Is semaglutide better than dulaglutide, or differently balanced?
What adding GIP activity does, on the current evidence, and what remains unresolved.
Retatrutide
Page 3 of 4 of this archive, newest first.
Why receptor selectivity is the least discussed number in incretin pharmacology
The class is described as though every molecule in it did the same thing. At the receptor, they demonstrably do not.
What we would need to measure to explain the response distribution
A catalogue of open questions, with an assessment of how likely each is to be resolved.
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.
Non-responders, and the honest state of the evidence about them
A catalogue of open questions, with an assessment of how likely each is to be resolved.
GIP was a failed target for thirty years. Then it was not.
The glucagon arm raises energy expenditure and also raises hepatic glucose output. Balancing those is the whole engineering problem.
The GLP-1 receptor is not a switch, and retatrutide is not a key
Receptor pharmacology explains more of the clinical picture than the dose does — and almost none of it appears in the material patients are given.
Is survodutide better than retatrutide, or differently balanced?
Head-to-head data exists for some of these comparisons and not for others. This piece says which.
Accumulation, trough, and the exposure curve nobody draws for patients
An accumulation model, drawn from published parameters, with its assumptions stated.
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.
From cell to clinic: where the extrapolation stops being safe
Receptor pharmacology is strong on average effects and almost silent on individual variation. That gap is where most reader questions live.
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.
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.
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.
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.
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
A catalogue of open questions, with an assessment of how likely each is to be resolved.
A missed dose, modelled: what happens to liraglutide concentrations over the following fortnight
Half-life, accumulation ratio and time to steady state are three separate quantities, and confusing them produces most of the bad advice in circulation.
The half-life question, answered properly
What the pharmacokinetic data supports about dose timing, missed doses and interruption.
One receptor, several signals: the case for reading retatrutide as a biased agonist
What the in-vitro data supports, what it does not, and where the extrapolation to a person begins.