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.
Pharmacology
Page 4 of 12 of this archive, newest first.
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The glucagon receptor arm, and why it is the hardest to reason about
A dual agonist is one molecule with two receptor activities. A co-formulation is two molecules in one pen. The coverage treats them as synonyms.
Attribution is the hard part
Rapid weight loss by any means raises gallstone risk. Separating that from a direct drug effect requires a comparator, and the trials have one.
Non-responders, and the honest state of the evidence about them
The mechanism is well described. The variance is not.
Target dose, effective dose, and the distance between them
The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth climbing.
Why the fifth week of a mazdutide dose feels different from the first
The exposure curve explains the timing of both the benefit and the side effects. It is almost never shown to the person injecting.
Vagal afferents, the area postrema, and the anatomy of nausea
Receptor expression maps explain the effect profile better than any dose-response curve.
Forty-four per cent: reading the nausea figure properly
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.
Background rates, and why they matter for attribution
Pancreatitis is rare, was adjudicated in the outcome programmes, and did not show the imbalance early case reports suggested.
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.
Do you need the top of the ladder?
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 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.
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.
The interventions with trial support, and the much longer list without
Dietary measures are widely recommended, plausible on mechanism, and supported mainly by observational data and clinical experience.
What the trials counted as intolerance
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 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 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.
When a symptom is information and when it is noise
Nausea and gastric delay attenuate over weeks at an unchanged dose. That single physiological fact is the entire justification for holding.
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.