Coming back to: The SOUL trial and oral semaglutide cardiovascular outcomes posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
The SOUL trial: cardiovascular outcomes trial for oral semaglutide in people with type 2 diabetes and cardiovascular disease or chronic kidney disease. It demonstrates that benefit appears to be a property of the molecule and exposure, not specific to the route.
Coming back to post #59, because the follow-up matters more than the original answer.
Why administration conditions matter for oral semaglutide and not for injectables: the oral formulation depends on a transient pH effect in the stomach. Anything that changes gastric pH or transit time changes absorption. Food does both.
Scoping that to what I have actually seen rather than what I have read.
Post #63 is right about the mechanism and I think understates the practical bit.
PIONEER 6 was a cardiovascular safety trial for oral semaglutide, not an efficacy trial. Non-inferiority for safety was demonstrated. The point estimates favoured the drug but the trial was not designed to establish benefit.
A guess, clearly labelled as one.
Post #63 describes the usual case. This is about the unusual one.
The gastrointestinal tolerability profile of the oral formulation is broadly similar in character to the injectable, which supports the effects being systemic rather than local irritation.
I would hold that lightly until someone with a larger sample weighs in.
PIONEER programme is phase 3 for oral semaglutide. The trials cover multiple indications and durations. Reading them requires attention to which trial is which because they are not all the same question.
No disagreement from me. Posting only so the question does not look ignored.
Confirming post #66 from a second method, which matters more than confirming it from a second person.
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.
It reads as pedantry until the day it does not.
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.
It is worth checking rather than assuming, which costs nothing.
The arithmetic in post #68 is right; the assumption feeding it is the part to check.
Timing consistency matters more for oral dosing than for weekly injection, because absorption depends on the state of the stomach and the state of the stomach varies through the day.
Reading it again, the caveat matters more than the finding.
Collapsed as off-topic by two members at trust level 3 or above
Oral semaglutide's bioavailability is low and variable, which is why the dose numbers are an order of magnitude different from the injectable. That is a formulation consequence and not a difference in potency.
This has been discussed before and I could not find the thread, so, again.
Building on post #70 rather than restating it.
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.
That is the version I would defend. It is not the version I started with.
The absorption enhancer in the licensed oral product works by transiently raising local gastric pH and promoting absorption across the mucosa. It is the reason the fasting and water-volume instructions are specific rather than cautious.
Research-use-only oral material is not a licensed tablet and there is no reason to assume it carries a functioning absorption-enhancement system at all. The formulation is most of the product here.
That is clearer than the version I had in my head. Thank you.
Post #74 is the version of this I will quote in future. One addition.
Anyone comparing published oral and injectable efficacy should check whether the comparison is within one trial or across two. Across two, the populations differ and the comparison is weak.
Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki.
Where I part company with post #77, and it is a narrow parting.
The thirty-minute wait before eating is not conservatism. Food in the stomach materially reduces absorption of the oral product, and the instruction exists because the pharmacokinetic studies measured how much.
The general answer and the answer for your case may diverge here.
Post #78 answers the question as asked. The question underneath it is different.
On variability: the between-person spread in exposure for oral semaglutide is wide enough that two people on the same dose can have quite different plasma concentrations. That is inherent to the absorption route.
Old habit: I write down the expected answer before I calculate it.
Why an oral formulation is a formulation achievement: the molecule is the same but the tablet is novel. Getting a peptide across the gastric epithelium at usable bioavailability is a chemistry problem, not a dose problem.
I would put this at better than even and not much better.
Dose equivalence between oral and injectable formulations is not a simple conversion and no published factor should be used as one. The two were developed and titrated separately.
Same conclusion as the reply above, reached differently, which is mildly reassuring.
Orforglipron is a small molecule rather than a peptide, which changes almost everything about how it is made, stored and analysed. Comparing it to oral semaglutide as though they were the same pharmaceutical problem is a category error.
Adding the caveat now so it does not have to be extracted later.
Worth separating two things that post #81 runs together.
Missed doses behave differently for a daily oral than for a weekly injection. With a short interval you are near a trough rather than perturbing a slowly moving average, and the labelling reflects that.
I looked this up rather than remembered it, which is the right order.
This follows post #81 rather than contradicting it.
Taking the oral product with more water than instructed reduces absorption rather than helping it. That is counter-intuitive and it is one of the few dosing instructions in this field with a clear pharmacokinetic basis.
This settles it for me, at least until somebody posts a reason it should not.
Oral bioavailability is variable between people. Some people absorb well; others absorb poorly. That inter-individual variation is larger than with injectables and is one reason the trial data for oral formulations receives different treatment.
Not the whole picture, but the part of it I can speak to.
PIONEER 6 is the cardiovascular outcome trial for oral semaglutide and it enrolled a diabetes population at high cardiovascular risk. Quoting it outside that population is an extrapolation.
That matches what I was told, which is not the same as knowing it.
Taking post #86 at face value and following it one step further.
Oral versus injectable exposure: comparing a 14 mg oral dose with a 0.5 mg injectable dose is comparing apples to a different fruit. The oral bioavailability is low enough that dose numbers are an order of magnitude different and not directly comparable.
That holds under the stated conditions and I have stated them.
Answering the question post #86 raises rather than the one it answers.
The SOUL trial: cardiovascular outcomes trial for oral semaglutide in people with type 2 diabetes and cardiovascular disease or chronic kidney disease. It demonstrates that benefit appears to be a property of the molecule and exposure, not specific to the route.
The practical argument for an oral is adherence, and the published adherence data is less flattering than the argument. Daily dosing with fasting requirements is not obviously easier than a weekly injection.