The kidney, the heart and the receptor nobody was looking for
The central effects are not a bonus. On the current evidence they are the principal mechanism of weight loss.
Pharmacology in 2024
Page 2 of 5 of this archive, newest first.
Escalating onto a rising curve
We work the arithmetic out in full, because it is arithmetic and it is short.
Holding the dose before surgery: for whom, for how long
The evidence is real, modest, and mostly retrospective. The guidance is correspondingly cautious and has been revised toward individualisation.
What STEP 4 and SURMOUNT-4 actually established
A plateau at an intermediate dose and a plateau at the maximum dose look identical from the outside and mean different things.
Do you need the top of the ladder?
The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth climbing.
The tolerability data everybody quotes and nobody reads
Trial adverse-event tables count episodes reported to a study nurse. They are the best data we have and they systematically under-record the mundane.
Amylin is not an incretin, and cagrilintide is not a GLP-1 agonist
The glucagon arm raises energy expenditure and also raises hepatic glucose output. Balancing those is the whole engineering problem.
What actually helps, ranked by evidence
The intervention with the clearest evidence is the one nobody frames as an intervention: adjusting the dose.
Where the receptor is: a tissue-by-tissue account of tirzepatide’s reach
The same receptor population that produces the therapeutic effect produces the commonest adverse one.
Holding a dose is a decision, not a failure
Reducing a dose is not going backwards. In a tolerability-limited class it is the mechanism by which the ceiling is found.
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.
Discontinuation rates, read honestly
An effect is dose-limiting when it prevents adequate intake, prevents normal activity, or produces a risk of its own. Discomfort alone is not the test.
Six things incretin pharmacology cannot currently predict
The mechanism is well described. The variance is not.
The limits of mechanism: why receptor data will not tell you who responds
The mechanism is well described. The variance is not.
The area postrema, and the anatomy of an unwanted effect
A single drug producing both constipation and diarrhoea looks contradictory until the motility data is read properly.
Target dose, effective dose, and the distance between them
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.
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 interventions with trial support, and the much longer list without
The intervention with the clearest evidence is the one nobody frames as an intervention: adjusting the dose.
Discontinuation rates, read honestly
An effect is dose-limiting when it prevents adequate intake, prevents normal activity, or produces a risk of its own. Discomfort alone is not the test.
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.