Beta-arrestin, cAMP, and the part of exenatide’s mechanism nobody quotes
The receptor is expressed in more tissues than the popular account allows, and that is the whole story.
Tirzepatide
Page 14 of 18 of this archive, newest first.
The substudies, read properly: who was scanned, when, and with what
What was pre-specified, what was exploratory, and what was calculated afterwards by people who did not run the trial.
The incretin receptors, ranked by how much we actually know about them
The class is described as though every molecule in it did the same thing. At the receptor, they demonstrably do not.
Which results should be repeated before they are investigated
What the pivotal programmes measured and how often, which is a more defensible template than most published monitoring schedules.
Six things incretin pharmacology cannot currently predict
The mechanism is well described. The variance is not.
A schedule that bends does not break
Nausea and gastric delay attenuate over weeks at an unchanged dose. That single physiological fact is the entire justification for holding.
The limits of mechanism: why receptor data will not tell you who responds
The mechanism is well described. The variance is not.
The glycated haemoglobin assay, and the eight conditions that break it
The alternatives with shorter windows, what they measure, and why they are rarely ordered.
Stepping down is part of titration
Nausea and gastric delay attenuate over weeks at an unchanged dose. That single physiological fact is the entire justification for holding.
The incretin receptors, ranked by how much we actually know about them
The receptor is expressed in more tissues than the popular account allows, and that is the whole story.
Do you need the top of the ladder?
A plateau at an intermediate dose and a plateau at the maximum dose look identical from the outside and mean different things.
What the tirzepatide schedule assumes about a person it has never met
We work the arithmetic out in full, because it is arithmetic and it is short.
Lean mass is a compartment, not a tissue
A body-composition report gives four decimal places and no confidence interval. That is the whole difficulty in one sentence.
Rapid weight loss moves eight analytes for reasons that have nothing to do with the drug
Three different explanations for the same abnormal number, and how to tell them apart.
Why "muscle-sparing" is a marketing term and not a measurement
The rule that a quarter of weight lost is lean tissue has been in textbooks for decades and does not survive close reading.
The lowest effective dose is a real concept with almost no data behind it
The commonest real-world strategy in this drug class is the least studied one.
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.
Randomised withdrawal is the cleanest design in this field and the least discussed
The regain trajectories, arm by arm, with the estimands named.
The advice is mostly reasonable. The certainty is not earned.
Almost every practical recommendation in circulation was established in a population that does not resemble the people now following it.
Reading the dulaglutide titration schedule as a regulatory artefact
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.