Revisiting: Holding a dose indefinitely: is there a documented downside?

Small methodological point on Holding a dose: repeating a measurement is cheap and resolves most of what is being argued about here at no cost to anyone.

How the published trials escalated: they used specific step sizes and intervals. The STEP programme used a particular cadence; the SURPASS and SURMOUNT programmes used slightly different ones. Reading them side by side shows the variation is real but small.

Dose equivalence between different incretin analogues is a weak concept. The molecules differ in structure, half-life, receptor selectivity, and in what has been studied clinically. One mg of semaglutide is not equivalent to one mg of something else in any meaningful sense.

The uncertainty is in the assumption, not in the calculation.

Worth separating two things that post #14 runs together.

Micro-titration: the concept of increments smaller than the labelled steps. It has no evidence base from trials but is described by some people. The downside is that very small increments are hard to measure accurately with a syringe.

I have said this before in a thread nobody could find, so it is worth repeating.

Confirming post #16 from a second method, which matters more than confirming it from a second person.

The starting dose in most of these programmes is a tolerance step and produces little effect by design. Judging the compound at the starting dose is judging the wrong thing.

I would treat the number as indicative rather than as a measurement.

Going back down a step is not a failure and the trials allowed it. Several protocols permitted a return to the previous dose for tolerability and then a second attempt at the step.

Helpful, and easy to find again, which is half of what a good reply is.

Titrating on tolerability rather than on the calendar: some people escalate when they tolerate a dose well, others escalate on the prescribed schedule regardless. The published trials used a calendar-based schedule. Tolerability-based escalation has no formal evidence base but is not uncommon in practice.

I had written a reply contradicting post #19 and deleted it. Here is what survived.

The four-week escalation interval is a convention from the pivotal trials, not a pharmacological constant. The pharmacological argument is that with a week-long half-life, four weeks approaches steady state and you can assess the dose fairly. That is an argument for not going faster. It is not an argument against going slower.

The reasoning is more useful than the number, which is why I have shown it.

Confirming post #23 from a second method, which matters more than confirming it from a second person.

A methods point on Holding a dose rather than a substantive one: if the comparison is not like for like, the difference you are measuring is the difference in method.

Answering the question post #23 raises rather than the one it answers.

Writing down the date, the dose and the site each week takes fifteen seconds and is the single most useful record anyone here keeps. Memory reconstructs a titration history that never happened.

I checked the source rather than the summary, and they differ.

Reaching a dose and staying there for a year: the question of whether a stable dose remains effective over years is mostly answered by the withdrawal trials and by real-world reports. The dose does not seem to stop working, but the longest trials are not indefinitely long.

Marking my uncertainty on Holding a dose explicitly. I am confident about the direction, much less confident about the size, and not confident at all that it generalises past the case in the first post.

Post #27 is the version of this I will quote in future. One addition.

Stepping down deliberately: the withdrawal trials show that stopping is followed by regain. The step-down literature is thinner. The conservative assumption is that stepping down is followed by some regain, with the magnitude unknown.

I would put a moderate confidence on that and no more.

Worth separating two things that post #27 runs together.

Steady state means the plasma concentration is stable from dose to dose. That happens around 4 to 5 half-lives. Before that, the concentration is rising with each dose. Escalating before steady state means escalating on incomplete information about the dose you are on.

That much is documented. The rest is how I have interpreted it.

This follows post #27 rather than contradicting it.

Holding a dose is well covered in the tag pages, and the older discussions are better than the recent ones because they were argued out properly. Worth twenty minutes before adding to this one.