What SELECT tells us about maintenance, and what it does not
Dose reduction is not withdrawal, and the trials that tested withdrawal cannot be read as testing it.
Tirzepatide
Page 6 of 18 of this archive, newest first.
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…
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.
Vagal afferents, the area postrema, and the anatomy of nausea
Receptor expression maps explain the effect profile better than any dose-response curve.
Why "muscle-sparing" is a marketing term and not a measurement
A tour of the source literatures, with an assessment of how far each legitimately reaches.
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.
The limits of mechanism: why receptor data will not tell you who responds
A catalogue of open questions, with an assessment of how likely each is to be resolved.
What the trial protocols permitted, and what the labels omitted
Reducing a dose is not going backwards. In a tolerability-limited class it is the mechanism by which the ceiling is found.
Do you need the top of the ladder?
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.
What TRIUMPH-1 tells us about maintenance, and what it does not
Dose reduction is not withdrawal, and the trials that tested withdrawal cannot be read as testing it.
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.
The limits of mechanism: why receptor data will not tell you who responds
A catalogue of open questions, with an assessment of how likely each is to be resolved.
What a low result means when intake has halved
Micronutrient guidance for this drug class is borrowed almost entirely from post-bariatric surveillance, where the anatomy is different and the deficiency mechanisms are not…
Diminishing returns, quantified
Where the curve flattens, what flattens with it, and what does not.
What the orforglipron schedule assumes about a person it has never met
The four-week step exists because four to five weeks is approximately how long a once-weekly drug takes to stop rising at a fixed dose. That is a good reason, and it is not…
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.
What the GLP-1 receptor actually does when liraglutide binds it
The receptor is expressed in more tissues than the popular account allows, and that is the whole story.
A reference interval is not a target, and a result outside one is not a diagnosis
Two sources of noise sit under every number: how reproducible the assay is, and how much the analyte varies within the same person on the same day.