Coming back to: The SOUL trial and oral semaglutide cardiovascular outcomes

The SOUL trial and oral semaglutide cardiovascular outcomes — setting out what I have, and where I think it stops being reliable.

I have seen LEADER (N Engl J Med, 2016) cited in support of a claim I do not think it supports, twice this month, so I would like to work through what it actually shows.

My reading is that the trial is sound for its own question and is being stretched to answer a different one. I might be wrong about that, which is why this is a topic rather than a correction.

What I would like from this discussion: someone who disagrees with me to say why, with the section of the paper they are relying on.

Fasting instructions are not optional advice. Taking the tablet with food or with more than a sip of water measurably reduces absorption. This is the one compound in the class where the instructions genuinely determine the exposure.

Trial adherence in an oral trial with strict administration requirements is genuinely worse than trial-published data often suggests. That is why the exposure variability in oral formulations is mentioned repeatedly in the discussions here.

SNAC is the sodium N-(8-[2-hydroxybenzoyl]amino) caprylate, an absorption enhancer that transiently raises local pH in the stomach and promotes gastric mucosal absorption. Without it, oral bioavailability of semaglutide would be too low for clinically useful dosing.

Worth separating two things that post #45 runs together.

Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing.

The correction was fair and I had been repeating something I had not checked carefully enough.

On post #54 — agreed on the reasoning, with one qualification.

Dose numbers for oral formulations are not comparable to injectable ones. The 14 mg oral dose is not equivalent to any injectable dose in the traditional comparison sense. They are different formulations with different pharmacokinetics and cannot be put on the same scale.

Picking up post #81: that is the part I would want checked first.

Orforglipron is a small molecule, not a peptide. That changes almost everything: no absorption enhancer required, no fasting window, chemical synthesis instead of peptide synthesis, different analytical methods entirely. Data from peptide agonists does not transfer.

Orforglipron is a small molecule, not a peptide. That changes almost everything: no absorption enhancer required, no fasting window, chemical synthesis instead of peptide synthesis, different analytical methods entirely. Data from peptide agonists does not transfer.