This is the version of the explanation I wish somebody had given me, written down before I forget what confused me. It is about semaglutide, and it is deliberately narrow — everything I am not confident about is marked as such.
What is actually established
Albumin binding above 99% is the whole reason weekly dosing works, and it is also why the trough matters more than the peak. People who dose late are not losing a peak, they are letting the trough fall, and the appetite effect tracks the trough.
The condition it depends on
"tolerable" needs defining. A dose you tolerate by eating almost nothing is not tolerated, it is being paid for somewhere else — usually in lean mass, sometimes in adherence three months later.
The practical version
For anyone assembling their own picture: Tmax is one to three days, terminal half-life about 165 to 170 hours, steady state at four to five weeks, and subcutaneous bioavailability near 89%. Those four numbers explain most of the questions people ask about timing.
What I am not sure about
So the question, as narrowly as I can put it: what the dose-response curve actually looks like above 1.7mg, because the trial means hide how few people account for the extra loss. Numbers rather than impressions, if you have them.
InsuranceTom said:Albumin binding above 99% is the whole reason weekly dosing works, and it is also why the trough matters more than the peak.
All true, with one condition: that curve is for people who reached the dose on schedule. Anyone who slowed the ladder for tolerability is on a different, flatter curve, and comparing yourself with the published mean will make you feel like a non-responder when you are not.
InsuranceTom said:Albumin binding above 99% is the whole reason weekly dosing works, and it is also why the trough matters more than the peak.
Filing a mild objection. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit. The trial means are being read too generously in this thread. STEP populations were selected, supported, and titrated by protocol, and the real-world curves are consistently a few points worse. That difference is not noise, it is what happens when you remove the study infrastructure.
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Browse GL BiochemAnswering the narrow version, because the broad one does not have a single answer. The dose-response is real but shallow at the top. Across STEP 1 and STEP 4 the gap between 1.7mg and 2.4mg is a couple of percentage points of body weight on average, and the average is carrying a wide spread — plenty of people at 1.7mg sit above the 2.4mg mean. If a dose is working and tolerable, "working" is the relevant variable, not "maximal".
FDA_TrackerJim said:All true, with one condition: that curve is for people who reached the dose on schedule.
That holds for the injectable. The oral formulation has different absorption behaviour and the dose numbers are not interchangeable, which is worth saying out loud because people quote them as if they were.