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.
Semaglutide
Page 7 of 18 of this archive, newest first.
Diminishing returns, quantified
Where the curve flattens, what flattens with it, and what does not.
What STEP 4 and SURMOUNT-4 actually established
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.
The supply gap as a clinical event
Why the reason for stopping changes what happens afterwards.
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.
What the GLP-1 receptor actually does when orforglipron binds it
The class is described as though every molecule in it did the same thing. At the receptor, they demonstrably do not.
Reading the semaglutide composition data without the press release
A substudy powered to describe a mean is not a substudy powered to detect a clinically meaningful individual change.
The substudies, read properly: who was scanned, when, and with what
The composition data comes from imaging substudies enrolling a few score participants at selected sites. It is the best evidence available and it is thin.
What the GLP-1 receptor actually does when survodutide binds it
The receptor is expressed in more tissues than the popular account allows, and that is the whole story.
The supply gap as a clinical event
Cost is the modal reason for discontinuation in every dataset we have seen, and it is absent from the clinical literature.
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.
The advice is mostly reasonable. The certainty is not earned.
Grading six widely repeated claims against the studies actually behind them.
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…
Vitamin D, adiposity, and a volume-of-distribution problem
Which markers are informative, which are confounded, and which move for reasons unrelated to nutrition.
Why "muscle-sparing" is a marketing term and not a measurement
Grading six widely repeated claims against the studies actually behind them.
Escalating onto a rising curve
What the published pharmacokinetics permit, what the labels state, and where the two diverge.
A supply gap is a pharmacological event
One omitted dose is a labelling question. Four omitted doses is a clinical one. The two are routinely conflated.
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.