-based percent change in bodyweight from baseline to week 112 of -21.9%, -16.6% and -9.9% respectively, all p below 0.0001; rescue tirzepatide available from week 84 for regain above 50% and received by 11 of 138, 35 of 142 and 60 of 90 participants; and the interpretation that reducing to 5 mg might provide an alternative to discontinuation.
Key figures