Online Clinic News

The Rest is History: Orexin Antagonists and the Rise and Shine of Daridorexant

2026-10-02T13:13:05.908+01:00

“I need to sleep. I can’t get no sleep.”

— Insomnia, Faithless

Insomnia is an insidious condition. The late Maxi Jazz of Faithless captured its frustration perfectly in their 1995 track Insomnia. Most of us have found ourselves, at some point, desperately wanting to sleep. Yet there is a cruel paradox to insomnia: the more desperately we want sleep to come, the more elusive it seems to become.

We spend around a third of our lives sleeping, and most adults need 7–9 hours of good-quality sleep each night. For many people, however, this is more dream than reality. A study published in 2024, using data from more than 160,000 UK Biobank participants in England, found that 29% reported usually experiencing symptoms of insomnia. The participants were aged 38–71 when assessed, and the data were collected in 2006–2010.¹

How we define insomnia is important here. An occasional bad night is different from insomnia disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines this as difficulty sleeping at least three nights a week for at least three months, despite having enough opportunity to sleep, with significant distress or impairment in everyday functioning. The National Institute for Health and Care Excellence (NICE) cites a survey estimate that around one in fourteen UK adults meets these criteria.²

It is tempting to think of insomnia as a modern affliction, brought on by hectic lifestyles, social media and smartphones. Sleeplessness has almost become a metaphor for the pressures of modern life — lying awake while our minds refuse to switch off. The scale of the problem is enormous, and its effects extend well beyond the dark hours. Insomnia can affect how we feel, think and function the following day. It is more than an inconvenience; it is an important public health problem in its own right.²

Many medicines have been used to treat insomnia over the years. Benzodiazepines and the so-called Z-drugs, including zopiclone and zolpidem, boost the action of GABA (gamma-aminobutyric acid), a chemical messenger that makes nerve cells less likely to fire, helping to calm the mind and promote sleep. Sedating antihistamines such as promethazine (Phenergan) work differently, blocking the action of histamine, which helps keep us awake. The downside will be familiar to people who have taken them: their effects may linger into the following day, leaving you drowsy, groggy and feeling as though you’ve done a few rounds with Tyson Fury.³

Perhaps the most extreme example was Michael Jackson. Suffering from chronic insomnia, Jackson was given propofol — a powerful intravenous general anaesthetic normally used for procedures and surgery — by his personal physician in an attempt to make him sleep. On 25 June 2009, Jackson died from acute propofol intoxication, with benzodiazepines also contributing. His death was a tragic reminder of how desperate the search for sleep can become, and how dangerous some attempts to induce it can be.

Medicines are only part of the picture. Cognitive behavioural therapy for insomnia, or CBT-I, is the recommended first treatment for long-term insomnia. It addresses the thoughts and habits that can keep the problem going, although access to it remains uneven.²

A breakthrough in our understanding of sleep came in the late 1990s with the discovery of orexin, a pair of neuropeptides produced by neurons in the lateral hypothalamus of the brain. Orexin binds to two receptors, OX₁R and OX₂R, and has a key role in maintaining wakefulness. This introduced a potentially new approach to treating insomnia. If the action of orexin could be blocked by introducing a molecule to prevent it binding, the wakefulness dial could be turned down without broadly suppressing brain activity. In other words, instead of trying to force the brain to sleep with sedatives, remove one of the signals telling it to stay awake.³

As a scientist, I’m acutely aware that a lot of important discoveries are made by chance. And the orexin story is one of these.

In 1998, Dr Masashi Yanagisawa, a Japanese-American molecular biologist, thought he might have discovered a new target for a weight-loss drug. His team had identified a new pair of peptides in the brain and named them orexins, from the Greek word for appetite. They then genetically engineered mice that couldn’t produce orexin, expecting them to eat less. At first, they didn’t seem to. So Yanagisawa started looking more closely at what the mice were actually doing. Mice are nocturnal, so he bought a Sony camcorder equipped with what was then the new “NightShot” infrared technology and used it to watch them in the dark.

At around the same time, a completely separate line of research was leading in the same direction. Dr Emmanuel Mignot, a sleep researcher at Stanford, had spent years studying narcolepsy in dogs. In 1999, his group identified a mutation in the gene coding for the OX₂R orexin receptor.

The two discoveries clicked neatly into place. Mice that couldn’t produce orexin developed narcolepsy, and dogs with a defective orexin receptor also developed narcolepsy. Orexin was clearly playing an important role in keeping the brain awake.³

For insomnia researchers, this raised an obvious question. Could you temporarily block the same signalling in someone who has difficulty falling or staying asleep? In principle, you would need a drug that blocked the orexin system during the night and then wore off by morning. In practice, finding one was much more difficult.

Among those pursuing the idea were scientists at the Swiss biotechnology company Actelion, founded by the husband-and-wife scientists Jean-Paul and Martine Clozel and their colleagues in 1997. The company began investigating the orexin system soon after its discovery. When Actelion was acquired by Johnson & Johnson in 2017, its drug-discovery operation and early-stage pipeline were spun out into a new company, Idorsia. Importantly, the orexin programme went with it. By then, after years of medicinal chemistry, the researchers had already selected a promising molecule known simply as ACT-541468. That molecule would eventually become daridorexant.⁴

Getting to that point had been a daunting medicinal-chemistry challenge. The aim was not simply to find a molecule that blocked orexin receptors, but one with the right properties: it needed to enter the brain rapidly (not an easy task), block both OX₁R and OX₂R receptors for long enough to cover a night’s sleep (around 8 hours), and then disappear sufficiently quickly to minimise next-day effects. According to Idorsia, the research programme involved the synthesis of more than 25,000 compounds before the team eventually arrived at daridorexant.

Marketed as Quviviq, daridorexant was approved in the United States in January 2022, followed by the European Union in April 2022 and subsequently Great Britain. It launched in the UK in October 2023.⁴

Daridorexant belongs to a class of insomnia medicines known as dual orexin receptor antagonists, or DORAs. There are two orexin receptors in the brain, OX₁R and OX₂R, and daridorexant blocks both — hence the term “dual”. By preventing orexin from activating these receptors, it turns down the signalling that helps keep us awake, making it easier for sleep to occur.³

So how well does it work? At three months in one of the main trials, sleep-lab measurements showed that people taking 50 mg daridorexant fell asleep an average of about 12 minutes sooner and spent about 18 minutes less awake during the night than those taking placebo. Patient-reported daytime sleepiness also improved compared with placebo.⁵

Sleep time is obviously important, but it’s not the whole story. How well people feel they have slept, and how they function the next day, matter too. A follow-up study suggests that the benefits can persist with continued treatment. Participants were followed for up to a year, although the longer-term findings were exploratory.²˒³

Daridorexant is not a cure for insomnia, and it won’t work for everyone. But it does represent a very different way of thinking about the problem. Rather than broadly suppressing brain activity, it targets one of the systems that keeps us awake.

And finally, if daridorexant doesn’t help, please check out some of my other blog posts and I’m sure sleep will come.

Sweet dreams.

References:

1. de Lange MA, Richmond RC, Eastwood SV, Davies NM. Insomnia symptom prevalence in England: a comparison of cross-sectional self-reported data and primary care records in the UK Biobank. BMJ Open. 2024;14: e080479. BMJ

2. NICE. Daridorexant for treating long-term insomnia. Technology appraisal guidance TA922. 18 October 2023. Recommendations, committee discussion and accompanying resource impact report (section 4.1). NICE Report

3. Muehlan C, Roch C, Vaillant C, Dingemanse J. The orexin story and orexin receptor antagonists for the treatment of insomnia. Journal of Sleep Research. 2023;32(6):e 13902. Journal of Sleep Research

4. Idorsia. Daridorexant. Research programme and regulatory history. Accessed 30 September 2026. Idorsia

5. Mignot E, Mayleben D, Fietze I, et al. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurology. 2022;21(2):125–139. Lancet Neurology

The Weight Is Over: Three Hormones, One Molecule — The Story of Retatrutide

2026-09-23T17:29:41.521+01:00

“I had three chairs in my house; one for solitude, two for friendship, three for society.”— Henry David Thoreau, Walden

Nature is all about balance. Push one biological lever and another often moves with it — usually in the opposite direction. Biology also hates waste. Why invent a new molecule for every job when the same one can take on multiple roles? Nowhere is this more apparent than in the control of metabolism.

Take glucagon, for example. We’re taught that it’s insulin’s counterweight. Insulin lowers blood glucose and glucagon tips the balance the other way, raising it. A perfectly balanced system designed to maintain homeostasis.

Eat too little and the body responds by trying to conserve energy. Eat too much and another complex interplay of hormonal signals comes into play. Hunger and fullness, energy storage and energy expenditure, rising and falling blood sugar — each carefully balanced against the other. But glucagon doesn’t just sit on one side of the blood-sugar seesaw. As with many biological processes, it has much more going on below the surface. And it is the exploration and engineering of this hidden world that ultimately led to retatrutide.¹

It turns out that glucagon also influences how much energy we use and encourages the metabolism and burning of stored fat. For scientists at Eli Lilly, this presented a challenge: could they harness this side of glucagon without tipping the blood-sugar balance too far the other way?

But weight loss is a team game, and glucagon wasn’t entering the field alone. Two other hormones were already very much in play: GLP-1 and GIP. Semaglutide showed us that activating a single hormone receptor (GLP-1) could reduce appetite and body weight. Tirzepatide then brought GIP into the team, activating both GIP and GLP-1 receptors to influence appetite, glucose regulation and body weight. A powerful duo.²

And here lay a possible answer to Lilly’s glucagon question. What if glucagon could be added to the mix, its effects on energy expenditure and fat metabolism working alongside the appetite- and glucose-regulating effects of GLP-1 and GIP?

Retatrutide was engineered to do exactly that: a single peptide with agonist (activating) activity at three different receptors — GLP-1, GIP and the glucagon receptor. It’s hard to overstate what an achievement this is. Engineering this kind of activity into a single molecule is a testament to human ingenuity and creativity. Nature provided the triumvirate; the clever part was learning how to bring all three under the control of one molecule.

Enough theory — what does it do in the real world? In a Phase 2 obesity trial, people receiving the highest dose of retatrutide lost an average of 24.2% of their starting body weight after 48 weeks — almost a quarter of their body weight in less than a year. In Lilly’s TRIUMPH-1 trial, participants receiving 12 mg of retatrutide lost an average of 28.3% after 80 weeks, while in an extension involving people with a starting BMI of at least 35, average weight loss reached 30.3% after two years. It is remarkable that these kinds of numbers can be achieved with a drug. For decades, bariatric surgery could achieve a degree of weight loss that medicines simply couldn’t approach. The clinical trial results with retatrutide suggest that this may no longer be a one-horse race.^3,4

And what about the question we started with — would adding glucagon send blood glucose spiralling out of control? So far, the answer appears to be no. Quite the opposite: studies have reported improvements in glycaemic control, including in people with type 2 diabetes. Retatrutide is now being studied specifically for diabetes in Lilly’s Phase 3 TRANSCEND-T2D programme.⁵

Of course, there is no such thing as a free biological lunch. Like other drugs acting on the incretin system, retatrutide can cause gastrointestinal side effects including nausea, diarrhoea and vomiting, and the dose needs to be increased gradually. It’s important to remember that retatrutide remains an experimental medicine and, at the time of writing, has not been approved by any regulatory authority anywhere in the world. Longer-term safety and efficacy are still being established in ongoing clinical trials.³ It’s not over the finish line yet. And it may never get there.

Which leaves one question weighing on me: where does all this go next? We have spent centuries trying to defeat our biology in the battle against weight gain. Retatrutide suggests that perhaps the answer was never to fight it at all, but to understand its competing signals well enough to rebalance them. Nature provided the orchestra. We are only just learning how to conduct it.

References:

1) Ansari S, Khoo B, Tan T. Targeting the incretin system in obesity and type 2 diabetes mellitus. Nature Reviews Endocrinology. 2024;20:447–459. doi:10.1038/s41574-024-00979-9.

2) Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nature Reviews Endocrinology. 2023;19:201–216. doi:10.1038/s41574-022-00783-3.

3) Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. 2023;389:514–526. doi:10.1056/NEJMoa2301972.

4) Eli Lilly and Company. Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial: TRIUMPH-1 topline results. Company news release, 21 May 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-powerful-weight-loss.

5) Eli Lilly and Company. Lilly’s triple agonist, retatrutide, drove substantial improvements in weight, A1C, knee osteoarthritis pain, and obstructive sleep apnea: TRANSCEND-T2D-1 topline results. Company news release, 6 June 2026. Further Information.

How SNAC-ing Has Transformed Weight-Loss Therapy

2026-09-11T07:54:37.633+01:00

“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 10^th 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.

Easter Public Holidays Opening

2026-04-03T12:08:32.896+01:00

We are open every day of the Easter holidays 2026

We will be open for same day private prescriptions until 2 pm on Good Friday and Easter Monday.

We will close at 12 noon on Easter Sunday.

Saturday is a normal working day, and there are no special opening times.

We will remain open for consultations around the clock, but there may be longer waiting times outside the hours set out above.

New Year Opening Times

2025-12-30T18:21:09.626+00:00

The Online Clinic is open until 7 pm on New Year's Eve and 2 pm on New Year's Day for same day prescriptions to collect from a local pharmacy. The clinic is open for consultations up to 7 pm on New Year's Day. We return to normal opening hours on Friday 2 January 2026.

If you require antibiotics urgently, then we can get a prescription to a local pharmacy for collection. Please be aware of restricted opening times at your local pharmacy.

Orforglipron: The Drug We’ve All Been Weighting For

2025-10-25T19:00:46.347+01:00

In the United Kingdom around 26% of adults are classified as obese and 38% overweight. By 2040, projections suggest 40% of adults could be classified as obese if current trends continue (Cancer Research UK Obesity Projection 2023). This has led to obesity being classified as a chronic relapsing disease and one of the costliest medical threats of the 21^st century. Food craving has both psychological and metabolic roots, with the brain’s reward system strongly linked to metabolic and hormonal signals. Over the past decade the discovery and development of GLP-1 agonists have led to a well validated pharmacological approach to hormonal control and direct suppression of appetite and food craving, leading to clinically significant and sustained reduction in body weight. These molecules mimic the natural hormone by binding to the GLP-1 receptor, triggering glucose lowering signals and appetite-suppression. It’s been estimated that over 100 obesity-related medicines are in active development, many targeting GLP-1 and the incretin pathway. Injectable peptides including Semaglutide (Wygovy) and Tirzepatide (Mounjaro) are among the greatest achievements in modern drug development, with spectacular results in the clinic fuelling unprecedent and relentless demands for drug product. Despite their success, these therapies come with practical challenges: they require injection, careful titration and storage at low temperature. Though not of great concern to patients, Novo Nordisk and Eli Lilly were concerned that patient adherence could be a major problem- most people hate needles and injections- with the only practical solution (if you’ll pardon the pun) being an oral drug.

Developing an oral version of a peptide drug is not a trivial undertaking and is often unsuccessful. Peptides rarely survive the strongly acid conditions in the stomach and are rapidly degraded. Semaglutide peptide is a chain of 31 amino acids and is rapidly digested by stomach acid and gut enzymes. Oral peptides are also difficult to absorb through the gut wall. Despite these challenges an oral version of Semaglutide -Rybelsus- has been developed by leveraging an absorption enhancer SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) that protects the peptide from acid and promotes absorption.¹ Rybelsus is currently only approved for type-2 diabetes and not weight loss. However, it’s not all good news. The absolute bioavalibility of Rybelsus (the amount of the swallowed dose reaching systemic circulation) is less then 1%! So almost all the drug is degraded. And the peptide is not easy to come by. Semaglutide is made using a three-step process: recombinant expression of a peptide precursor, chemical modification and formulation. This is an expensive and complex undertaking so every gram counts. Injectable Semaglutide on the other hand is 100% bioavalible via subcutaneous absorption. High demand for Semaglutide has been an ongoing challenge for the manufacturer, with global supply chain instability, patent challenges and concomitant price hikes. That said, Novo Nordisk submitted an FDA application in May 2025 for an oral formulation of Semaglutide as a treatment for obesity, with a regulatory decision expected in late 2025.²

The real solution to this challenge is to discover and develop a drug that mimics the biological properties of a large peptide but is a smaller molecule stable enough to survive oral dosing without the challenges described above. Eli Lilly accepted the gauntlet and developed Orforglipron-the first (yet to be approved) small molecule GLP-1 receptor agonist to successfully complete phase 3 clinical trials.

Small molecules are generally easier to manufacture, show greater chemical stability and exhibit higher oral bioavailability (estimated to be 40-60% for Orforglipron). Speaking as someone with a background in drug discovery and development this is truly a holy grail in any drug development programme. Formulation as a once-a-day pill that can be dispensed in standard foil packets, discreetly swallowed (with or without food)- with no needles in sight- is vindication enough. Reduced manufacturing and storage costs will broaden accessibility- another important goal in the fight against obesity. Easier prescribing makes the physicians job much more straightforward too.

Does it work? All the clinical data suggest it does- matching and in some cases outperforming oral Semaglutide and comparing favourably with injected drug. Results from the recently completed obesity trial (ATTAIN-1), show that Orforglipron at its highest dose achieved an average weight loss of ~12.4 % over 72 weeks versus placebo, along with significant improvements in cardiometabolic risk markers. The results exceed expectation and regulatory review is imminent.³

This truly is a new dawn in the fight against obesity. Many more oral anti-obesity drugs will emerge in coming years, with lower therapeutic doses and improved tolerability.⁴ Searching for new indications and dual modalities is already at an advance stage. Orforglipron represents a milestone in a long journey that can only improve the health and wellbeing of us all.

1) 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

2) Novo Nordisk website 1 May 20025

3) Eli Lilly website 17^th April, 7^th August, 17^th September 2025

4) Quarterly view of the GLP-1 pipeline and anticipated indications August 2025.; The expanding benefits of GLP-1 medicines: Cell Reports Medicine 102214, July 2025

Christmas Day Opening Hours 2023

2023-12-24T16:18:59.915+00:00

The Online Clinic will be open every day over the Christmas and New Year period but will close early on Christmas Day - 12:30 pm. Urgent same day prescriptions will be issued up until that time. The clinic will be open until 2 pm on the public holidays for same day prescriptions. Please note that there are no courier collections on the public holidays, so there will be a delay with any prescriptions for delivery. We strongly recommend selecting the collection option for antibiotic prescriptions.

Easter Sunday Opening Hours 2023

2023-04-08T16:20:37.4435227+01:00

The Online Clinic will be open every day over the Easter holiday weekend but will close early on Easter Sunday - 12 noon. Emergency same day prescriptions will be issued up until that time. The clinic will be open until 6 pm on the public holidays for same day prescriptions. Please note that there are no courier collections on the public holidays, so there will be a delay with any prescription for delivery.

New Year's Day Opening Hours

2022-12-31T13:44:36.099+00:00

The Online Clinic will be open from 12 noon to 5 pm on New Year's Day 2023 for consultations and same day prescriptions.

Christmas Opening Hours 2022

2022-12-23T18:44:42.071+00:00

The Online Clinic will be open every day over the Christmas and New Year period but will close early on Christmas Day - 12 noon. Emergency same day prescriptions will be issued up until that time. The clinic will be open until 2 pm on the public holidays for same day prescriptions. Please note that there are no courier collections on the public holidays, so there will be a delay with any prescription for delivery.