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. If it helps: the failure mode here is usually boring rather than dramatic.
PIONEER 6 cardiovascular safety, read as a safety trial rather than an efficacy one — setting out what I have, and where I think it stops being reliable.
Posting a small dataset on PIONEER 6 cardiovascular safety. It is mine, it is uncontrolled, and the method is stated so it can be discounted appropriately.
What I would like is not agreement but a second dataset collected by someone with no stake in mine. If one exists I would rather read it than argue for this one.
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.
The honest answer is that it depends, and here is what it depends on.
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.
Take the reasoning and check the arithmetic; I do not always get it right.
Post #3 and I disagree about the size of the effect, not about the direction.
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.
Taking post #3 at face value and following it one step further.
The confident answers on PIONEER 6 cardiovascular safety and the well-sourced answers are not the same answers, which is the most useful thing I have learned reading this category.
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.
That holds for the case as described. Change the assumptions and it may not.
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.
If it helps: the failure mode here is usually boring rather than dramatic.
Building on post #7 rather than restating it.
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.
I have changed my mind on this once already, so take it as current rather than settled.
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.
Excipients are not inert from an analytical point of view. A certificate for a formulated tablet has to account for them, and one that reports a purity figure without saying what the figure is a proportion of is ambiguous.
The conclusion is tentative; the arithmetic underneath it is not.
Answering the question post #10 raises rather than the one it answers.
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.
That is all I can say without guessing.
Adding the measurement that post #16 says would settle 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.
That distinction has done more work for me than anything else in this category.
I had read the opposite somewhere and cannot now find where, which tells me something.
Answering the PIONEER 6 cardiovascular safety question as asked, then the question I think is meant. As asked: yes, with the qualification below. As meant: it depends on how the first measurement was taken.
I had written a reply contradicting post #19 and deleted it. Here is what survived.
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.
Post #19 and I disagree about the size of the effect, not about the direction.
The arithmetic on PIONEER 6 cardiovascular safety is the easy part and it is where the errors are, which is an uncomfortable combination. Show your working and someone will catch it.
Taking post #19 at face value and following it one step further.
My position on PIONEER 6 cardiovascular safety is current rather than settled. I have revised it once already and I expect to again, so treat it accordingly.
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.
Post #24 put the caveat in the right place and I want to underline it.
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.
That is the honest state of it as of this week.
If you are new and reading this thread for the answer to PIONEER 6 cardiovascular safety: the answer is conditional, the conditions are in the third reply, and the rest of the thread is worth skipping.
The arithmetic in post #27 is right; the assumption feeding it is the part to check.
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.
I checked the source rather than the summary, and they differ.
| Topic | Participants | Replies | Views | Activity |
|---|---|---|---|---|
|
Oral versus injectable exposure: comparing apples to a different fruit
Oral versus injectable exposure: comparing apples to a different fruit — setting out what I have, and where I think it stops being reliable. Something about oral versus injectable exposure does not reconcile…
|
+19 | 23 | 332 | 8mo |
|
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. SOUL trial and oral semaglutide — I have the observation and I do not trust my…
|
+100 | 104 | 4.2k | 5mo |
|
Oral versus injectable exposure: comparing apples to a different fruit — a second dataset
Posting this under the heading it deserves: Oral versus injectable exposure: comparing apples to a different fruit — a second dataset Everything below is what sits behind that. Something about Oral versus…
|
+27 | 31 | 17k | 25d |
|
The SOUL trial and oral semaglutide cardiovascular outcomes
Posting this under the heading it deserves: The SOUL trial and oral semaglutide cardiovascular outcomes Everything below is what sits behind that. Collecting what is known about SOUL trial and oral…
|
2 | 7.1k | 9h | |
|
Why oral semaglutide needs an absorption enhancer at all — one year on
Why oral semaglutide needs an absorption enhancer at all — one year on — that is the question, and I have not found it answered plainly anywhere I have looked. Reading back through what has been written here…
|
+11 | 15 | 17k | 24d |
| Topic | Participants | Replies | Views | Activity |
|---|---|---|---|---|
|
Composite endpoints and the component doing the work
Composite endpoints and the component doing the work Writing it up because I had to work it out twice and would rather nobody else did. Collecting what is known about composite endpoints in one place, because…
|
+3 | 7 | 33k | 13h |
|
Journal club: what we got wrong in an earlier session
On the subject in the title: Journal club: what we got wrong in an earlier session Working notes rather than a conclusion. Bringing a claim rather than a paper, because the claim is the thing circulating. The…
|
+114 | 125 | 2.5k | 23h |
|
Journal club: SURMOUNT-OSA and a hard endpoint in a soft field
Posting this under the heading it deserves: Journal club: SURMOUNT-OSA and a hard endpoint in a soft field Everything below is what sits behind that. Collecting what is known about SURMOUNT-OSA in one place,…
|
+47 | 51 | 617 | 16mo |
|
Semaglutide half-life: where the 165 to 184 hour figure comes from — what changed since
Posting this under the heading it deserves: Semaglutide half-life: where the 165 to 184 hour figure comes from — what changed since Everything below is what sits behind that. Putting the numbers in the first…
|
+125 | 132 | 39k | 16mo |
|
Why oral semaglutide needs an absorption enhancer at all — one year on
Why oral semaglutide needs an absorption enhancer at all — one year on — that is the question, and I have not found it answered plainly anywhere I have looked. Reading back through what has been written here…
|
+11 | 15 | 17k | 24d |