What did SURMOUNT-5 do with participants who could not tolerate a step?

This came up because two published schedules for the same agent differ.

I would like to know the limits of what can be inferred from this.

What I am trying to avoid is over-reading a single result, which I have done before.

What can I legitimately conclude from this figure?

The steady-state arithmetic is worth doing once, because it explains most of what people find confusing about weekly dosing.

Escalating in response to a plateau is a specific and common error of reasoning. A plateau after four to six months is the expected trajectory in every trial in the class — the curve flattens because energy expenditure falls with mass, not because the receptor stopped working. A dose step may still be reasonable; "the loss stopped" is not by itself the reason.

The part that matters: steady state, worked: with a half-life of about seven days and weekly administration, the accumulation ratio is roughly 1/(1 − 0.5) = 2, and you get to within about 97 per cent of steady state after five half-lives, so around thirty-five days — five weeks — after any dose change. A four-week step interval therefore has you escalating at roughly 94 per cent of the previous dose’s steady state, which is close enough to be sensible and not so close as to be conservative.

I would add that tolerability is not a proxy for benefit. Tolerating a higher dose easily is not evidence that you need one.

Escalate on tolerability, hold when it costs you, and do not confuse a flattening curve with a failing drug.

edited 6 Feb 2025 by bufferline42 — added a caveat about sampling

For a compound with a seven-day half-life, dose timing is much less consequential than people expect and dose rate is much more consequential.

The maintenance question turns on what you are maintaining. If the objective is weight maintenance, the withdrawal-extension data suggests that a fraction of the therapeutic dose retains a substantial fraction of the effect. If the objective is the cardiovascular or renal endpoint, the trials that demonstrated those endpoints used the full dose, and extrapolating downward is not supported by anything.

The argument against splitting a weekly dose is arithmetic rather than ideological. Peak-to-trough ratio for a seven-day half-life compound dosed weekly is about two. Split it into twice-weekly and the ratio falls to roughly 1.4. That is a real reduction in fluctuation and a negligible one in absolute terms, and you have doubled the number of stopper piercings and the number of small-volume measurements, each of which carries its own error.

The label instructions for a missed weekly dose differ between agents, and reading the actual prescribing information rather than a summary is worth the ten minutes — the thresholds are specific and the reasoning behind them is stated.

Write down in advance what would make you hold a step, because deciding that in the middle of a bad week is not when you are at your most analytical.

Worth being precise here: answering this requires distinguishing the maximum studied dose from the maximum useful dose. The trials established the former. The latter is a per-person question that the trials were not designed to answer.

Missing a dose by three days on a weekly schedule takes the trough down by less than a factor of 1.35, which is well inside the variation you would see between two on-time weeks. Missing it by five or more days is where the label instructions start to differ between agents, and the reason is how close the next scheduled dose is rather than any mechanistic threshold.

If you take one thing from this: dose rate drives tolerability, dose level drives exposure, and they are separate levers.

The titration schedule is a tolerability instrument, not an efficacy one. Nothing in the ladder is there to make the compound work better; every step exists to make the gastrointestinal adverse-event curve survivable.

Holding at a step for longer than four weeks before escalating does appear to reduce cumulative gastrointestinal burden, which is unsurprising given that adverse events cluster in the one to two weeks after each increase. What it does not do is change where you end up, provided you get there.

SURMOUNT-1 used a twenty-week escalation of tirzepatide in 2.5 mg increments to maintenance doses of 5, 10 and 15 mg weekly, and reported a clear dose-response across those maintenance levels — which is the closest thing to evidence that the top of the ladder does more than the middle.

The short version: four-week steps because that is steady state, and the ladder is about the side effects, not the result.