Escalating onto a rising curve
We work the arithmetic out in full, because it is arithmetic and it is short.
Tirzepatide
Page 9 of 18 of this archive, newest first.
Fat mass fell more than lean mass. That is the finding, and it is not the headline.
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.
From cell to clinic: where the extrapolation stops being safe
The mechanism is well described. The variance is not.
Vagal afferents, the area postrema, and the anatomy of nausea
A tour of the tissues where the receptor is expressed, and what happens in each.
The advice is mostly reasonable. The certainty is not earned.
Almost every practical recommendation in circulation was established in a population that does not resemble the people now following it.
The GLP-1 receptor is not a switch, and survodutide is not a key
What the in-vitro data supports, what it does not, and where the extrapolation to a person begins.
The incretin receptors, ranked by how much we actually know about them
Selectivity, potency and efficacy are three different measurements. The trade routinely reports none of them.
The upper rungs, ranked by evidence
Where the curve flattens, what flattens with it, and what does not.
Two sessions a week, and the evidence behind the prescription
One randomised trial has combined a GLP-1 receptor agonist with supervised exercise. Its result is the single most useful piece of evidence in this area.
The out-of-range flag is a statistical convention with a printer attached
A twelve-analyte panel in a perfectly healthy person has roughly even odds of producing at least one flagged result.
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.
Vagal afferents, the area postrema, and the anatomy of nausea
A tour of the tissues where the receptor is expressed, and what happens in each.
The limits of mechanism: why receptor data will not tell you who responds
Receptor pharmacology is strong on average effects and almost silent on individual variation. That gap is where most reader questions live.
What a month without the drug does to tolerability
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…
What STEP 8 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.
SURMOUNT-OSA was built to answer the stopping question, and it did
The evidence on stopping is better than the evidence on almost anything else in this field, because somebody deliberately randomised it.
When a symptom is information and when it is noise
A dose held long enough stops being a pause and becomes a maintenance decision. That transition is rarely made explicitly.
Two sessions a week, and the evidence behind the prescription
The older-adult diet-and-exercise trials are the closest analogue to rapid pharmacological weight loss, and they are twenty years old.
A year after stopping: what the trials found at the far end
The variance around the mean regain trajectory is large and unexplained, exactly as it is for the weight loss.
Do you need the top of the ladder?
The dose-response curve in this class flattens near its top. That has direct consequences for whether the final rung is worth climbing.