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

My records go back to the first dose with dates, so I can reconstruct the timeline exactly.

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 can I legitimately conclude from this figure?

Mechanically, 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.

The part that matters: 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.

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.

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

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.

Put another way, 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.

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

edited 27 Sept 2025 by a_lindgren — fixed an arithmetic slip in the third paragraph

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.

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.

The caveat that matters: dose decisions on a licensed medicine belong with a prescriber, and dose decisions on research-use-only material belong to a category where nobody has any obligation to you at all.

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