What did SUSTAIN-6 do with participants who could not tolerate a step?

The label documentation for the agent in question is ambiguous on exactly this point.

I have read the primary source rather than the summary, which has left me with more questions.

I understand the headline. I do not understand the footnotes, and the footnotes look important.

What would I need in addition before this supported a decision?

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

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.

Stated carefully, where the label ladders differ between agents, the differences track the potency ratio and the tolerability profile rather than anything deeper. It is worth reading the ladders side by side once, because the pattern — small starting dose, four-week steps, a defined maintenance range and a defined maximum — is identical in structure across the class.

One qualification — this is protocol arithmetic and reported practice, not a recommendation. The compounds in question are not approved for human use when supplied for research.

Read the actual prescribing information for the agent in question. It is short, specific, and more reliable than any summary of it.

Four weeks is not a magic number, it is approximately five half-lives, which is the interval over which a weekly compound reaches steady state after a dose change. Escalating faster means escalating onto a rising concentration.

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.

It helps to be literal here: 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.

The pharmacokinetics of the acylated agonists are well described: absorption from the subcutaneous depot is slow and rate-limiting, the elimination half-life is approximately one week, and steady state is reached in four to five weeks. Every dosing question in this section follows from those three facts.

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

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.

Put another way, 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.

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.

SURMOUNT-4 is the withdrawal trial to read on the maintenance question: after an open-label lead-in, randomised withdrawal produced substantial regain in the placebo arm while continued treatment produced continued loss. It is the cleanest available answer to "what happens if I stop".

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

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.

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 STEP programme escalated semaglutide over sixteen weeks in four-week steps to 2.4 mg weekly, and the trial-product estimand versus treatment-policy estimand distinction accounts for most of the difference between the figures quoted from those papers.

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