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ForumsOral GLP-1 AgonistsDanuglipron dose optimization — looking for input

Danuglipron dose optimization — looking for input

bbq_ray_KC Thu, Jan 9, 2025 at 9:03 AM 12 replies 1,816 viewsPage 1 of 3
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bbq_ray_KC
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Jan 9, 2025 at 9:03 AM#1

A reference post rather than a discussion. Corrections are the point; I would rather this be right than mine. 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

So the question, as narrowly as I can put it: how much of the oral variability is the SNAC absorption window and how much is dose, because the two get conflated constantly. I have searched first, so if this is covered somewhere point me at it and I will read it.

— bbq_ray_KC · corrections welcome and will be edited into this post with credit
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HPLC_Greg
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Jan 9, 2025 at 9:53 AM#2
bbq_ray_KC 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.

No disagreement with bbq_ray_KC. One condition attached. 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.

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Dr.PeteFamMed
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Jan 9, 2025 at 10:43 AM#3
bbq_ray_KC 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.

3 23LindaRN_retired, tommy_boulder, hyun_seoul
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PharmD_Rodriguez
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Jan 9, 2025 at 11:33 AM#4

Answering the narrow version, because the broad one does not have a single answer. 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.

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sarah_TO
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Jan 9, 2025 at 4:17 PM#5
HPLC_Greg said:
Orforglipron is the more interesting oral story because it is not a peptide at all.

Same pattern here, and in the same order.

Last edited: Jan 9, 2025 at 8:17 PM
1 21DanielChem_CHI
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