The supply gap as a clinical event
The trials studied planned withdrawal. Almost nobody stops that way.
Titration
Page 8 of 14 of this archive, newest first.
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.
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.
The shortage years, and what they taught about interruption
The trials studied planned withdrawal. Almost nobody stops that way.
Why people actually stop, in the order they actually stop
Why the reason for stopping changes what happens afterwards.
What the trials counted as intolerance
The ceiling varies severalfold between people, and nothing measurable at baseline predicts where it sits.
What happens when the drug is taken away: three randomised answers
What was withdrawn, from whom, after how long, and what was measured afterwards.
Tolerability is the ceiling, and the ceiling is personal
Trial discontinuation figures are a floor, not an estimate: trial populations are supported in ways ordinary patients are not.
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.
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 dose you were told to reach and the dose you will actually stay on
The published ladder exists because a protocol needed a single number. Practice has never followed it exactly, and the regulatory file never assumed it would.
What TRIUMPH-3 tells us about maintenance, and what it does not
Every withdrawal trial compared full dose against nothing. The clinically interesting comparison — full dose against a reduced one — has not been randomised.
Attribution is the hard part
Pancreatitis is rare, was adjudicated in the outcome programmes, and did not show the imbalance early case reports suggested.
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…
What SURPASS-4 tells us about maintenance, and what it does not
Every withdrawal trial compared full dose against nothing. The clinically interesting comparison — full dose against a reduced one — has not been randomised.
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.
The arithmetic of a step: what doubling a dose actually asks of you
What the published pharmacokinetics permit, what the labels state, and where the two diverge.
What the trials counted as intolerance
We set out the questions that distinguish a symptom to manage from a dose to change.