The kidney, the heart and the receptor nobody was looking for
The central effects are not a bonus. On the current evidence they are the principal mechanism of weight loss.
Semaglutide
Page 13 of 18 of this archive, newest first.
Escalating onto a rising curve
We work the arithmetic out in full, because it is arithmetic and it is short.
The dose that got you here and the dose that keeps you here
What the labels permit, what clinicians do, and the size of the gap between them.
What the placebo arms of the withdrawal trials actually tell us
What was withdrawn, from whom, after how long, and what was measured afterwards.
Accumulation, trough, and the exposure curve nobody draws for patients
An accumulation model, drawn from published parameters, with its assumptions stated.
What STEP 4 and SURMOUNT-4 actually established
A plateau at an intermediate dose and a plateau at the maximum dose look identical from the outside and mean different things.
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.
Where the receptor is: a tissue-by-tissue account of tirzepatide’s reach
The same receptor population that produces the therapeutic effect produces the commonest adverse one.
From cell to clinic: where the extrapolation stops being safe
Receptor pharmacology is strong on average effects and almost silent on individual variation. That gap is where most reader questions live.
Weight regain is not a failure of willpower and it is not a mystery
Regain begins immediately, proceeds at a decelerating rate, and does not usually return to baseline within the observed follow-up. Each of those three clauses matters.
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 dose that got you here and the dose that keeps you here
The commonest real-world strategy in this drug class is the least studied one.
Every fortnight, every third week, seasonally: an unstudied practice
An absence of evidence is not evidence of harm. It is also not a licence.
Where the receptor is: a tissue-by-tissue account of tirzepatide’s reach
The same receptor population that produces the therapeutic effect produces the commonest adverse one.
Two scans, six weeks apart, and the arithmetic of believing the difference
A body-composition report gives four decimal places and no confidence interval. That is the whole difficulty in one sentence.
Holding a dose is a decision, not a failure
Reducing a dose is not going backwards. In a tolerability-limited class it is the mechanism by which the ceiling is found.
Beta-arrestin, cAMP, and the part of exenatide’s mechanism nobody quotes
The receptor is expressed in more tissues than the popular account allows, and that is the whole story.
The incretin receptors, ranked by how much we actually know about them
The class is described as though every molecule in it did the same thing. At the receptor, they demonstrably do not.
Maintenance dosing: what is licensed, what is practised, and what is evidenced
Dose reduction is not withdrawal, and the trials that tested withdrawal cannot be read as testing it.
Which results are findings and which are consequences of the weight loss
The estimated glomerular filtration rate is calculated from creatinine, creatinine comes from muscle, and muscle mass is falling. The arithmetic is unforgiving.