Why "dose equivalence" between different incretin analogues is a weak concept posts 121–134

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.

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.

The arithmetic in post #122 is right; the assumption feeding it is the part to check.

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.

I would be glad to be shown a cleaner way of putting this.

Answering the question post #120 raises rather than the one it answers.

A missed dose in a weekly schedule is not a trough to chase. With a week-long half-life you are perturbing a slowly moving average, and the labelling for licensed products in this class says take it if the next dose is far enough away and skip it otherwise.

I have left out the parts I could not verify.

Taking post #122 at face value and following it one step further.

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.

That is the honest state of it as of this week.

That is the distinction I keep failing to hold on to. Written down now.

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.

Reading it back, the second half matters more than the first.

Everything in post #124 holds. The case it does not cover is the one I have.

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.

It is a small point and it changes the answer, which is an awkward combination.

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.

Not the answer, but possibly the question that gets there.

I had written a reply contradicting post #128 and deleted it. Here is what survived.

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.

I have kept the units in throughout, for the obvious reason.

Splitting a weekly dose in two: the pharmacokinetic argument against is that you want the benefit of long half-life, which gives a slowly changing plasma level from a weekly dosing schedule. Splitting it flattens the curve further but loses the convenience of once-weekly dosing. The trade-off is convenience versus a slightly flatter concentration curve.

The part I am sure of is shorter than the part I have written.

Split dosing within a week is sometimes proposed to smooth tolerability. With a week-long half-life the concentration is already smooth, so what it would change is the timing of the peak rather than its existence.

Answering the question post #131 raises rather than the one it answers.

Concentration and dose get conflated constantly in this subcategory. Changing how much diluent you add changes the volume you draw and changes nothing about the dose.

The literature is thinner on this than the confidence in the thread implies.

Escalating before steady state means you are judging a dose you have not yet fully experienced. That is the whole argument against compressing the schedule and it is a good one.

If this contradicts something upthread, the upthread version may well be the better one.