Escalating past the approved maximum, examined honestly

The approved maximum doses in this class were not set by running out of efficacy. They were set by running out of tolerability at a point where additional efficacy had already become small. Semaglutide at 2.4 mg weekly was selected over higher doses examined in earlier ranging work; tirzepatide at 15 mg sits at the top of a series in which each increment produced less than the one before. That shape — rising benefit, flattening quickly, with symptom burden that does not flatten — is the defining feature of the class and the reason the ceiling exists.

Stepping down is part of the method

Dose reduction in this class carries a stigma that the pharmacology does not justify. Because the ceiling is set by tolerability and tolerability varies severalfold between people, the only way to find an individual ceiling is to move until it is reached and then move back. A reduction is the second half of that measurement.

There is a practical detail worth stating. Reduction takes effect on the same kinetics as escalation, which means the relief is not immediate: a person dropping from 15 mg to 10 mg is still carrying substantial exposure from the higher dose for a fortnight, and concluding after five days that the reduction has not helped is premature.

There is also an arithmetic trap for vial users. Halving a dose halves exposure at steady state, but the transition takes three to four weeks, and during that transition the person is at neither dose. Anybody adjusting downward to escape a symptom should expect the answer to arrive on a three-week timescale, not a three-day one.

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.¹ 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.

Above the approved maximum

There is no published sustained-dosing human data above the approved maxima for the current generation of incretin agonists. Higher doses were examined in earlier ranging work and in some cases in dedicated comparisons; the pattern was consistently more adverse events and modest incremental efficacy. The dedicated semaglutide dose-comparison study in type 2 diabetes, which compared 2.0 mg against 1.0 mg weekly, found a further HbA1c reduction of a few tenths of a percentage point with a broadly comparable safety profile — a real but small gain at a doubling of dose.²

That is the shape of the evidence at the top of the curve: real increments, shrinking fast. Extrapolating it upward past the studied range is not supported, and the Journal declines to speculate about doses for which no human exposure data exists.

We report that off-label escalation occurs because it does and because pretending otherwise makes coverage useless. We do not report it as a strategy, and readers should note that research-use-only material is not approved for human use in any jurisdiction and carries no assurance of identity, content, sterility or endotoxin limit.

The shape of the curve, stated numerically

Across the programmes the exposure-response relationship for weight is approximately log-linear over the lower and middle range and flattens above it, while the relationship for gastrointestinal adverse events is closer to linear in dose and does not flatten in the same range. That divergence is the ceiling.

In glycaemic endpoints the flattening is even more pronounced. HbA1c reduction in the tirzepatide diabetes programme differed by roughly a quarter of a percentage point between the 5 mg and 15 mg arms in the head-to-head against semaglutide, which is a small difference against a threefold dose range.³ For a person whose objective is glycaemic control rather than weight, the argument for the upper rungs is correspondingly weaker.

The general point is that the class has two dose-response curves running in parallel and only one of them flattens. Any discussion of escalation that quotes the efficacy curve without the tolerability curve is quoting half a graph, which is how the top of the ladder came to be treated as an obvious destination.

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.⁴

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.

Readers who think a paragraph above has outrun its evidence should write to the standards desk. Titration is a subject on which practically everybody has an opinion and practically nobody has a trial, and our correction log for this file is longer than we would like. That is the correct outcome of publishing numbers in a field where the numbers keep being checked.