A design note on withdrawal trials, and why the run-in matters

The Journal has read all three of the relevant reports in full, and the most striking feature of the coverage they generated is how much of it treated the results as a scandal rather than as an answer. That a treatment for a chronic condition stops working when it is stopped is not a finding about the treatment. It is a finding about the condition, and it places these drugs in the same category as antihypertensives, statins and inhaled corticosteroids, none of which anybody expects to work after they are discontinued.

What a randomised withdrawal design does

A randomised withdrawal design begins with an open-label lead-in during which all participants receive the active drug and escalate to a target dose. Those who tolerate it and complete the lead-in are then randomised, usually two to one or one to one, to continue the drug or to receive matching placebo, and both arms are followed for a defined period with weight as the primary endpoint.

The design has two properties worth naming. Because randomisation occurs after the response, it isolates the effect of continuing from the effect of having lost weight, which a conventional parallel-group trial cannot do. And because the population has been selected for tolerating the drug, the withdrawal arm is not a general population — it is an enriched one, which makes the arm comparison internally valid and limits how far the absolute figures generalise.

Regulators favour the design for chronic-use products precisely because it answers the duration question. Its cost is ethical rather than statistical: participants who have achieved a substantial benefit are randomised to lose it, which is defensible only where the question is genuinely open and the follow-up is bounded. The Journal notes that all three withdrawal designs in this class published their regain data in full, which is more than can be said for several older obesity programmes.

The STEP 1 extension: two-thirds back within a year

The pivotal semaglutide obesity trial ran for sixty-eight weeks with a mean weight reduction of approximately 14.9 per cent on 2.4 mg weekly against 2.4 per cent on placebo.¹ An extension followed a subset of participants for a further fifty-two weeks after both the drug and the lifestyle intervention were withdrawn, which makes it an off-treatment observation rather than a randomised withdrawal.

By week 120 — a year after stopping — participants who had received semaglutide had regained approximately two-thirds of the weight they had lost, finishing on average around 5.6 per cent below their original baseline against approximately 0.1 per cent for the former placebo group.² Improvements in glycaemic parameters, blood pressure and lipids reverted broadly in step with the weight.

Two details are consistently dropped from summaries. The residual benefit was real: a mean 5.6 per cent reduction sustained a year after stopping is not nothing, and it is more than most non-pharmacological interventions achieve while they are still being delivered. And the lifestyle support was withdrawn at the same time as the drug, so the extension describes the removal of an entire intervention package rather than of a molecule.

STEP 4: the randomised switch to placebo

STEP 4 is the cleanest test of continuation in the semaglutide programme. All participants took semaglutide through a twenty-week escalation to 2.4 mg weekly, achieving a mean reduction of approximately 10.6 per cent. They were then randomised two to one to continue semaglutide or to switch to placebo for a further forty-eight weeks, with lifestyle support maintained in both arms.³

Those who continued lost a further 7.9 per cent, reaching roughly 17.4 per cent below their original baseline at week 68. Those switched to placebo regained approximately 6.9 per cent, ending near 5 per cent below baseline. The between-group difference of about fifteen percentage points is the effect of continuing treatment for a year, measured in a population that had already demonstrated a response.

The design detail that matters most is that lifestyle support continued in the placebo arm. This is not a comparison of drug against nothing; it is a comparison of drug plus support against support alone, in people who had lost weight on the drug. The regain observed is therefore what happens with the behavioural intervention still running, which makes it a more conservative estimate of the drug contribution rather than a less one.

SURMOUNT-4 and the steeper curve

SURMOUNT-4 applied the same architecture to tirzepatide with a longer lead-in. Participants escalated over thirty-six weeks of open-label treatment to their maximum tolerated dose of 10 or 15 mg weekly, achieving a mean reduction of approximately 20.9 per cent, and were then randomised one to one to continue or to switch to placebo for fifty-two weeks.⁴

Continuation produced a further mean reduction of about 5.5 per cent, for a total near 25.3 per cent at week 88. Withdrawal produced a mean regain of about 14 per cent of body weight, leaving that arm approximately 9.9 per cent below original baseline. The between-arm difference of roughly fifteen percentage points is similar in magnitude to STEP 4 despite the much larger initial loss.

The steeper regain in absolute terms is the expected consequence of a larger loss rather than evidence of anything peculiar to the agent. It is nonetheless the figure most often quoted without its denominator, and a fourteen-point regain from a twenty-one-point loss is a materially different statement from a fourteen-point regain from a ten-point loss. Both arms in this trial ended below where they began, and the arm that stopped ended roughly where the continued arm of the semaglutide programme did.

What the three designs agree on

The parent programmes establish the losses from which the withdrawal arms fall: approximately 14.9 per cent at sixty-eight weeks for semaglutide 2.4 mg in adults without diabetes, approximately 20.9 per cent at seventy-two weeks for tirzepatide 15 mg, and — the only continuous two-year comparator anybody has — approximately 15.2 per cent sustained at week 104 with treatment maintained throughout.⁵⁶

Read together, the withdrawal evidence supports four statements and does not support a fifth. Regain begins promptly after cessation, within weeks rather than months. It proceeds at a decelerating rate, with the steepest portion in the first three to six months. It does not, within twelve months of follow-up, return participants fully to their original baseline; residual reductions of roughly five to ten per cent persist at one year in all three datasets. And continued treatment maintains and usually extends the loss, with the extension diminishing as the plateau is approached.

The statement not supported is that the drugs cause weight regain, or that stopping leaves a person worse off than never having started. Nothing in these datasets shows overshoot above the original baseline at a group level. Every arm that stopped remained below where it began at the end of follow-up.

The Journal makes this point repeatedly because the contrary claim circulates widely and is often accompanied by a mechanistic story about metabolic damage. The withdrawal trials are the direct test of that claim and they do not support it. What they do support is the unremarkable proposition that a treatment for a chronic condition works while it is being taken.

When the indication is not weight

The withdrawal question changes shape when the drug was prescribed for something other than weight. In the cardiovascular outcome trial of semaglutide in overweight and obesity without diabetes, the reduction in major adverse cardiovascular events emerged over years of continued treatment, and the trial provides no information about what happens to that benefit on cessation.⁷ The same applies to the renal outcome data in chronic kidney disease with type 2 diabetes, where the effect on kidney disease progression was measured over a median of several years of treatment.⁸

There is no reason to expect an outcome benefit that accrues over years to persist after the exposure ends, and no trial has tested it. For a person taking the drug for glycaemic control, stopping has an immediate and measurable consequence in HbA1c over the following three months. For a person taking it for cardiovascular or renal risk, stopping has no measurable short-term consequence at all, which makes the decision harder rather than easier.

This is the situation in which the Journal thinks the withdrawal-trial coverage has done the most damage. Framing discontinuation as a weight question invites a person taking the drug for kidney disease to reason about it in the wrong currency entirely.

The first six weeks after the last injection

Exposure falls on a predictable schedule. A week after a final weekly injection roughly half the steady-state concentration remains; at two weeks a quarter; at four weeks a few per cent. Appetite returns along a curve that lags the concentration curve somewhat, and delayed gastric emptying resolves over a similar interval, so the sensation of early fullness that has been governing meal size for months disappears over about a month.

What people report, and the Journal reports it as report rather than as measurement, is that the appetite return is experienced as abrupt rather than gradual — as a threshold being crossed somewhere in the third or fourth week rather than as a smooth ramp. That is consistent with a non-linear relationship between receptor occupancy and the perceived effect, which is what the dose-response data would predict, and it is not consistent with the exposure curve alone.

Glycaemic parameters follow their own timescale. Fasting glucose responds within days to weeks; HbA1c, which reflects the preceding three months with the recent weeks weighted most heavily, will not show the full consequence of stopping for a full quarter. A panel drawn four weeks after cessation will understate the change, and this is a specific and common misreading. In the trial population with type 2 diabetes, where glycaemic control was a co-primary concern, the treatment effect on HbA1c was of the order of one and a half percentage points, which is the scale of what a cessation eventually undoes.⁹

Restarting after a long gap: what to expect

Restarting after months away is well tolerated in general and the response is broadly reproducible: people who lost weight on an agent and stopped generally lose weight again on resuming, at a similar rate. There is no established phenomenon of a diminished second response in this class, and the withdrawal trials that re-offered treatment after their observation periods did not report one.

Three practical features recur. Escalation has to start again from a low dose for tolerability reasons, which means several weeks before the previous maintenance exposure is re-established. The nausea of a second escalation is frequently reported as worse than the first, for which the Journal has seen no mechanistic explanation and would not rule out reporting bias. And the weight trajectory on restarting begins from wherever the person now is, so a second course is a longer project than the first if regain was substantial.

None of this constitutes advice about whether to restart, which is a clinical decision. It is offered as a description of what the trial reports and the correspondence describe, and readers should note that no trial has been designed to study re-initiation as its primary question.

The lifestyle intervention is a confound in both directions

Every trial in this class delivers a behavioural intervention alongside the drug: energy-restriction targets, activity targets, and regular contact with a study team. That contact is itself an intervention of measurable effect, which is why placebo arms in these programmes lose two to three per cent of body weight rather than nothing. Where the behavioural component was deliberately intensified, the placebo arm lost around 5.7 per cent over sixty-eight weeks, which is a useful upper bound on what contact and counselling alone achieved in these populations.¹⁰

It matters for the withdrawal question in a way that is usually elided. The semaglutide off-treatment extension withdrew the drug and the lifestyle support together, so its regain figure describes the removal of a package.² The STEP 4 and SURMOUNT-4 withdrawal arms kept the lifestyle component running, so their regain figures describe the removal of a molecule with support maintained.³⁴ Those are different experiments and the second is the more conservative.

Anybody comparing regain figures across the three should therefore expect the extension to look worse, and it does. The Journal states which withdrawal design a figure comes from every time it quotes one, because the alternative is pooling two different experiments into a single number that describes neither. The same caution applies to the frequent comparison with dietary weight-loss regain, where the behavioural intervention is the whole of the treatment.

How the Journal reports a regain figure

Four things accompany every regain number in these pages. Which withdrawal design it comes from, because an off-treatment extension and a randomised placebo switch are different experiments. Whether the lifestyle intervention continued in the arm being described. What the denominator is — regain as a percentage of body weight, as a percentage of the weight lost, or as a final position relative to original baseline, three quantities that are routinely quoted interchangeably. And the follow-up duration, because the regain curve decelerates and a figure at six months is not a figure at a year.

The third of those is where most of the misreporting happens. A statement that participants regained two-thirds is a proportion of loss; a statement that they regained eleven per cent is a proportion of body weight; a statement that they finished 5.6 per cent below baseline is a final position. All three can describe the same arm and they are not interchangeable.

Where a source we are quoting has not stated its denominator, we say that rather than inferring it. Readers who find a regain figure in these pages without its design and its denominator have found an error, and the standards desk would like to hear about it at standards@compoundjournal.com.

What this piece is not

This is reporting on a body of trial evidence and it is not advice about whether or how to stop taking a medicine. The decision to discontinue an agent prescribed for glycaemic control, cardiovascular risk or kidney disease is materially different from the decision to discontinue one prescribed for weight, and in every case it belongs with a clinician who has seen the person and knows why the drug was started.

Two further notes. Compounds sold for research use only are not approved for human use in any jurisdiction, and nothing here should be read as guidance about using them or about stopping their use. And where this piece describes what clinicians report doing about maintenance dosing, that is description of practice and not a schedule anybody should adopt from a magazine.

The Journal takes correspondence on this subject at letters@compoundjournal.com and factual challenges at standards@compoundjournal.com. Letters describing a personal experience of stopping are read with attention and are published, where they are published, as accounts rather than as evidence — a distinction this department tries hard to preserve in both directions.

The Journal will keep pressing the maintenance question, because it is answerable, cheap to answer, and unanswered for reasons that are commercial rather than scientific. A dose-reduction trial in this class would cost a small fraction of a pivotal programme and would change the treatment of millions of people. Its absence is the single most conspicuous gap in the literature this department covers.