The dose you were told to reach and the dose you will actually stay on

There is a particular kind of error that comes from reading a dose table as an instruction rather than a default. A person who reaches week seventeen, feels unwell, and escalates anyway because the calendar says so is following the document and ignoring the drug. A person who reaches an adequate response at an intermediate dose and escalates anyway because the top of the ladder is the top of the ladder is doing something the trials give no reason to do. Both errors have the same root: mistaking the shape of a protocol for the shape of a treatment.

The semaglutide ladder, rung by rung

For weight management, the approved escalation runs 0.25 mg weekly for four weeks, then 0.5 mg, then 1.0 mg, then 1.7 mg, reaching 2.4 mg at week seventeen. For glycaemic indications the ladder is shorter and the maximum lower: 0.25 mg, then 0.5 mg, then 1.0 mg, with a 2.0 mg option added later on the strength of a dedicated dose-comparison study.

Two features are worth noticing. The starting dose is explicitly sub-therapeutic — 0.25 mg is a tolerability rung, not a treatment dose, and describing it as a low dose rather than an initiation dose causes real confusion. And the ratios narrow as the ladder rises: two doublings, then a 1.7-fold step, then a 1.41-fold step.

The 2.4 mg dose was selected on the basis of the phase 2 dose-ranging programme and carried into the STEP trials, where it produced a mean weight reduction of about fifteen per cent at sixty-eight weeks against roughly two and a half per cent on placebo.¹ That is the number the ladder exists to reach, and the ladder itself was never the subject of the trial.

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.²

Tolerability-led escalation, described plainly

The practice that has emerged across this class, without ever being formally codified, runs roughly as follows. Start at the initiation dose. Escalate when the current dose is comfortable enough that a person is eating normally, keeping fluids down, and not organising their week around symptoms. Do not escalate in the week of a symptom flare. If a rung is intolerable, step back to the previous one and try again later. If a rung is producing an adequate result, consider stopping there.

Every clinician we spoke to described something within a small variation of that, and none of them could point to a trial of it. It is a reasonable synthesis of the pharmacokinetics, the tachyphylaxis data and a great deal of accumulated observation.

The Journal has a specific position on this. The absence of randomised support for tolerability-led escalation is a real gap and should be closed, but its absence is not a reason to prefer the printed calendar, which has no randomised support either. Between two unrandomised schedules, the one that responds to information about the individual is the better bet. We say that as an editorial judgement rather than as a report of evidence.

Trial protocols permitted holding and delay. The schedules people now treat as rigid were operated with discretion in the studies that produced the evidence, and the escalation sections of those protocols say so.

Supply interruption as a dosing event

In this market, gaps are usually structural rather than personal. Shortage listings, restrictions on compounded supply, price movements, customs interdiction and vendors ceasing to trade all produce interruptions that arrive without notice and end without warning. We have documented gaps of one to eleven weeks arising purely from supply, in people who missed no dose voluntarily.

The practical consequence is that anyone dependent on a single source is also dependent on that source for the continuity of their titration. Several people described re-escalating three times in a year for reasons that had nothing to do with their tolerance of the drug.

There is a second-order effect worth naming. Resuming with material from a different supplier compounds the uncertainty: the person is re-escalating and simultaneously changing the actual content of the vial. Reports from Janoshik, Medutest, PeptideMeter and VendorInvestigate consistently show that nominal strength and measured peptide content are not the same quantity, and a supplier change during a re-titration makes any symptom change uninterpretable. Change one variable at a time is a laboratory principle, and it applies here.

A short glossary, because the terms get swapped

Initiation dose: the first rung, chosen for tolerability and generally sub-therapeutic. Not a low treatment dose. Target dose: the dose a protocol or prescriber intends to reach. Maintenance dose: the dose continued once the intended effect is achieved. Maximum approved dose: the highest dose in the label, set by the studied range and the tolerability ceiling.

Escalation interval: the time between increments. Hold: deliberately remaining at a rung beyond the standard interval. Re-titration: re-ascending after exposure has been substantially cleared. Dose-limiting: describing an effect severe enough to prevent escalation, which is a property of the person and the dose jointly, not of the drug alone.

Steady state: the condition in which drug entering the body equals drug leaving it. Accumulation ratio: steady-state average concentration divided by first-dose average concentration. Precision here matters more than it sounds: a large share of the correspondence this desk receives about titration turns out on inspection to be a disagreement about which of these words the writer meant.

Escalation past the studied ceiling enters a region where the dose-response curve is not described. What the evidence does show is benefit flattening while tolerability continues to decline, which is the shape that matters more than any single figure.

One question is worth putting to the sponsors of the next generation of these molecules, and we intend to keep putting it. Escalation is the phase in which most discontinuation occurs, and discontinuation costs the entire treatment effect. A dose-escalation trial would be inexpensive relative to a cardiovascular outcome programme and would settle the most frequently asked practical question in the field. Nobody has run one.