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.
Semaglutide
Page 10 of 18 of this archive, newest first.
A few hundred participants carry the whole body-composition argument
What was pre-specified, what was exploratory, and what was calculated afterwards by people who did not run the trial.
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.
Vitamin D, adiposity, and a volume-of-distribution problem
Reduced intake is a plausible mechanism for deficiency. Reduced absorption is not, and the two are conflated in most of the advice.
Side effects, cost, supply, target: four reasons with four trajectories
Real-world persistence figures, with their definitions stated, because the definitions are doing most of the work.
Tapering: a word borrowed from drugs with withdrawal syndromes
What a slow reduction could plausibly buy, and what it certainly cannot prevent.
What the outcome trials measured in the kidney
Estimated glomerular filtration rate is a calculation with muscle mass in the denominator of its assumptions. In this population that matters.
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.
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 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…
Side effects, cost, supply, target: four reasons with four trajectories
Why the reason for stopping changes what happens afterwards.
Maximum tolerated is not maximum approved
A plateau at an intermediate dose and a plateau at the maximum dose look identical from the outside and mean different things.
Amylin is not an incretin, and cagrilintide is not a GLP-1 agonist
The glucagon arm raises energy expenditure and also raises hepatic glucose output. Balancing those is the whole engineering problem.
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.
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.
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.
HbA1c and its lag: what a result three months old is telling you
A robust, cheap, standardised assay with a specific and well-catalogued set of failure modes, several of which are common in this population.
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.