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ForumsOral GLP-1 AgonistsIs oral sema actually as effective as the injection version? — looking for input

Is oral sema actually as effective as the injection version? — looking for input

BiostatsBrad Wed, Jun 26, 2024 at 3:35 AM 11 replies 1,970 viewsPage 1 of 3
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BiostatsBrad
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Jun 26, 2024 at 3:35 AM#1

This is the version of the explanation I wish somebody had given me, written down before I forget what confused me. It is about oral semaglutide, and it is deliberately narrow — everything I am not confident about is marked as such.

What is actually established

Oral semaglutide is absorbed in the stomach with the help of SNAC, which locally raises pH and protects the peptide long enough to cross. That mechanism is fragile: bioavailability is roughly 1% and highly sensitive to gastric contents, so a mouthful of coffee genuinely changes the exposure. This is why the label wants 30 minutes and no more than half a glass of plain water.

The condition it depends on

Worth adding that the tablet is taken daily, so a missed dose costs far less than a missed weekly injection. That is a genuine advantage nobody lists.

The practical version

The practical numbers: about 1% oral bioavailability, 30 minutes fasted before food, no more than 120ml of plain water, and coffee counts as food for this purpose.

What I am not sure about

The bit I cannot resolve on my own is how much of the oral variability is the SNAC absorption window and how much is dose, because the two get conflated constantly. Tell me what I have not thought of.

— BiostatsBrad · corrections welcome and will be edited into this post with credit
46 16LindaRN_retired, tommy_boulder, hyun_seoul and 43 others
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LipidDoc_ATL
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Jun 26, 2024 at 3:58 AM#2
BiostatsBrad said:
Oral semaglutide is absorbed in the stomach with the help of SNAC, which locally raises pH and protects the peptide long enough to cross.

That is correct as far as it goes, and here is where it stops going. Orforglipron is the more interesting oral story because it is not a peptide at all. Being a small molecule it does not need SNAC, does not need the fasting window, and has oral bioavailability in the tens of percent rather than about one.

45 15traveltech_sara, AttorneyGrant, DebRD_ATL and 42 others
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TrialNerd_Beth
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Jun 26, 2024 at 4:21 AM#3
BiostatsBrad said:
Oral semaglutide is absorbed in the stomach with the help of SNAC, which locally raises pH and protects the peptide long enough to cross.

I do not accept that the fasting window is a minor inconvenience. Adherence data on daily orals with timing requirements is consistently worse than weekly injections, and a drug you take imperfectly is a lower dose than the one on the box.

Last edited: Jun 26, 2024 at 8:21 AM
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PedsEndoPhilly
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Jun 26, 2024 at 4:44 AM#4

Taking the question as asked, rather than the general version of it. The OASIS programme put 50mg oral in the same territory as 2.4mg injectable — around 15% mean weight loss — but it needed a dose 20 times larger to get there because almost none of the tablet is absorbed. The dose numbers are not comparable across routes and quoting them side by side confuses people.

Last edited: Jun 26, 2024 at 9:44 AM
43 13Dr.LeslieOBGYN, MikeNYC_runner and 40 others
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sarah_TO
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Jun 26, 2024 at 6:50 AM#5
LipidDoc_ATL said:
Orforglipron is the more interesting oral story because it is not a peptide at all.

Same experience, arrived at from the opposite direction.

42 12DanielChem_CHI, marco_milano, pam_columbus and 39 others
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