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.
Retatrutide
Page 2 of 4 of this archive, newest first.
From cell to clinic: where the extrapolation stops being safe
The mechanism is well described. The variance is not.
The GLP-1 receptor is not a switch, and survodutide is not a key
What the in-vitro data supports, what it does not, and where the extrapolation to a person begins.
Vagal afferents, the area postrema, and the anatomy of nausea
A tour of the tissues where the receptor is expressed, and what happens in each.
The limits of mechanism: why receptor data will not tell you who responds
Receptor pharmacology is strong on average effects and almost silent on individual variation. That gap is where most reader questions live.
Three receptors, one peptide: the design problem behind triple agonism
Head-to-head data exists for some of these comparisons and not for others. This piece says which.
The limits of mechanism: why receptor data will not tell you who responds
Receptor pharmacology is strong on average effects and almost silent on individual variation. That gap is where most reader questions live.
What the GLP-1 receptor actually does when tirzepatide binds it
The class is described as though every molecule in it did the same thing. At the receptor, they demonstrably do not.
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.
The glucagon receptor arm, and why it is the hardest to reason about
What adding GIP activity does, on the current evidence, and what remains unresolved.
What the GLP-1 receptor actually does when exenatide binds it
The receptor is expressed in more tissues than the popular account allows, and that is the whole story.
Dual, triple, co-formulated: a taxonomy the coverage keeps collapsing
The glucagon arm raises energy expenditure and also raises hepatic glucose output. Balancing those is the whole engineering problem.
Non-responders, and the honest state of the evidence about them
The mechanism is well described. The variance is not.
What we would need to measure to explain the response distribution
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.
Why a drug that acts on the pancreas changes what food tastes like
A tour of the tissues where the receptor is expressed, and what happens in each.
The kidney, the heart and the receptor nobody was looking for
The same receptor population that produces the therapeutic effect produces the commonest adverse one.
Albumin, fatty-acid chains, and the engineering that made a weekly incretin possible
An accumulation model, drawn from published parameters, with its assumptions stated.
Why a drug that acts on the pancreas changes what food tastes like
A tour of the tissues where the receptor is expressed, and what happens in each.
Non-responders, and the honest state of the evidence about them
The mechanism is well described. The variance is not.