A Brief History of Oral Peptides
Semaglutide is a peptide. Your stomach’s entire job is to destroy peptides.
It’s the whole point of your stomach. Your GI tract is a 30-foot disassembly line for proteins. Acid denatures them, pepsin cleaves them, trypsin finishes the job. The mucus layer on your intestines blocks absorption as well.
Anything that looks like a chain of amino acids gets shredded into fragments before it can reach your bloodstream. This is what’s supposed to happen. It’s how you digest food. It’s also the reason that for over a century, every attempt to deliver a therapeutic peptide by mouth has run into the same wall.
The first attempt at oral insulin was in 1922, one year after the protein’s discovery. Researchers gave patients the highest doses they could tolerate and got nothing close to the effect of a simple injection. That was a hundred years ago. Since then, thirteen different companies have tried to crack oral insulin. Nine decades of work, and not a single commercial product exists. Peptide drugs on average have oral bioavailability below 1-2%. For comparison, metformin, one of the most common diabetes drugs in the world, has oral bioavailability of 40-60%.
So when Novo Nordisk announced they’d figured out how to deliver semaglutide in a pill, it was a genuinely remarkable scientific achievement. They didn’t fully solve the oral peptide problem, but they just barely squeezed past it using a molecule called SNAC.
How SNAC Works
SNAC, salcaprozate sodium, was developed by a company called Emisphere Technologies over the course of decades. Emisphere started screening modified amino acid compounds for permeation-enhancing effects in the 1990s, eventually landing on SNAC as their lead candidate. Their first commercial product using SNAC was an oral vitamin B12, approved as a medical food in 2015.
Novo Nordisk partnered with Emisphere in 2007 and licensed the technology for their GLP-1 program. In 2020, Novo acquired Emisphere outright for $1.8 billion, assigned about a hundred researchers in Copenhagen to improving SNAC, and got to work expanding it across their pipeline.
SNAC actually does three things simultaneously:
It buffers the local pH in your stomach, which suppresses pepsin activation and protects semaglutide from degradation.
It changes the polarity of the solution around the dissolving tablet, which prevents semaglutide molecules from clumping into oligomers, keeping them in their active monomeric form.
It incorporates itself into the lipid membranes of your gastric cells, temporarily fluidizing them so that semaglutide molecules can slip through via transcellular transport.
Fifteen years of development, over 9,500 patients across ten phase 3 trials, and the result is 0.8% bioavailability.
99.2% of what you swallow gets destroyed. That 0.8% is the entire product.
SNAC is not a general-purpose permeation enhancer. It’s remarkably specific. Novo tried it with liraglutide, a closely related GLP-1 analog, and it failed because liraglutide forms oligomers that SNAC can’t break apart the same way. Even within the same drug class, against a molecule that differs by a handful of amino acids, the technology didn’t transfer. It’s not a generic “absorption booster” you can swap in and out.
SNAC Alternatives
SNAC is also not the only permeation enhancer anyone’s ever tried. There’s sodium caprate, known as C10. Novo Nordisk actually used C10 to develop an oral long-acting insulin called IO338, which got to phase 2 trials and achieved an estimated oral bioavailability of 1-2%, higher than semaglutide. But it took roughly 60 times the subcutaneous dose to get equivalent blood sugar effects, and the cost of that much insulin made the product commercially impractical.
Then there’s sodium caprylate, C8, used in a technology called TPE, Transient Permeation Enhancer, developed by a company called Chiasma. TPE is the basis for Mycapssa, an oral formulation of octreotide approved by the FDA in June 2020 for acromegaly. It’s the only other FDA-approved oral peptide drug that relies on a permeation enhancer. Its oral bioavailability is about 0.7%. The 20mg oral dose replicates the pharmacokinetic profile of a 0.1mg subcutaneous injection.
So to summarize the state of the art in oral peptide delivery: there are exactly two FDA-approved products that use permeation enhancers to get peptides into your bloodstream through your GI tract. Both achieve sub-1% bioavailability. Both required over a decade of development, thousands of clinical trial participants, and hundreds of millions of dollars. Both use specific, well-characterized chemical enhancers with published mechanisms of action and extensive safety data. And scientists in the field describe the need for better permeation enhancers as one of the largest unmet needs in pharmaceutical development.
What is Hims selling?
Hims doesn’t have SNAC. They don’t have C10. They don’t have TPE. When Reuters asked what absorption technology they use in their $49 oral semaglutide pill, the company said “liposomal technology that is intended to support absorption” and declined to elaborate. No published pharmacokinetic data. No bioavailability studies. No human clinical trials. Novo’s CEO Mike Doustdar said you’re flushing $49 down the toilet. For sure biased. But he’s also describing what happens to every unprotected peptide anyone has ever swallowed.
One rat study exists showing that sodium glycocholate liposomes can improve semaglutide absorption via intestinal bile acid transporters. Rats. Not humans. And “improve” is doing some heavy lifting when you’re starting from a baseline of near zero.
I keep thinking about the person who signs up for Hims oral semaglutide. Someone who couldn’t afford Wegovy at $1,350 a month, watched the price drop to $149 and still couldn’t swing it, sees $49 and finally feels like the system is working for them. They take their pill every morning. They believe their obesity, a genuine chronic disease, is being treated.
Or maybe they’re paying for a mint flavored placebo while a serious condition goes unmanaged for months.
After the Shortage
Hims started during a legitimate drug shortage, filling a real gap, using a compounding exemption Congress created for exactly this situation. Patients got access to injectable semaglutide they couldn’t otherwise get. Revenue went through the roof. Stock hit all-time highs.
The shortage ended in February 2025. The FDA gave compounders until May to wind down. Hims kept going, rebranded “compounding” as “personalization,” built a million square feet of manufacturing facilities, and launched an oral pill with unproven absorption tech while the FDA’s warning letter about their deceptive marketing was still warm.
We decided as a society that "it might work" isn't good enough for something you put in your body every day to treat a chronic disease. We built an entire regulatory apparatus, the FDA, clinical trials, bioavailability studies, post-market surveillance, specifically because "trust us" from a company with a financial incentive to sell you something is not a substitute for evidence.
The system is slow and expensive and sometimes maddeningly bureaucratic and certainly delays life saving innovation. There are times for regulatory discretion.
And honestly, some of the most important medical advances in the last decade have happened in the gray space of regulation. Compounding pharmacies during the semaglutide shortage were operating in that gray space, and patients genuinely benefited. Right to try laws exist because sometimes the regulatory timeline and the patient’s timeline don’t match. The tension is valid and I don’t think the people who push on regulatory boundaries are always wrong.
But there’s a difference between operating in a gray area because the rules haven’t caught up to a genuine medical need, and operating in a gray area because it’s profitable and you’re hoping enforcement is slow.
The FDA just referred Hims to the DOJ. Hims pulled their oral semaglutide. Their stock is down 60% from highs. And somewhere a person is taking their $49 pill every morning, trusting that it works, with no published evidence that it does.
This article ties some interesting pharmaceutical history to a questionable narrative.
Let's assume you're right and the Hims oral semaglutide doesn't work. (Without further information, I'd give it 70% odds they're using SNAC and unwilling to admit it for legal reasons). Hims primarily sells injectable semaglutide, which doesn't have the same problems. You said it yourself: there are people with genuine medical need for GLP-1s that can't afford the official route, regardless of whether the FDA says there's a shortage, and grey market is their only option.
The hypothetical sad story feels particularly dishonest here. GLP-1s aren't like statins, you can readily observe for yourself whether they're working. Your hypothetical patient is likely to switch to injections after a few weeks, and still be better off than if they didn't have affordable options for GLP-1s at all.
This issue is complicated, and you can certainly make arguments for cracking down on compounding as part of a necessary if unfortunate tradeoff between increasing access to medication and encouraging innovation. But to ignore this tradeoff and present Hims exclusively as a villain... that I find unconvincing.