Non-responders, and the honest state of the evidence about them
The mechanism is well described. The variance is not.
Pharmacology — 2024
Receptors, exposure, and what the molecules actually do.
Three weeks off is a fresh start, whether or not you want one
Concentrations fall by half a week, so a month away leaves a small fraction of steady state. Resuming at the previous dose presents the receptor with a step it has not seen…
Antiemetics, laxatives and the thin literature underneath them
Constipation is the most tractable of the effects and the most consistently under-managed.
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.
Severity grading, and the gap between a grade and an experience
Almost every figure in circulation about tolerability comes from six publications. This is what they say.
Reflux, early satiety, and the volume the stomach will accept
The clinical effect profile is almost fully predictable from where the receptor is expressed, which is unusual and useful.
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.
Why the fifth week of a dulaglutide dose feels different from the first
An accumulation model, drawn from published parameters, with its assumptions stated.
Delayed emptying explains some of this, and not all of it
What scintigraphy and breath-test studies established about emptying rate, and what they did not.
The interventions with trial support, and the much longer list without
We separate what is supported, what is reasonable, and what is folklore, and we do not pretend the boundaries are crisp.
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.
Maximum tolerated is not maximum approved
Weight reduction in the long programmes flattens at roughly sixty to seventy-two weeks. The timing is consistent, predictable and almost never mentioned in advance.
Discontinuation rates, read honestly
Roughly four to seven per cent of trial participants discontinued for adverse events, mostly gastrointestinal, mostly during escalation. That is the empirical size of the…
Why your endoscopist wants to know about your injection
Holding a dose before a procedure has a kinetic problem: a weekly drug with a seven-day half-life cannot be cleared by skipping one injection.
The mechanism behind the mechanism
The receptor populations that produce satiety and the ones that produce nausea overlap substantially. That is why the ceiling of this drug class is where it is, and it is…
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.