PIONEER 6 cardiovascular safety, read as a safety trial rather than an efficacy one — does this still hold?

PIONEER 6 cardiovascular safety, read as a safety trial rather than an efficacy one — does this still hold? — that is the question, and I have not found it answered plainly anywhere I have looked.

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.

Answering the question the opening post raises rather than the one it answers.

The honest answer on PIONEER 6 cardiovascular safety is that it depends, and the useful part is the list of what it depends on. Four items, in rough order of how much they matter.

Most people get the first two right and then argue about the fourth.

This is the sort of exchange that makes the archive worth searching.

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.

The disagreement above is smaller than it looks once the terms are fixed.

Everything in post #2 holds. The case it does not cover is the one I have.

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.

The number is defensible. The precision I gave it is not.

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.

I am confident about the direction and much less about the magnitude.

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.

If that is already documented somewhere, ignore me and link it.

Post #8 answers the question as asked. The question underneath it is different.

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 separated what I observed from what I concluded, which does not always happen.

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.

I would treat the number as indicative rather than as a measurement.

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.

Narrowing post #9, because the general version has more than one answer.

Reframing PIONEER 6 cardiovascular safety slightly, because I think the disagreement is about the question rather than the answer. If the question is "does it happen", yes. If it is "how often", nobody here knows.

Adding what did not work for me on PIONEER 6 cardiovascular safety, since the failures never get written up and they are half the useful information.

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.

I would put the burden of proof on the interesting explanation, not the dull one.