“Now I’m not a saint, but I’m not a sinner/ And everything’s cool as long as I’m getting thinner” The Fear, Lilly Allen
The road to Wegovy has been long and winding. Our fascination with finding a simple way to lose weight has been centuries in the making—a story of strange remedies, scientific breakthroughs and costly false starts. In Victorian times, slimming preparations could contain ingredients that today sound like a poisoners shopping list: thyroid extracts, arsenic and strychnine. Herbal remedies based on bladderwrack and powerful laxatives were popular, while the twentieth century brought amphetamine-like stimulants and an increasingly inventive succession of diet pills. At the more bizarre end of the spectrum was the supposed practice of deliberately swallowing tapeworms - or their eggs - in the hope that an unwanted passenger in the intestine might consume some of your calories. Fortunately, modern obesity medicine has travelled a very long way from such hair-raising concoctions- although hair-raising remedies are perhaps a story for another time.
The arrival of GLP-1 medicines such as semaglutide (Wegovy) has arguably marked a paradigm shift in the treatment of obesity. Rather than trying to stimulate the body or prevent nutrients being absorbed, these drugs mimic a naturally occurring hormone involved in appetite and blood-sugar regulation. By acting on GLP-1 receptors, including those involved in the brain pathways that regulate appetite, semaglutide helps people feel fuller, reduces hunger and food cravings and, ultimately, reduces how much they eat.
Like many things in life, however, there was a catch: semaglutide is a peptide.
When I started my career in drug discovery, one of the cardinal rules was that if a drug was a protein or peptide, it generally had to be given by injection. Swallow it as a tablet and two formidable obstacles stood in its way. First, the acidic, enzyme-rich environment of the digestive system is designed to break down proteins and peptides, just as it breaks down the proteins in food. Second, even if the molecule survives, large peptide molecules do not readily pass through the wall of the gastrointestinal tract and into the bloodstream.
Insulin is perhaps the most famous example. Efforts to develop an insulin tablet began soon after insulin itself was discovered: experiments with oral insulin were being carried out as early as the 1920’s. Over the following century there have been countless formulations, coatings, nanoparticles and absorption enhancers, but no conventional oral insulin tablet has replaced the injection.1 Other difficult-to-absorb medicines, including calcitonin and heparin, have presented similar challenges.
So how did semaglutide apparently break one of the rules of drug development? The answer lies partly with a rather less famous molecule called SNAC, or sodium N-[8-(2-hydroxybenzoyl)amino] caprylate.2
SNAC isn’t a drug. It neither suppresses appetite nor activates the GLP-1 receptor. Instead, it is an absorption enhancer—because, despite the name, SNAC-ing has never been a reliable route to weight loss. Formulated into the tablet, SNAC creates a protective microenvironment as the tablet dissolves, helping semaglutide survive and pass through the cells of the stomach wall into the bloodstream.3 This is an unusual route. Most conventional oral medicines—including paracetamol, ibuprofen, aspirin and many common antibiotics—are absorbed mainly through the small intestine. Oral semaglutide, by contrast, is absorbed predominantly through the epithelial cells lining the stomach. Having worked on the challenge of oral drug absorption myself, I find it a remarkable feat of pharmaceutical engineering.
But there is a guilty secret hiding here: more than 98% of the drug is never absorbed!
By conventional standards, oral semaglutide has remarkably low absolute bioavailability—the proportion of a dose that reaches the bloodstream unchanged. Around 70–90% of an oral dose of paracetamol reaches the systemic circulation, while the figure for ibuprofen is approximately 80%. For Wegovy tablets, it is only around 1–2%—meaning that more than 98% of the semaglutide dose does not reach the bloodstream. That may sound extraordinarily wasteful, but it reflects the formidable barrier presented by the digestive system. An injection bypasses that barrier, which helps explain the apparently huge difference in dose: injectable Wegovy is given in a few milligrams once a week, whereas oral Wegovy is taken at doses of up to 25 mg every day.
The tablet works because its absorption mechanism does not need to be perfect; it needs only to deliver enough semaglutide to produce a therapeutic effect. That echoes a lesson I learned early in my career: nothing in drug development is ever perfect. Progress comes from balancing compromises until enough medicine reaches its target, safely and reliably, to produce a meaningful effect.
Semaglutide happens to be remarkably well suited to this apparently inefficient delivery system. It is highly potent and, once in the circulation, has a half-life of approximately one week—meaning that after seven days, about half of the absorbed drug remains in the body. With daily dosing, the small amounts absorbed from successive tablets gradually accumulate, a little like repeatedly topping up a slowly draining reservoir. The long half-life also helps compensate for considerable day-to-day variation in absorption, producing more stable semaglutide levels over time.
In this case, then, the answer to delivering a peptide orally was to reframe the problem. The aim was not to make absorption conventionally “good”, but to make it good enough for the right peptide. SNAC provides the opportunity for absorption; semaglutide’s potency and persistence make that small opportunity therapeutically useful. It is this careful matching of drug and delivery system that makes oral semaglutide so unusual.
Another intriguing feature of swallowing a pill is just how strongly food and drink can affect absorption. This explains why oral Wegovy comes with a particular set of instructions: the tablet should be taken after fasting for at least eight hours, swallowed whole with a small amount of water, and followed by a wait of at least 30 minutes before eating, drinking or taking other oral medicines. When so little of the drug is absorbed in the first place, even your morning coffee becomes an important part of the formulation strategy. These instructions aren't an afterthought added by fussy regulators - they are part of the machinery that makes the drug work. SNAC needs to create the right local conditions around the dissolving tablet. Food, additional tablets and larger quantities of fluid can interfere with that process. With only a small percentage of the dose being absorbed in the first place, relatively modest changes can matter.
Oral semaglutide is not entirely new. Some readers may already know it as Rybelsus, a semaglutide tablet licensed to treat type 2 diabetes. Its development established that SNAC could help semaglutide cross the stomach lining and reach the bloodstream. Oral Wegovy builds on that same approach. Both medicines combine semaglutide with SNAC, but they are licensed for different purposes and use different dosing regimens. Rybelsus is prescribed at lower doses to manage type 2 diabetes, while oral Wegovy is gradually increased to a maintenance dose of 25 mg once daily for weight management.
The clinical results show why this matters. In the pivotal OASIS 4 trial, adults who were overweight or obese who were assigned oral semaglutide 25 mg lost an estimated average of 13.6% of their starting weight over 64 weeks, compared with 2.2% among those receiving placebo. This analysis reflected outcomes across all participants, including those who stopped treatment or used another weight-loss intervention. Almost half of those assigned oral semaglutide lost at least 15% of their starting weight—a staggering result for a tablet from which only a tiny fraction of the active drug is absorbed.4
In June 2026, the MHRA (Medicines and Healthcare products Regulatory Agency, the UK body responsible for regulating medicines and medical devices) approved Wegovy tablets for weight management in the UK - the first GLP-1 receptor agonist tablet authorised in the UK specifically for weight loss.5,6 Conventional wisdom said this tablet shouldn’t work. But sometimes a pharmaceutical Trojan horse can slip past nature’s defenses where brute force has stumbled.
So, where next? Given everything we have learned, the obvious next step is to replace the peptide with a much smaller, more robust molecule—one that is inherently more bioavailable and does not require strict dosing requirements.
Eli Lilly took up the gauntlet and developed orforglipron, licensed in the UK on 10th August 2026 as Foundayo.7 It is a small-molecule drug that activates the same GLP-1 receptor but is less vulnerable to digestive enzymes and more readily absorbed. Orforglipron has an absolute oral bioavailability of approximately 77–79% in healthy volunteers—dramatically higher than the 1–2% reported for oral Wegovy. As a result, it behaves much more like a conventional tablet and can be taken at any time of day, with or without food or water. Small molecules are also generally easier to manufacture consistently at the multi-ton scale that may be required for a medicine in such high demand.
The journey from monstrous Victorian slimming concoctions to precisely engineered GLP-1 medicines has been extraordinary. From quack cures and questionable remedies has evolved a sophisticated field of medicine—one that is transforming not only weight loss, but our understanding and treatment of obesity, one of the world’s greatest health challenges.
References:
1) Recent work exploring glucose-responsive nanoparticles that release insulin when blood glucose rises. These have reduced hypoglycaemia in animal studies, but have not yet been proven in humans, Journal of Pharmacy and Pharmacology, Volume 78, Issue 7, July 2026, rgag078
2) A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes. Reviews in Endocrine and Metabolic Disorders 2022, 23, 979-994.
3) Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Science Translational Medicine, 2018, 10, eaar7047.
4) Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity. New England Journal of Medicine 2025, 393, 1077-1087.
5) MHRA first GLP-1 tablet for weight loss approved in the UK. 11 June 2026, https://www.gov.uk/government/news/first-glp-1-tablet-for-weight-loss-approved-in-the-uk
6) Wegovy tablets (semaglutide), Summary of Product Characteristics. Novo Nordisk / electronic Medicines Compendium, 2026.
7) See earlier blog post describing the development and clinical data for Orforglipron. See also https://www.gov.uk/government/news/uk-first-in-europe-to-authorise-orforglipron-for-weight-management-and-type-2-diabetes.