The upper rungs, ranked by evidence
Where the curve flattens, what flattens with it, and what does not.
Titration
Page 2 of 14 of this archive, newest first.
What STEP 4 and SURMOUNT-4 actually established
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.
Adverse events by dose, adverse events by week
Almost every figure in circulation about tolerability comes from six publications. This is what they say.
Dose-limiting: a definition worth being strict about
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.
Seasonal use, holiday use, and the honest state of the evidence
A great deal of practice has grown up around intermittent schedules. The randomised evidence for any of them is, as far as the Journal can establish, nil.
Target dose, effective dose, and the distance between them
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.
Holding the dose before surgery: for whom, for how long
This is the single interaction with ordinary medical care that patients most need to disclose, and it is the one most often not asked about.
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.
What the tirzepatide schedule assumes about a person it has never met
What the published pharmacokinetics permit, what the labels state, and where the two diverge.
Tolerability is the ceiling, and the ceiling is personal
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 supply gap as a clinical event
Cost is the modal reason for discontinuation in every dataset we have seen, and it is absent from the clinical literature.
Forty-four per cent: reading the nausea figure properly
Severity in these tables is graded by interference with activity, not by how unpleasant the experience was. Those are different measurements.
The lowest effective dose is a real concept with almost no data behind it
A survey of the maintenance evidence, which is shorter than the survey of the withdrawal evidence.
The mechanism behind the mechanism
Delayed gastric emptying is a mechanism that becomes an adverse effect above a threshold. It is not a complication in the ordinary sense.
Pancreatitis, obstruction, gallbladder: three things nausea can be
Rapid weight loss by any means raises gallstone risk. Separating that from a direct drug effect requires a comparator, and the trials have one.
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.
A design note on withdrawal trials, and why the run-in matters
The evidence on stopping is better than the evidence on almost anything else in this field, because somebody deliberately randomised it.
REWIND was built to answer the stopping question, and it did
Three randomised withdrawal designs have tested what happens when treatment stops. Their results are consistent and they are consistently misreported.
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.
Dose-limiting: a definition worth being strict about
Trial discontinuation figures are a floor, not an estimate: trial populations are supported in ways ordinary patients are not.