A year after stopping semaglutide 2.4 mg, the 327 participants followed in the STEP 1 trial extension had regained 11.6 of the 17.3 percentage points they had lost, leaving them 5.6% below where they started (PMID 35441470). That is two thirds of the loss coming back inside twelve months.
The sharper test is SURMOUNT-4, because it randomised the withdrawal rather than observing it. After 36 weeks on the maximum tolerated tirzepatide dose, during which 670 adults lost a mean of 20.9%, half continued and half switched to placebo. Over the next 52 weeks the continuing group lost a further 5.5%. The placebo group gained 14.0% (PMID 38078870).
- STEP 1 extension: 17.3% lost by week 68, 11.6 percentage points regained by week 120, net 5.6% below baseline.
- SURMOUNT-4: continuing tirzepatide produced a further 5.5% loss over 52 weeks while switching to placebo produced a 14.0% gain.
- STEP 4 switched people to placebo while keeping the lifestyle programme running, and they still gained 6.9% over 48 weeks against a 7.9% further loss on continued semaglutide.
- Cardiometabolic improvements moved back toward baseline alongside the weight in the STEP 1 extension.
- No trial has tested tapering, and none of these trials measured whether regained weight comes back as fat or lean tissue.
Three trials, three ways of asking the question
These are not three versions of one result. They differ in what was withdrawn, from whom, and for how long, and the differences matter when reading the numbers.
| Trial | Design | What stopped | Result after withdrawal |
|---|---|---|---|
| STEP 1 extension (PMID 35441470) | Observational follow up of 327 completers, exploratory analyses only | Semaglutide 2.4 mg and the lifestyle programme | Regained 11.6 points of 17.3 over 52 weeks, net 5.6% below baseline |
| STEP 4 (PMID 33755728) | Randomised withdrawal, 803 adults after a 20 week run in to 2.4 mg | Semaglutide only, lifestyle programme continued | Placebo group gained 6.9% over 48 weeks while the continued group lost a further 7.9% |
| SURMOUNT-4 (PMID 38078870) | Randomised withdrawal, 670 adults after 36 weeks on 10 mg or 15 mg tirzepatide | Tirzepatide only, diet and activity continued | Placebo group gained 14.0% over 52 weeks while the continued group lost a further 5.5% |
STEP 1 extension: the real world shape
STEP 1 randomised 1961 adults with overweight or obesity and no diabetes to semaglutide 2.4 mg or placebo for 68 weeks (PMID 33567185). At week 68 everything stopped, including the lifestyle support, and a subset from Canada, Germany, the UK and selected US and Japanese sites was followed for another year.
This is the closest any of the three comes to what happens when someone simply comes off treatment, because the diet and activity programme ended too. It is also the weakest statistically: the extension analyses were all exploratory, the subset was 327 of the original 1961, and the spread was wide, with a standard deviation of 7.7 percentage points on that 11.6 point regain. Averages here hide people who kept most of their loss and people who went past their starting weight.
STEP 4: the drug alone, with support still in place
STEP 4 ran a 20 week open run in, escalating 902 adults to semaglutide 2.4 mg. The 803 who reached the maintenance dose, having lost a mean 10.6% by then, were randomised to continue or to switch to placebo for 48 more weeks, with the lifestyle intervention kept running in both arms.
The continued group lost another 7.9%. The switched group gained 6.9%, a 14.8 percentage point gap. Waist circumference, systolic blood pressure and physical functioning all separated the same way. Since the only thing that changed was the drug, this is the cleanest demonstration that the lifestyle programme alone did not hold the weight.
SURMOUNT-4: the largest regain measured
SURMOUNT-4 used a 36 week open label lead in on the maximum tolerated tirzepatide dose, 10 mg or 15 mg, then randomised 670 adults to continue or switch to placebo for 52 weeks. The lead in produced a 20.9% mean reduction, which is a deeper starting point than either semaglutide trial, and the regain was correspondingly larger at 14.0%.
The maintenance figures put it most plainly. At week 88, 89.5% of those who continued tirzepatide had kept at least 80% of their lead in weight loss, against 16.6% of those on placebo. Across the full 88 weeks the continued group was 25.3% below baseline and the placebo group 9.9%.
Weight is not the only thing that comes back
The STEP 1 extension tracked cardiometabolic markers through the off treatment year and reported that the improvements seen to week 68 reverted toward baseline at week 120 for most variables. Blood pressure, lipids and glycaemic measures followed the weight rather than persisting as a lasting benefit of having lost it.
That finding is why the authors framed their conclusion around the chronicity of obesity and the need for ongoing treatment to maintain improvements, rather than around willpower after discontinuation.
Stopped working and stopped taking are different questions
People search for both in the same words, so it is worth separating them. Nothing in these trials shows these drugs losing their effect over time while they are being taken. The continued arms kept losing: a further 7.9% over 48 weeks in STEP 4 after the run in, and a further 5.5% over 52 weeks in SURMOUNT-4 after an already large 36 week reduction.
What does happen is that the curve flattens. Most of the loss in these trials lands in the first year while the dose is escalating and the deficit is new, and the rate slows afterwards even on an unchanged dose. A flattening curve reads like the drug has stopped working, and in the trial data it is the normal shape of a continuing response.
Phentermine, which shows up in the same searches, is a genuinely different case. Its label indicates it only as a short term adjunct of a few weeks and says in its own indications section that the limited usefulness of agents of this class should be weighed against the risks of using them. There is no tolerance curve in that label to quote, but the labelled duration answers the question in a way no GLP-1 label does.
What these trials do not tell you
Three gaps are worth naming, because the confident answers circulating online are not coming from this evidence.
- Tapering. All three trials stopped the drug or switched to placebo outright. None tested a gradual reduction, so there is no trial basis for claiming a taper changes the regain curve.
- Who regains fastest. The standard deviations are wide and none of these analyses identified predictors of regain that would let an individual estimate their own trajectory.
- What the regained weight is made of. These trials measured body weight, not body composition, during withdrawal. Whether the kilograms that return are distributed the way the ones that left were is not something they answer, and it matters, given that about a quarter of what comes off is lean mass.
For what the loss looks like on the way down rather than back up, the trial by trial figures for semaglutide are collected in how much weight you can lose on Wegovy, and the GLP-1 weight loss calculator will run those same trial percentages against your own starting weight.
FAQ
Do you regain weight after stopping a GLP-1?
In every trial that has tested it, yes, on average. STEP 1 extension participants regained 11.6 of 17.3 percentage points in the year after stopping semaglutide 2.4 mg. SURMOUNT-4 participants switched to placebo gained 14.0% over 52 weeks, while those who continued tirzepatide lost a further 5.5%.
How fast does the weight come back?
The STEP 1 extension measured at a single point, one year after treatment ended, so it gives an endpoint rather than a curve. SURMOUNT-4 recorded a 14.0% mean gain over 52 weeks on placebo. Neither published a month by month regain rate.
Does keeping up the diet and exercise prevent regain?
It did not prevent it in STEP 4 or SURMOUNT-4, where the lifestyle programme continued in both arms and the placebo groups still gained 6.9% and 14.0% respectively. The STEP 1 extension, in which the lifestyle support also stopped, produced a similar picture.
Does semaglutide stop working after a while?
The trials do not show a loss of effect during treatment. Participants who continued semaglutide in STEP 4 lost a further 7.9% over 48 weeks after an initial 10.6%, and the tirzepatide equivalent in SURMOUNT-4 lost a further 5.5%. What flattens is the rate of loss, not the response.
How long can you take phentermine before it stops working?
Its label does not frame it as a long term treatment at all: phentermine is indicated as a short term adjunct of a few weeks, and the label states that the limited usefulness of this class should be weighed against the risks. No tolerance timeline is published in it.
Is it better to taper off than to stop outright?
No trial has tested that. STEP 1, STEP 4 and SURMOUNT-4 all stopped the drug or substituted placebo, so any claim about tapering changing the outcome is going beyond the evidence that exists.
Sources
- 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. PMID: 35441470
- Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. *JAMA*. 2024;331(1):38-48. PMID: 38078870
- Rubino D, Abrahamsson N, Davies M, et al. 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;325(14):1414-1425. PMID: 33755728
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). *N Engl J Med*. 2021;384(11):989-1002. PMID: 33567185
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). *N Engl J Med*. 2022;387(3):205-216. PMID: 35658024
- Phentermine hydrochloride tablets prescribing information, sections 1 Indications and Usage and 6 Adverse Reactions, via DailyMed.
This article is for information only and is not medical advice. Dosing, suitability and any change to treatment are decisions for your prescriber.