Reading the semaglutide composition data without the press release
A substudy powered to describe a mean is not a substudy powered to detect a clinically meaningful individual change.
Tirzepatide
Page 7 of 18 of this archive, newest first.
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.
There is no discontinuation syndrome, and that changes the argument
The best argument for tapering is behavioural rather than pharmacological, and it deserves to be made on its own terms.
What STEP 4 and SURMOUNT-4 actually established
The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth climbing.
The substudies, read properly: who was scanned, when, and with what
The composition data comes from imaging substudies enrolling a few score participants at selected sites. It is the best evidence available and it is thin.
Grams per kilogram of what? The denominator problem in protein guidance
The denominator matters more than the ratio: per kilogram of body weight, of ideal weight, or of lean mass gives three different targets.
A supply gap is a pharmacological event
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…
Escalating past the approved maximum, examined honestly
Higher doses of these molecules have been studied. In general they produced modest additional efficacy and disproportionate additional symptom burden, which is why the…
Escalating onto a rising curve
What the published pharmacokinetics permit, what the labels state, and where the two diverge.
What the GIP receptor adds: reading orforglipron as two drugs in one sequence
The glucagon arm raises energy expenditure and also raises hepatic glucose output. Balancing those is the whole engineering problem.
A supply gap is a pharmacological event
One omitted dose is a labelling question. Four omitted doses is a clinical one. The two are routinely conflated.
Bone density during rapid weight loss: what is known, which is less than you would hope
What the Journal would want measured before treating this as settled in either direction.
The advice is mostly reasonable. The certainty is not earned.
The gap between a defensible recommendation and a confident one is where most of the harm in this subject lives.
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 that got you here and the dose that keeps you here
Every withdrawal trial compared full dose against nothing. The clinically interesting comparison — full dose against a reduced one — has not been randomised.
Percentage of loss, absolute kilograms, and the sleight of hand between them
The trials measured mass. Nobody measured whether the participants got weaker.
Grams per kilogram of what? The denominator problem in protein guidance
A survey of what the meta-analyses support, with the populations named.
The out-of-range flag is a statistical convention with a printer attached
A flag is a probability statement about a population. It is not a statement about the person holding the printout.
The imaging substudy is an afterthought in the protocol and the centrepiece of the debate
The trials measured mass. Nobody measured whether the participants got weaker.
The one randomised trial that combined an incretin with supervised exercise
Mass and function are different endpoints and training affects them differently. Most coverage treats them as one.