Would a sublingual dose be possible/more effective? Research in other (um, yeah, medicinal!) compounds shows that it can be an effective pathway to the bloodstream rather than trying to survive the digestive system.
Sublingual is even harder. The sublingual mucosa is thin but selective. It strongly favors molecules that are small, lipophilic and uncharged. Semaglutide is about 8-10x too big, highly polar and charged.
Injection is really the only method with any substantial bioavailability. BUT, low (<1%) bioavailability does not necessarily mean useless.
If the drug has a relatively low marginal cost of production, and the stomach just breaks down 99% of it without side effects, you can just manufacture 100x more, give it orally, and eat the cost of the 99% that gets lost along the way.
Injectable Semaglutide/Tirzepatide (>99.8% pure) are currently sold at a profit from China for around $2-3/weekly dose. Rybelsus (oral semaglutide) is sold at roughly the same cost per milligram, even though it's made in FDA-approved facilities (you just need to take >= 40x more milligrams per month, bringing it to $1000/month in the USA)
So manufacturing oral doses 100x higher than injectable seems to be economically viable.
Ancedotal but it's really hard for me to do insufflation because of the discomfort. Of course if my life depended on it I could probably do it but otherwise I'd rather not.
Injection is really the only method with any substantial bioavailability. BUT, low (<1%) bioavailability does not necessarily mean useless.