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.
Pharmacology in 2025
Page 4 of 5 of this archive, newest first.
The upper rungs, ranked by evidence
Where the curve flattens, what flattens with it, and what does 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.
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…
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…
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 a month without the drug does to tolerability
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…
The mechanism behind the mechanism
A single drug producing both constipation and diarrhoea looks contradictory until the motility data is read properly.
Delayed emptying explains some of this, and not all of it
A single drug producing both constipation and diarrhoea looks contradictory until the motility data is read properly.
When a symptom is information and when it is noise
The practice is near-universal, clinically sensible, and supported by observational data rather than randomised comparison. We say which is 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.
Antiemetics, laxatives and the thin literature underneath them
Constipation is the most tractable of the effects and the most consistently under-managed.
The eighteenth month, and the conversation that should have happened in the third
The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth climbing.
Holding a dose is a decision, not a failure
Nausea and gastric delay attenuate over weeks at an unchanged dose. That single physiological fact is the entire justification for holding.
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 trials counted as intolerance
The ceiling varies severalfold between people, and nothing measurable at baseline predicts where it sits.
Holding the dose before surgery: for whom, for how long
A drug that delays gastric emptying complicates the assumption behind every fasting instruction in perioperative medicine. The professional bodies have moved twice on this…
Stepping down is part of titration
Every major phase 3 protocol in this class allowed escalation to be delayed for tolerability. Almost no product label explains the mechanics of doing so.
The trade has decided the ceiling is arbitrary. The trials disagree.
Higher doses of these molecules have been studied. In general they produced modest additional efficacy and disproportionate additional symptom burden, which is why the…
What a month without the drug does to tolerability
The convention — resume lower, re-escalate — is not caution. It follows directly from the elimination half-life.