What STEP 4 and SURMOUNT-4 actually established

Ask what the lowest dose that maintains a result is, and the literature goes quiet. The withdrawal-design trials answer a different question: they compare continuing at the achieved dose against stopping, and they answer it emphatically in favour of continuing. The intermediate case — continue at half the dose, or at the same dose every other week — has been examined in small studies and modelled at length and randomised almost not at all. Given that cost is the commonest reason for discontinuation, this is an evidence gap with a price attached.

What the protocols allowed and the labels lost

The pivotal protocols in this class permitted escalation to be delayed. In the semaglutide obesity programme, participants unable to tolerate a dose increase could remain at the previous dose and attempt escalation later; the tirzepatide programme contained comparable provisions, with defined windows and a limit on how long a participant could remain below target before being counted as not having reached it.

This matters for how the efficacy figures should be read. The mean weight reductions quoted from STEP and SURMOUNT were produced by populations in which a meaningful minority spent time below their assigned target dose. The trials therefore already contain the effect of flexible titration, and the flexible approach is not a departure from the evidence but part of how the evidence was generated.

What the labels carry forward is the ladder. What they largely omit is the permission. A prescriber who reads only the label sees a fixed calendar; a prescriber who reads the trial documentation sees a calendar with a documented escape valve. The Journal has raised this with two regulatory affairs specialists, both of whom regarded it as a known and unglamorous gap in how trial conduct is translated into prescribing information.¹

When the curve flattens, and why

In the sixty-eight-week semaglutide obesity trials, weight reduction decelerated visibly from around week forty and was close to flat by week sixty. Extended follow-up to a hundred and four weeks found the reduction broadly maintained rather than extended, which is the clearest available statement that the plateau is a plateau and not a pause.²

The mechanism is not mysterious. Energy requirement falls with mass. A person who has lost fifteen per cent of body weight requires materially less energy at rest and in movement, and the intake reduction produced by a fixed dose of a fixed drug eventually equals that lower requirement. Balance is restored and weight stops changing. The drug has not weakened; the target has moved.

Two inferences commonly drawn from a plateau are unsupported. The first is that receptors have desensitised — difficult to reconcile with the rapid and near-complete regain observed on withdrawal. The second is that the dose must therefore be increased, which in the trials produced a further step down the flattening dose-response curve rather than a resumption of the earlier slope. The plateau is predictable, is predicted, and is almost never mentioned to anyone before it happens.

Target dose against maximum dose

The SURMOUNT-1 results are the clearest available illustration of a flattening curve. At seventy-two weeks the mean weight reductions were approximately fifteen per cent at 5 mg, nineteen and a half per cent at 10 mg and twenty-one per cent at 15 mg, against about three per cent on placebo.³ The step from 5 mg to 10 mg bought roughly four and a half percentage points; the step from 10 mg to 15 mg bought roughly one and a half.

Set against that, gastrointestinal adverse events and discontinuation for adverse events both rose across the dose range. The question of whether the top rung is worth climbing is therefore a genuine trade-off rather than a formality, and it will have different answers for different people.

The Journal has no view on where any individual should stop. We have a strong view on how the question should be framed: not as whether to reach the maximum, but as what the next increment is expected to add and what it is expected to cost. Framed that way, a decision to remain at an intermediate dose is a defensible reading of the dose-response data rather than a compromise.

What the withdrawal designs established

Two trials in this class were built specifically to answer what happens when treatment stops. In the semaglutide programme, participants who had escalated to the top dose over twenty weeks were then randomised to continue or to switch to placebo; those continuing lost a further eight per cent of body weight over the following forty-eight weeks while those withdrawn regained about seven per cent.⁴ In the tirzepatide programme, a thirty-six-week open-label lead-in was followed by randomised continuation or withdrawal, with the continuation group losing a further five and a half per cent and the withdrawal group regaining approximately fourteen per cent.⁵

These are among the most informative results in the field and they are frequently over-read. What they establish is that the effect is maintained by continued exposure and reverses without it. What they do not establish, because neither design examined it, is whether a reduced maintenance dose would hold the result. The comparison was full dose against nothing.

Given that cost is the leading reported reason for stopping, a randomised comparison of full-dose against half-dose maintenance would be one of the highest-value trials nobody has run.

Maintenance dosing: the honest state of the evidence

Practices described to us include remaining at the dose that produced the result, reducing by one rung after target is reached, extending the interval to ten or fourteen days, and stopping entirely with a plan to resume on regain. The first is what the trials tested. The others are extrapolations of varying boldness.

The interval-extension approach deserves a specific caution. Because exposure is governed by the ratio of half-life to dosing interval, moving from weekly to fortnightly dosing on a seven-day half-life does not halve average exposure — it reduces it and also converts a fairly smooth concentration profile into a pronounced peak-and-trough cycle. Whether appetite regulation tolerates that oscillation is an empirical question and the answer is not in the literature.

Our position is that maintenance is the largest under-studied decision in the treatment course, that the trials answer continuation against cessation and nothing in between, and that anyone presenting a specific maintenance protocol as evidence-based is overstating what exists. Readers who know of a randomised maintenance-dose comparison we have missed should write to standards@compoundjournal.com.

Re-titration in practice

The convention after a long interruption is to resume one or two rungs below the previous dose and re-escalate on the standard interval. Clinicians described re-escalation as generally faster than the original ascent, on the grounds that a person who previously tolerated a rung is likely to tolerate it again, but there is no trial evidence for accelerated re-titration and the kinetic argument for four-week steps applies unchanged.

Two failure modes recur. The first is resuming at the previous top dose because that was the dose on the last prescription, which reproduces first-exposure symptoms in someone who has forgotten what they were like. The second is the opposite: restarting at the initiation dose after a two-week gap, which discards several weeks of adaptation for no reason.

Both are avoidable with the residual-exposure figures and a note of the date of the last injection. The Journal has come to regard that date as the single most useful piece of information a person on this treatment can keep, and the one most reliably absent when it is needed.

A dose is a number about a vial

Everything above assumes the dose administered is the dose intended. For licensed pens that assumption is reasonable. For research-grade lyophilised powder it is an assumption that should be examined, because a titration schedule built on an unreliable starting figure propagates the error through every subsequent rung.

Two distinct quantities are involved. Chromatographic purity describes the proportion of peptide-related material that is the intended peptide. Peptide content describes what fraction of the vial mass is peptide at all, the remainder being counter-ions, residual solvent, water and excipient. A vial can be ninety-nine per cent pure and contain substantially less peptide than its label states, and content is the figure that determines a dose.

Of the four independent services this market relies on, all report purity and only some report content routinely. Janoshik, Medutest, PeptideMeter and VendorInvestigate have each published results in which nominal and measured strength diverged. The Journal has argued in Analytics that content should be reported as standard, and we repeat it here for a titration-specific reason: without it, the arithmetic of a step is being performed on a number nobody has measured.

Non-standard concentrations and the errors they cause

Compounded and grey-market preparations are frequently supplied at concentrations that do not correspond to any licensed presentation. That is not in itself a quality problem, but it removes every mental shortcut a person may have acquired, and it interacts badly with escalation.

The recurring error is arithmetic rather than clinical: a person who has learned that a particular volume equals a particular dose changes vial, keeps the volume, and changes the dose without intending to. We have seen this reported in both directions and at magnitudes exceeding a full rung on the ladder.

Two habits protect against it. Recompute the volume-to-dose conversion whenever the vial changes, from the stated content and the reconstitution volume, rather than carrying the old figure forward. And write the result down somewhere attached to the vial, because the calculation is easy and the recall is not. The Journal covers the underlying arithmetic in the injection-practice file; the point here is that changing vials mid-titration converts a titration decision into a units problem, and units problems are where the largest errors in this field occur.

How the Journal reports dose figures

Three conventions govern the numbers in this file. Weight-change figures are quoted with the estimand named, because the treatment-policy and trial-product analyses in the obesity programmes differ by two to three percentage points and secondary coverage habitually mixes them. Doses are quoted as the weekly amount, not as a pen volume or a unit count, because volume and units depend on concentration and concentration varies. And where a figure derives from a responder analysis rather than a primary endpoint, we say so.

Where we describe practice rather than evidence, the text says so explicitly. A substantial part of what is known about titration in this class is craft knowledge held by clinicians, and reporting it is legitimate journalism. Presenting it as trial data is not.

Nothing in this file is medical advice. The Journal does not recommend doses, schedules, products or suppliers. Several compounds discussed here are sold for research use only and are not approved for human use in any jurisdiction. Decisions about treatment belong with a licensed clinician who has examined the person concerned.

Five things about titration nobody can currently answer

First, the optimal escalation interval. No adequately powered randomised comparison of intervals at a fixed target dose exists for any molecule in this class.

Second, the optimal hold duration for a person who has not adapted at four weeks. Practice ranges from four to twelve weeks on no comparative evidence at all.

Third, the lowest maintenance dose that preserves a result. The withdrawal trials compared full dose with nothing.

Fourth, whether tolerability at one rung predicts tolerability at the next. Clinicians assume it does, plausibly, and the published dose-ranging data is not analysed in a way that answers the question.

Fifth, whether any measurable baseline characteristic predicts the ceiling. Nothing published does so usefully, which mirrors the situation for efficacy: mean behaviour in this class is well characterised and individual variation is not.⁶

The Journal lists these not as a complaint about researchers but as a map of where confident advice is currently outrunning its evidence. Anyone offering a precise answer to any of the five is offering an opinion, and should be read as doing so.

The Journal ends where the evidence does. Escalation intervals in this class rest on a kinetic argument that is sound and on a randomised comparison that does not exist. Dose holding rests on a documented adaptation and on clinical consensus. Maintenance rests on two withdrawal trials that answered a narrower question than the one readers ask. None of that makes the current practice wrong; it makes it provisional, and provisional practice deserves to be described as such rather than printed as a table.