After hearing again and again, for years, that peptide drugs can’t be dosed orally because the gut just digests them, now the news is that the pharmaceutical industry has succeeded in making oral versions of GLP-1 peptides. So what gives?

Looking at this paper, it seems the answer is the combination of:

  1. Permeation enhancers (the main topic of the paper). These seem to be pretty crude: one of the ones discussed in that paper is sodium caprate, literally a soap. Soaps disrupt the lipid bilayers of cell membranes, making holes in the cell membranes of gut cells to let stuff through that otherwise wouldn’t get through.

  2. Avoiding digestive enzymes via a timed-release pill that only releases its contents after most of the digestion is done.

  3. Small-ish molecules. These GLP-1 drugs are relatively small, “peptides” rather than “proteins”. Not that there’s any hard-and-fast distinction between those two categories, but they’re smaller targets rather than bigger ones, which helps at evading digestion and also makes them able to sneak through smaller holes in cell membranes.

  4. Accepting low and highly variable bioavailability. Only a single-digit percentage is absorbed, and that percentage varies a lot from person to person. So they crank up the dose to compensate, and hope the variability doesn’t result in overdoses.

The obvious downside of using permeation enhancers to make microscopic holes in your gut to let in these peptides is that it may let in other stuff that is undesirable, but when the alternative is punching a much larger hole in your skin with a needle, maybe that’s fine.

So, no miracle breakthrough, just a lot of hard work and a lot of accepting downsides.