Rybelsus (semaglutide) is an oral GLP-1 receptor agonist licensed in the UK for treating type 2 diabetes mellitus in adults. Whilst generally well tolerated, allergic reactions to Rybelsus can occur, though they remain uncommon. It is crucial to distinguish genuine hypersensitivity reactions—such as rash, swelling, or breathing difficulties—from the more frequent gastrointestinal side effects like nausea or abdominal discomfort. Recognising the signs of an allergic reaction to Rybelsus and knowing when to seek medical attention can ensure prompt management and prevent serious complications. This article outlines how to identify allergic symptoms, what steps to take if a reaction occurs, and which alternative diabetes treatments may be suitable.

What Is Rybelsus and How Does It Work?

Rybelsus (semaglutide) is an oral medication licensed in the UK for the treatment of type 2 diabetes mellitus in adults. It belongs to a class of medicines called glucagon-like peptide-1 (GLP-1) receptor agonists. Rybelsus is the first GLP-1 receptor agonist available in tablet form, offering an alternative to injectable formulations such as Ozempic (also semaglutide) and other similar agents.

The mechanism of action centres on mimicking the naturally occurring hormone GLP-1, which is released by the intestine in response to food intake. Semaglutide works by:

• Stimulating insulin secretion from pancreatic beta cells in a glucose-dependent manner, which helps lower blood sugar levels when they are elevated

• Suppressing glucagon release, thereby reducing glucose production by the liver

• Slowing gastric emptying, which prolongs the feeling of fullness

• Acting on appetite centres in the brain, which may contribute to reduced calorie intake

Rybelsus treatment begins with a 3 mg once-daily starter dose for 30 days, which is not therapeutic for glycaemic control but helps establish tolerability. The dose is then increased to 7 mg once daily. After at least 30 days on the 7 mg dose, it may be increased to 14 mg once daily if additional glycaemic control is needed.

The tablet must be taken on an empty stomach with a small amount of water (up to 120 ml), at least 30 minutes before any food, drink, or other oral medications. Tablets should be swallowed whole and not split, crushed or chewed. If a dose is missed, the patient should skip that dose and take the next scheduled dose the following day. This specific administration requirement is necessary because semaglutide has low oral bioavailability, and the formulation includes an absorption enhancer (salcaprozate sodium, or SNAC) to facilitate uptake across the gastric mucosa.

According to NICE guidance (NG28), GLP-1 receptor agonists like Rybelsus may be considered in specific circumstances, including as part of treatment intensification when other treatments have not achieved adequate glycaemic control. NICE recommends considering a GLP-1 receptor agonist in combination with metformin and a sulfonylurea when triple therapy is required and insulin would be the next step, particularly in patients with a BMI of 35 kg/m² or above (adjusted for ethnicity) or for whom weight loss would benefit obesity-related comorbidities. While Rybelsus may lead to weight reduction, it is not licensed for weight management in the UK.

Recognising Allergic Reactions to Rybelsus

Allergic reactions to Rybelsus are uncommon but can occur, as with any medication. Hypersensitivity reactions, including anaphylaxis, have been reported rarely with semaglutide. It is important to distinguish between true allergic (hypersensitivity) reactions and the more common gastrointestinal side effects that many patients experience when starting GLP-1 receptor agonists.

Common gastrointestinal side effects (not allergic) include:

• Nausea, vomiting, and diarrhoea

• Abdominal pain or discomfort

• Reduced appetite

• Constipation

These symptoms typically improve over time as the body adjusts to the medication and are related to the drug's mechanism of action rather than an immune response.

Signs of a genuine allergic reaction may include:

• Skin manifestations: rash, hives (urticaria), itching, or redness

• Swelling: particularly of the face, lips, tongue, or throat (angioedema)

• Respiratory symptoms: difficulty breathing, wheezing, or tightness in the chest

• Cardiovascular symptoms: rapid heartbeat, dizziness, or feeling faint

Anaphylaxis is a severe, life-threatening allergic reaction that requires immediate emergency treatment. Warning signs include:

• Sudden onset of widespread rash or flushing

• Swelling of the throat or tongue causing difficulty swallowing or breathing

• Severe breathlessness or wheezing

• Feeling faint, dizzy, or collapsing

• Abdominal cramping with vomiting

The Medicines and Healthcare products Regulatory Agency (MHRA) monitors adverse drug reactions through the Yellow Card scheme. Patients, carers and healthcare professionals can report suspected side effects via the Yellow Card website (yellowcard.mhra.gov.uk) or the Yellow Card app to contribute to ongoing safety surveillance.

What to Do If You Experience an Allergic Reaction

If you suspect you are experiencing an allergic reaction to Rybelsus, the appropriate response depends on the severity of your symptoms.

For mild symptoms (such as a minor rash or mild itching without other features):

• Stop taking Rybelsus and do not take your next dose

• Contact your GP or diabetes specialist nurse as soon as possible for advice

• Document when the symptoms started and any other medications or foods you have consumed

• Your healthcare provider will assess whether the reaction is likely to be allergic and advise on alternative treatments

For moderate symptoms (such as more extensive rash, facial swelling, or mild breathing difficulties):

• Stop taking the medication immediately

• Seek urgent medical advice by contacting NHS 111 or attending an Urgent Treatment Centre

• If symptoms worsen whilst waiting for advice, proceed to your nearest Emergency Department

For severe symptoms or suspected anaphylaxis (difficulty breathing, throat swelling, collapse, or widespread severe rash):

• Call 999 immediately or go straight to your nearest Emergency Department

• If you have been prescribed an adrenaline auto-injector (e.g., EpiPen) for previous allergic reactions, use it according to instructions whilst waiting for emergency services

• Lie flat with legs raised (unless breathing is difficult, in which case sit upright)

• Do not attempt to drive yourself to hospital

After any allergic reaction, it is essential to:

• Inform all your healthcare providers about the reaction, including your GP, diabetes team, and pharmacist

• Ensure the allergy is documented in your medical records

• Consider wearing a medical alert bracelet if you have experienced a severe reaction

• Report the reaction to the MHRA via the Yellow Card scheme (yellowcard.mhra.gov.uk)

Your healthcare team will arrange appropriate follow-up and discuss alternative diabetes management strategies. Anyone who has experienced suspected anaphylaxis should be referred to a specialist allergy service for further assessment.

Who Is at Higher Risk of Allergic Reactions?

Whilst allergic reactions to Rybelsus can theoretically occur in anyone, certain factors may influence individual susceptibility.

General risk factors for drug allergies include:

• Previous allergic reactions to medications, particularly to semaglutide in any form

• History of multiple drug allergies or hypersensitivity reactions

• Atopic conditions such as asthma, eczema, or hay fever (though these do not necessarily predict drug allergy)

Specific considerations for Rybelsus:

According to the UK Summary of Product Characteristics (SmPC), the only contraindication to Rybelsus is hypersensitivity to semaglutide or to any of the excipients in the formulation.

Patients who have previously experienced allergic reactions to semaglutide in any form (Rybelsus, Ozempic or Wegovy) should not take Rybelsus, as the same active ingredient is present in all these products. Cross-reactivity with other GLP-1 receptor agonists (such as liraglutide, dulaglutide, or exenatide) is uncertain, and specialist advice should be sought if considering these alternatives after a reaction to semaglutide.

It is important to note that gastrointestinal side effects with previous GLP-1 medications do not constitute an allergy and should not automatically preclude Rybelsus use.

The tablet formulation of Rybelsus contains excipients (inactive ingredients) including salcaprozate sodium (SNAC), microcrystalline cellulose, povidone, and magnesium stearate. Individuals with known hypersensitivity to any of these components should not take Rybelsus, though allergies to these excipients are rare.

Before prescribing Rybelsus, healthcare professionals should take a thorough allergy history and document any previous adverse reactions to diabetes medications. Patients should be counselled on recognising allergic symptoms and provided with clear instructions on when to seek medical attention. There is no routine allergy testing recommended before starting Rybelsus in the absence of a relevant history.

Alternative Treatments If You Cannot Take Rybelsus

If you experience an allergic reaction to Rybelsus or have contraindications to its use, numerous alternative treatments are available for managing type 2 diabetes. Your healthcare team will work with you to identify the most appropriate option based on your individual circumstances, glycaemic control targets, other medical conditions, and personal preferences.

Alternative oral medications include:

• Metformin: typically the first-line treatment for type 2 diabetes, working by reducing glucose production in the liver and improving insulin sensitivity

• SGLT2 inhibitors (such as dapagliflozin, empagliflozin, or canagliflozin): these work by increasing glucose excretion through the kidneys and offer cardiovascular and renal benefits

• DPP-4 inhibitors (such as sitagliptin, linagliptin, or saxagliptin): these enhance the body's own incretin system with a lower risk of hypoglycaemia

• Sulfonylureas (such as gliclazide): these stimulate insulin release but carry a risk of hypoglycaemia and weight gain

• Thiazolidinediones (pioglitazone): improves insulin sensitivity but may cause fluid retention and weight gain

Injectable alternatives:

• Other GLP-1 receptor agonists: such as liraglutide, dulaglutide, or exenatide may be considered, but if you have had a confirmed allergic reaction to semaglutide specifically, other semaglutide products should be avoided. Cross-reactivity with other GLP-1 receptor agonists is uncertain and would require specialist assessment

• Insulin therapy: various regimens available, from once-daily basal insulin to multiple daily injections, depending on individual needs

According to NICE guidance (NG28), treatment intensification should be individualised, considering:

• HbA1c targets and current glycaemic control

• Cardiovascular or renal comorbidities (where SGLT2 inhibitors may be preferred)

• Risk of hypoglycaemia

• Impact on body weight

• Patient preferences and ability to adhere to treatment

Lifestyle modifications remain fundamental to diabetes management regardless of medication:

• Structured education programmes (such as DESMOND)

• Dietary modifications with support from a dietitian

• Regular physical activity

• Weight management where appropriate

• Smoking cessation and alcohol moderation

Your diabetes care team, which may include your GP, practice nurse, diabetes specialist nurse, and consultant endocrinologist, will review your treatment plan regularly and adjust medications as needed to achieve optimal glycaemic control whilst minimising side effects and risks. If you have experienced an allergic reaction to Rybelsus, ensure this is clearly documented in your medical records to prevent inadvertent re-exposure.

Frequently Asked Questions