What the trials counted as intolerance
The ceiling varies severalfold between people, and nothing measurable at baseline predicts where it sits.
Pharmacology
Page 7 of 12 of this archive, newest first.
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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.
The steps get smaller as the ladder gets higher, and that is deliberate
What the published pharmacokinetics permit, what the labels state, and where the two diverge.
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.
How a peptide that lasts seven days binds a receptor that recycles in minutes
A tour of what happens in the thirty seconds after binding, and why it matters at week thirty.
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…
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.
When to stop escalating and when to stop entirely
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
We set out the questions that distinguish a symptom to manage from a dose to change.
The interventions with trial support, and the much longer list without
Almost nothing in the standard management repertoire has been tested in a randomised trial in this specific population. We say what is extrapolated and from where.
Holidays, surgery, sickness: interruption in practice
Supply interruption is the commonest cause of unplanned re-titration in this market, and it is almost never framed that way.
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.
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.