Why "dose equivalence" between different incretin analogues is a weak concept

Dose and effect are not linear across the studied range for every compound in this class. Assuming a doubled dose gives a doubled effect is the reasoning error behind most disappointment.

When a dose reduction is the correct response to a side effect: if a side effect is dose-dependent (nausea, constipation, injection discomfort), reducing the dose is a reasonable response. If the side effect is not dose-dependent (e.g., hypoglycemia with insulin), dose reduction does not address the issue.

Coming back to post #16, because the follow-up matters more than the original answer.

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.

This is the sort of thing that ought to be settled and apparently is not.

Picking up post #18: that is the part I would want checked first.

Holding at a dose that is working is a legitimate position and it is not what the trial protocols did. The protocols escalated to a target because they were measuring the target dose, not finding each person's minimum.

Posted with less confidence than the sentence structure implies.

On post #16 — agreed on the reasoning, with one qualification.

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.

The short version is the first sentence; the rest is why.

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 want the raw data before agreeing with my own summary of it.

If you are stepping up mainly because the schedule says so rather than because the current dose has stopped doing what you wanted, that is worth noticing before rather than afterwards.

One more caveat and then I will stop qualifying: the sample selected itself.

Thank you for taking the time. That was more work than a reply usually is.

Picking up post #21: that is the part I would want checked first.

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.

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.

Stating my assumptions rather than smuggling them in.

Post #25 answers the question as asked. The question underneath it is different.

Holding a dose indefinitely: the trials did not study indefinite holding at a non-maximum dose. The trials escalated to a target and then held that. What happens if you stay at an intermediate dose for years is not formally studied and extrapolation is the best available reasoning.

One case, stated as one case.

Worth separating two things that post #25 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.

A titration plan written down in advance is easier to stick to and easier to abandon deliberately. An improvised one becomes a series of decisions made on the worst day of each week.

Where I part company with post #25, and it is a narrow parting.

Doubling after a miss adds a peak for no gain and is not what any labelling in this class recommends. That is a description of the labelling rather than advice about anyone's situation.

Post #29 is the version of this I will quote in future. One addition.

The arithmetic of an intermediate dose: if the label says 1.0 mg and 2.0 mg, a dose strictly between them is off-label by definition. Some people compute it anyway. The reasoning is pharmacological — e.g., "I will split the difference between steps" — but it is reasoning from theory, not from evidence.