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

Asked 23 Jun 2025Modified 10 months agoViewed 11k times
13

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?

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askedbac_or_bust33k13723 Jun 2025
8Same situation here, so I will follow this one. – Dr_Ilse_Vandenberg 7 months ago
7How long since the last increase? That is the first thing anyone will ask. – amara_nwachukwu 5 months ago
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4 Answers

Accepted answer first, then by votes
49

Accepted answer

SURMOUNT-2 would have written it into the protocol, and the wording is the part that matters. Escalation protocols in this class generally permit a delay at the current level, sometimes a single step down with a later re-attempt, and count a participant as remaining in the arm throughout. That is analytically important: an intention-to-treat analysis keeps them at their randomised assignment regardless of the dose they were actually taking, so the "top dose" arm contains people who never reached the top dose. Find the protocol amendment history as well as the paper, because tolerability rules are among the things most often revised mid-programme, and dose-escalation decisions are made under supervision — nothing here is medical advice.

Start with the half-life, because the interval between steps should be at least four half-lives or you are escalating before the previous step has expressed itself.

Liraglutide titrates weekly rather than four-weekly because its half-life is about thirteen hours, so steady state is reached within days. The interval follows the pharmacokinetics in both cases.

Holding a step for eight weeks instead of four is a legitimate approach with no efficacy cost at the destination, and it is what the trials effectively did for anyone who tolerated poorly.

Trial data show gastrointestinal adverse events concentrated in the escalation phase and declining at stable doses.

Hold rather than escalate while symptoms are active. Always.

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answered · acceptedDr_Nadia_Farsi104k24710 Aug 2025
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18

The short version: four-weekly steps for the weekly agents, hold rather than escalate when symptoms are active, and slower is always available.

The published semaglutide weight-management schedule steps 0.25, 0.5, 1.0, 1.7 and 2.4 mg at four-week intervals, with 0.25 mg as an initiation step rather than a therapeutic one.

The part that matters: titrating downward is available too. Stepping back and holding is a normal adjustment rather than a failure.

A schedule described here is a published schedule for a licensed product and is not a recommendation.

Stepping back is a normal adjustment, not a failure.

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answerednine_point_nine60k14821 Aug 2025
15

Answering this needs the agent and the current step, since the schedules differ and the reason they differ is pharmacokinetic.

Escalating while gastrointestinal symptoms are still active is the commonest avoidable error. Tolerance to the previous step has not developed, and the new step lands on top of it.

Put another way, the dose that produces an acceptable result with acceptable tolerability is the endpoint, not the top of the schedule. A substantial fraction of trial participants did well below the maximum.

The top of the schedule is not the target. The working dose is.

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

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answeredDr_Bram_Verhoeven84k2482 Sept 2025
12

Escalating while symptomatic resets the tolerance process and is the mechanism behind most miserable titrations.

For an agent with a one-week half-life, steady state after a dose change is reached in about four to five weeks. Escalating at two weeks means escalating from a position you have not yet reached, and the resulting exposure is higher than the schedule intends.

Efficacy in the trials was dose-related but with substantial response at intermediate doses, which is why the maximum is not a target for everyone.

The caveat is that titration decisions belong with a clinician who knows what else is on board.

Four half-lives between steps, minimum. Work it out for your agent.

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answeredDr_Nadia_Farsi104k24713 Sept 2025
6Same experience here, different supplier. – Dr_Sara_Kuusela 7 months ago
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Ask PeptideStack is a static archive. Posting is closed, but the norms are worth stating: answer the question that was asked, show your working, cite the trial or the certificate, and say plainly where the evidence runs out.

Not medical advice. Research-use-only compounds are not approved for human use.