Rybelsus (semaglutide) represents a significant advancement as the first oral GLP-1 receptor agonist for type 2 diabetes mellitus, offering an alternative to injectable formulations. Despite this innovation, Rybelsus has not achieved widespread adoption in UK clinical practice. Several interconnected factors explain why Rybelsus is not as popular as might be expected: stringent dosing requirements that demand fasting administration with minimal water at least 30 minutes before food or other medications, relatively high cost compared to established alternatives, NHS formulary restrictions favouring more cost-effective options, and strong competition from SGLT2 inhibitors and injectable GLP-1 receptor agonists with proven cardiovascular benefits and simpler administration.

What Is Rybelsus and How Does It Work?

Rybelsus (semaglutide) is an oral medication licensed for the treatment of type 2 diabetes mellitus in adults. It belongs to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists. Rybelsus represents a significant pharmaceutical innovation as the first GLP-1 receptor agonist available in tablet form, whereas other medications in this class—such as Ozempic, Victoza, and Trulicity—require subcutaneous injection.

The mechanism of action centres on mimicking the effects of the naturally occurring hormone GLP-1. When blood glucose levels rise after eating, Rybelsus stimulates insulin secretion from pancreatic beta cells in a glucose-dependent manner. This means insulin release occurs primarily when blood sugar is elevated, reducing the risk of hypoglycaemia compared to some other diabetes medications. Additionally, semaglutide suppresses glucagon secretion (a hormone that raises blood glucose), slows gastric emptying to moderate post-meal glucose spikes, and acts on appetite centres in the brain to promote satiety.

Clinical trials have demonstrated that Rybelsus effectively reduces HbA1c (a measure of long-term blood glucose control) and is associated with weight loss in many patients—an important benefit given the strong link between obesity and type 2 diabetes. The medication is indicated as monotherapy when metformin is inappropriate, or as add-on therapy to other glucose-lowering medications.

Rybelsus is contraindicated in type 1 diabetes, diabetic ketoacidosis, and is not recommended during pregnancy or breastfeeding. When used with sulfonylureas or insulin, there is an increased risk of hypoglycaemia, and dose adjustments of these medications may be needed. Treatment begins with a 3 mg daily dose for 30 days, then increases to 7 mg daily, with a further increase to 14 mg daily if additional glycaemic control is needed.

Despite these advantages, Rybelsus has not achieved the widespread adoption that might be expected from such an innovative oral GLP-1 receptor agonist. Understanding the reasons behind its relatively limited popularity requires examination of practical, economic, and comparative clinical factors.

Practical Challenges: Dosing Requirements and Absorption Issues

One of the principal barriers to Rybelsus uptake relates to its complex dosing requirements, which differ markedly from most oral diabetes medications. To achieve adequate absorption, Rybelsus must be taken under very specific conditions that many patients find inconvenient or difficult to maintain consistently.

The tablet must be swallowed whole (not split, crushed or chewed) with no more than 120 ml of plain water on an empty stomach, at least 30 minutes before the first food, drink, or other oral medications of the day. These stringent requirements exist because semaglutide is a peptide that would normally be degraded in the gastrointestinal tract; the tablet formulation includes an absorption enhancer (salcaprozate sodium, or SNAC) that temporarily increases gastric pH and facilitates absorption across the stomach wall.

Non-adherence to these instructions significantly reduces drug absorption and therapeutic efficacy. For patients with busy morning routines, those who take multiple medications, individuals who work night shifts, or people who simply forget the specific timing requirements, maintaining this regimen can prove challenging. If a dose is missed, patients should skip that dose and take the next scheduled dose the following day; they should not take a double dose to make up for the missed one.

Furthermore, even with perfect adherence, the bioavailability of oral semaglutide is relatively low (approximately 0.4-1% compared to subcutaneous administration) and shows considerable inter-patient variability. This means the tablet must contain a much higher dose of active ingredient than injectable formulations, and individual variation in absorption can affect treatment response.

Some patients may experience gastrointestinal side effects—including nausea, vomiting, diarrhoea, and abdominal discomfort—which are common across the GLP-1 receptor agonist class. Patients should be advised to seek medical attention for severe, persistent abdominal pain (which might indicate pancreatitis), and to maintain adequate hydration if experiencing gastrointestinal effects. There is also a need to monitor for diabetic retinopathy complications, particularly in patients with pre-existing retinopathy.

Important drug interactions include increased exposure to levothyroxine, which may require thyroid function monitoring. Ideally, all oral medications should be separated from Rybelsus by at least 30 minutes. Patients should report any suspected side effects via the MHRA Yellow Card Scheme.

Cost and NHS Availability of Rybelsus in the UK

Economic factors play a substantial role in explaining why Rybelsus remains less popular than might be anticipated. The medication is considerably more expensive than established first-line and second-line diabetes treatments, and NHS funding decisions reflect cost-effectiveness assessments that influence prescribing patterns.

The National Institute for Health and Care Excellence (NICE) provides guidance on the use of GLP-1 receptor agonists, including oral semaglutide, in its guideline for type 2 diabetes management (NG28). NICE recommends GLP-1 receptor agonists only under specific circumstances and when certain criteria are met. These include use as monotherapy when metformin is contraindicated or not tolerated, or as dual or triple therapy in combination with other glucose-lowering drugs. Importantly, NICE guidance stipulates that treatment should be continued only if there is adequate glycaemic control (HbA1c reduction of at least 11 mmol/mol [1%]) and, where applicable, weight loss of at least 3% at 6 months.

The cost per patient is significantly higher than generic alternatives such as metformin, gliclazide, or even some SGLT2 inhibitors that are available at reduced prices through NHS commercial arrangements. Many NHS Integrated Care Boards (ICBs) have developed local prescribing formularies that position Rybelsus as a third-line or later option, reserving it for patients who have failed multiple other therapies or who have specific contraindications to alternatives.

Local formulary restrictions in some areas add administrative burden for prescribers, potentially discouraging use. General practitioners may need to provide detailed justification for prescribing Rybelsus rather than less expensive alternatives, and some areas require specialist initiation or endorsement through systems such as Blueteq. This contrasts with the relatively unrestricted availability of metformin, sulfonylureas, and even some injectable GLP-1 receptor agonists that have established cost-effectiveness profiles.

Recent NHS England supply constraints affecting GLP-1 receptor agonists (2023-2024) have also influenced prescribing patterns and limited new initiations of these medications, including Rybelsus.

For patients seeking treatment outside the NHS, the monthly cost of Rybelsus on private prescription can be substantial, potentially limiting accessibility for those without significant disposable income.

Comparing Rybelsus to Other Type 2 Diabetes Treatments

When clinicians and patients evaluate diabetes treatment options, Rybelsus faces stiff competition from both established oral agents and other GLP-1 receptor agonists, each with distinct advantages.

Metformin remains the cornerstone first-line treatment for type 2 diabetes according to NICE guidelines. It is inexpensive, generally well-tolerated, has an extensive safety record spanning decades, and has long-standing use with supportive evidence suggesting cardiovascular benefits. Most newly diagnosed patients will trial metformin before considering alternatives, and many achieve adequate glycaemic control without needing additional agents.

SGLT2 inhibitors (such as dapagliflozin, empagliflozin, and canagliflozin) have gained considerable favour as second-line agents. These medications offer not only glucose-lowering effects but also proven cardiovascular and renal protective benefits, which are particularly valuable for patients with established cardiovascular disease, heart failure or chronic kidney disease. NICE guidance (NG28) now recommends SGLT2 inhibitors as the preferred option for patients with these conditions. They can be taken with or without food, have straightforward once-daily dosing, and are increasingly cost-effective through NHS commercial arrangements. For many patients and prescribers, SGLT2 inhibitors represent a more practical and evidence-based choice than Rybelsus.

Injectable GLP-1 receptor agonists—including semaglutide (Ozempic), dulaglutide (Trulicity), and liraglutide (Victoza)—offer an interesting comparison. While requiring injection (typically once weekly for semaglutide and dulaglutide), these formulations achieve higher bioavailability and more consistent drug levels than oral semaglutide. Many patients initially resistant to injections find that modern pre-filled pens are relatively painless and convenient, requiring only weekly administration without dietary restrictions. The injectable formulations have robust cardiovascular outcomes trial data demonstrating reduced risk of major adverse cardiovascular events, which strengthens their position in treatment algorithms for high-risk patients.

For patients who strongly prefer oral medication and have not achieved targets with metformin and other conventional agents, DPP-4 inhibitors (such as sitagliptin or linagliptin) offer a simpler oral alternative without the dosing restrictions of Rybelsus, albeit with more modest efficacy.

Patient preference varies considerably. Some individuals value the oral route sufficiently to accept the dosing constraints of Rybelsus, whilst others find the practical requirements too burdensome and prefer either simpler oral agents or the convenience of weekly injections. Oral semaglutide showed cardiovascular non-inferiority in the PIONEER 6 trial, though more recent evidence continues to emerge. When selecting diabetes treatments, clinicians must balance efficacy, safety, convenience, cost, and individual patient circumstances in line with NICE guidance.

In this complex landscape, Rybelsus occupies a relatively narrow niche—suitable for selected patients who require GLP-1 receptor agonist therapy, strongly prefer oral administration, can adhere to strict dosing requirements, and meet local prescribing criteria. These multiple constraints help explain why Rybelsus has not achieved the popularity that its innovative oral formulation might initially suggest.

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