What did STEP 2 do with participants who could not tolerate a step?

I have been on a stable schedule for eleven weeks, so this is not a first-week question.

I have the document in front of me and I can read the numbers. What I cannot do is interpret them.

I am reasonably comfortable with statistics and completely uncomfortable with chromatography, or vice versa.

Which parts of this are informative and which are decoration?

The relevant detail is that what the label says and what the trial protocols permitted are different documents, and the difference is instructive: protocols generally allowed a step to be delayed or reversed for intolerance, and a substantial minority of participants used that provision.

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.

Mechanically, 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 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.

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

It helps to be literal here: 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.

Stated carefully, 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.

Worth noting that inter-individual variability in exposure at a given dose is substantial, which is why the ladder exists rather than a single population dose.

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.