The ceiling is a tolerability finding, not an efficacy one
Higher doses of these molecules have been studied. In general they produced modest additional efficacy and disproportionate additional symptom burden, which is why the…
Maintenance
Page 3 of 9 of this archive, newest first.
Target dose, effective dose, and the distance between them
The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth climbing.
Diminishing returns, quantified
Escalation beyond the label is common in this market. Reporting that it happens is not the same as reporting that it works.
What happens when the drug is taken away: three randomised answers
A withdrawal trial answers a narrower question than it appears to. This piece states which question.
What the pharmacokinetics permit and what they cannot tell you
The schedules in circulation, described accurately, with their evidentiary status attached.
Not everybody regains at the same rate, and nobody knows why
The variance around the mean regain trajectory is large and unexplained, exactly as it is for the weight loss.
What the placebo arms of the withdrawal trials actually tell us
Three randomised withdrawal designs have tested what happens when treatment stops. Their results are consistent and they are consistently misreported.
The label says four weeks. The clinic says whatever holds.
The published ladder exists because a protocol needed a single number. Practice has never followed it exactly, and the regulatory file never assumed it would.
Escalating past the approved maximum, examined honestly
Where the curve flattens, what flattens with it, and what does not.
SURPASS-3 was built to answer the stopping question, and it did
Three randomised withdrawal designs have tested what happens when treatment stops. Their results are consistent and they are consistently misreported.
The shortage years, and what they taught about interruption
Why the reason for stopping changes what happens afterwards.
What STEP 4 and SURMOUNT-4 actually established
Weight reduction in the long programmes flattens at roughly sixty to seventy-two weeks. The timing is consistent, predictable and almost never mentioned in advance.
Diminishing returns, quantified
Where the curve flattens, what flattens with it, and what does not.
The supply gap as a clinical event
A supply interruption is a discontinuation with no notice, no taper and no plan. That is a distinct clinical situation.
When a symptom is information and when it is noise
Nausea and gastric delay attenuate over weeks at an unchanged dose. That single physiological fact is the entire justification for holding.
What STEP 4 and SURMOUNT-4 actually established
The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth climbing.
A supply gap is a pharmacological event
Concentrations fall by half a week, so a month away leaves a small fraction of steady state. Resuming at the previous dose presents the receptor with a step it has not seen…
The eighteenth month, and the conversation that should have happened in the third
What the trials measured was continuation against withdrawal. What patients want to know is continuation at a lower dose, and that study has largely not been done.
Escalating past the approved maximum, examined honestly
Higher doses of these molecules have been studied. In general they produced modest additional efficacy and disproportionate additional symptom burden, which is why the…
Escalating onto a rising curve
What the published pharmacokinetics permit, what the labels state, and where the two diverge.