What SURPASS-3 tells us about maintenance, and what it does not

The Journal has asked several clinicians how they handle maintenance and received a consistent answer that is not in any guideline: reduce by one escalation step, hold for eight to twelve weeks, watch the weight, and go back up if it moves. That is defensible empiricism and it is not evidence. We report it as what is being done rather than as what is supported, and we note that the absence of a dose-reduction trial in a drug class of this commercial scale is a choice somebody made.

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.

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.¹

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.

The dose-reduction trial that has never been run

Set the three withdrawal trials side by side and a conspicuous absence appears. All three compared a full maintenance dose against placebo. None compared a full dose against a reduced one. The comparison that the great majority of successfully treated people actually face — can I take less of this and hold what I have — has not been randomised at any dose, in any programme, for any agent in this class.

The commercial explanation is straightforward and the Journal states it without much comment: a trial demonstrating that a third of the dose maintains most of the effect would reduce the revenue per treated patient by roughly the same fraction, and sponsors are not obliged to run trials against their own interest. The regulatory explanation is that maintenance dosing falls outside the approved label question, which is whether the product is effective at the studied dose.

The result is that an enormous amount of clinical practice is being conducted on inference. What can be inferred is that the dose-response curve for weight effect flattens at the top of the range, which suggests a step down would cost less than proportionally. Whether the curve is the same shape descending as ascending is unknown, and hysteresis in either direction would not be surprising.

It is worth noting what the one head-to-head weight trial in this class did and did not do. It compared two agents at their respective licensed doses and reported the difference in weight outcome; it did not establish dose equivalence between them, and it cannot be used to convert a maintenance dose of one into a maintenance dose of the other.² Pharmacies asked to substitute during the shortage period had no equivalence basis to work from, whatever the conversion tables in circulation implied.

What is actually being done, reported as practice

The Journal has asked clinicians in four jurisdictions how they manage maintenance and received a broadly consistent description that appears in no guideline. Reduce by one escalation step once the weight has been stable for a period; hold for eight to twelve weeks, which is long enough for the new exposure to reach steady state and for a trend to become visible; if the weight rises by more than a small threshold, return to the previous step. Some reduce again after a further stable interval; most do not go below the second step.

Two things recommend this approach and neither is evidence. It follows the pharmacokinetics, in that eight to twelve weeks is comfortably longer than the four to five weeks required to reach steady state at the new dose, so the observation is not being made on a still-changing exposure. And it is reversible, which a decision to stop is not in the same easy way.

The Journal reports this as description, not endorsement. It is not a dosing recommendation, no trial supports it, and the appropriate person to design a maintenance strategy is a clinician who knows the patient. We report it because a practice this widespread deserves to be described accurately rather than left to circulate in fragments.

Intermittent schedules: the evidence, stated in full

This section is short because the evidence is. The Journal has searched the trial registries and the published literature for any randomised comparison of an intermittent schedule against a standard weekly schedule for any GLP-1 receptor agonist or dual agonist, at any dose, for any indication. We have found none. We have also found no observational cohort large enough to characterise outcomes on such a schedule with the standard confounders addressed.

What exists is dose-ranging data from the phase 2 programmes, which establishes that lower average exposures produce smaller weight effects, and pharmacokinetic modelling, which establishes what average exposure and what peak-to-trough ratio a given interval would produce. Neither tells you whether a fortnightly schedule maintains weight in somebody who has already lost it, which is the question actually being asked.

An absence of evidence is not evidence of harm and the Journal does not present it as such. It is, however, the entire evidentiary position, and readers encountering confident protocols for intermittent use should know that the confidence is not coming from data. Nothing in this section is advice, and the compounds sold for research use only that appear in some of these protocols are not approved for human use.

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.

What would settle the maintenance question

The Journal’s position is that three trials would resolve almost everything currently argued about in this area, and that all three are straightforward. The first is a dose-reduction design: after a lead-in to target, randomise to full dose, one step down, two steps down, or placebo, and follow for a year with weight as the primary endpoint. It would establish the shape of the descending dose-response curve and would cost a fraction of a pivotal programme.

The second is an interval design: after a lead-in, randomise to weekly, fortnightly and three-weekly administration at the same nominal dose. It would answer the intermittent-schedule question directly and would settle whether the exposure pattern matters independently of average exposure.

The third is a taper design: randomise abrupt cessation against a stepped reduction over twelve weeks, with appetite, eating behaviour and weight measured for a year afterwards. It would test the only argument for tapering that is worth testing.

None of the three is under way as far as the Journal can establish. Readers who know otherwise should write to letters@compoundjournal.com; a registered protocol for any of them would be news in this department.

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 correspondence this department receives on stopping divides almost evenly between people frightened by regain figures they have seen quoted without denominators and people who stopped without difficulty and cannot understand the alarm. Both groups are reading the same trials. The difference is almost entirely a matter of which number was quoted to them and whether anybody explained what it was a proportion of.