Rybelsus (semaglutide) is an oral GLP-1 receptor agonist licensed in the UK for treating type 2 diabetes mellitus in adults. A common concern amongst patients and prescribers is whether Rybelsus can cause hypoglycaemia—dangerously low blood sugar levels. Understanding the hypoglycaemia risk profile of Rybelsus is essential for safe prescribing and patient counselling. When used alone, Rybelsus carries a low intrinsic risk of hypoglycaemia due to its glucose-dependent mechanism of action. However, the risk increases significantly when combined with certain other diabetes medications, particularly sulphonylureas or insulin. This article examines the evidence, risk factors, and practical guidance for managing hypoglycaemia risk in patients prescribed Rybelsus.

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 can be used as monotherapy when metformin is inappropriate, or as an add-on therapy in combination with other diabetes medications. It belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists, which work by mimicking the action of a naturally occurring hormone that helps regulate blood glucose levels.

The mechanism of action of Rybelsus involves several complementary pathways. Firstly, it stimulates insulin secretion from pancreatic beta cells in a glucose-dependent manner—meaning insulin is only released when blood glucose levels are elevated. Secondly, it suppresses glucagon secretion, a hormone that raises blood sugar by promoting glucose release from the liver. Additionally, Rybelsus slows gastric emptying, which moderates the rate at which glucose enters the bloodstream after meals, and may reduce appetite, contributing to weight loss in many patients (though weight loss is a recognised effect, not a licensed indication).

Crucially, the glucose-dependent nature of Rybelsus is significant when considering hypoglycaemia risk. Because insulin secretion is only triggered when glucose levels are raised, Rybelsus carries a low intrinsic risk of causing hypoglycaemia when used as monotherapy. This distinguishes it from other diabetes medications such as sulphonylureas or insulin, which can stimulate insulin release regardless of blood glucose levels.

Rybelsus is typically initiated at a dose of 3 mg once daily for one month, then increased to 7 mg daily. If further glycaemic control is needed, the dose may be increased to a maximum of 14 mg daily. The tablets must be taken on an empty stomach with a small amount of water (up to 120 ml), at least 30 minutes before food, drink, or other oral medications to ensure adequate absorption. Tablets should be swallowed whole and not split, crushed or chewed. According to NICE guidance (NG28), GLP-1 receptor agonists like Rybelsus may be considered as part of treatment regimens when other therapies have not achieved adequate glycaemic control, particularly in patients with specific needs around weight management or cardiovascular risk. Local NHS formulary and commissioning arrangements may apply to oral semaglutide prescribing.

Risk Factors That Increase Hypoglycaemia Risk With Rybelsus

While Rybelsus alone has a low inherent risk of causing hypoglycaemia, certain clinical scenarios and combinations significantly increase this risk. Understanding these factors is essential for both patients and healthcare professionals to prevent potentially serious episodes of low blood sugar.

The most important risk factor is concomitant use with other glucose-lowering medications. When Rybelsus is prescribed alongside sulphonylureas (such as gliclazide, glimepiride, or glipizide) or insulin, the risk of hypoglycaemia increases substantially. Both sulphonylureas and insulin stimulate insulin secretion or provide exogenous insulin regardless of blood glucose levels, and when combined with the glucose-lowering effects of Rybelsus, blood sugar can drop too low. The MHRA and product literature recommend that dose reductions of sulphonylureas or insulin may be necessary when initiating Rybelsus to mitigate this risk.

Other risk factors include:

• Renal impairment – While Rybelsus itself does not require dose adjustment in renal impairment, reduced kidney function can affect glucose metabolism and the clearance of concomitant medications, potentially increasing hypoglycaemia risk when combined with sulphonylureas or insulin.

• Hepatic impairment – Liver disease can impair gluconeogenesis (glucose production) and drug metabolism, raising the likelihood of low blood sugar, particularly with combination therapy.

• Irregular meal patterns or inadequate carbohydrate intake – Skipping meals, fasting, or consuming insufficient carbohydrates while on glucose-lowering therapy increases hypoglycaemia risk.

• Increased physical activity – Unplanned or intense exercise enhances glucose uptake by muscles and can precipitate hypoglycaemia, especially in patients on combination therapy.

• Alcohol consumption – Alcohol inhibits hepatic glucose production and can mask hypoglycaemia symptoms, increasing both risk and severity.

• Elderly patients – Older adults may have reduced awareness of hypoglycaemia symptoms (hypoglycaemia unawareness) and are more vulnerable to complications.

• Acute illness or poor oral intake – Vomiting, diarrhoea or reduced food intake during illness can increase hypoglycaemia risk, particularly if medication doses are not adjusted.

Patients prescribed Rybelsus in combination with sulphonylureas or insulin should receive individualised counselling about hypoglycaemia recognition, prevention strategies, and the importance of regular blood glucose monitoring. They should also be aware of DVLA guidance regarding driving safety when at risk of hypoglycaemia.

Recognising and Managing Low Blood Sugar on Rybelsus

Hypoglycaemia is generally defined as a blood glucose level below 4.0 mmol/L, though symptoms can occur at higher levels in some individuals, particularly those with chronically elevated blood sugar. Recognising the signs and knowing how to respond promptly is crucial for patient safety.

Early warning symptoms of hypoglycaemia include:

• Trembling or shakiness

• Sweating (often profuse)

• Palpitations or rapid heartbeat

• Hunger

• Anxiety or irritability

• Pallor (pale skin)

• Difficulty concentrating or confusion

• Tingling around the lips

If hypoglycaemia progresses without treatment, more severe symptoms can develop, including drowsiness, visual disturbances, seizures, loss of consciousness, and in extreme cases, coma. Severe hypoglycaemia (requiring assistance from another person) constitutes a medical emergency requiring immediate intervention.

Immediate management of mild to moderate hypoglycaemia follows the '15-15 rule' recommended by Diabetes UK and the NHS:

1. Consume 15–20 grams of fast-acting carbohydrate immediately. Suitable options include:

2. 150–200 ml of fruit juice or non-diet fizzy drink

3. 4–5 glucose tablets

4. 5–6 standard jelly babies

5. 1–2 tubes of glucose gel

6. Wait 15 minutes, then recheck blood glucose if possible.

7. If blood glucose remains below 4.0 mmol/L, repeat step 1.

8. Once blood glucose normalises, consume a longer-acting carbohydrate (such as a slice of bread, biscuits, or the next scheduled meal) to prevent recurrence.

For severe hypoglycaemia where the patient is unconscious or unable to swallow safely, never attempt to give anything by mouth. Emergency treatment with intramuscular or nasal glucagon (if available and the person is trained) or immediate ambulance attendance (dial 999) is required. Hospital treatment typically involves intravenous glucose administration.

Patients on Rybelsus combined with sulphonylureas or insulin should be advised to carry glucose tablets or a fast-acting carbohydrate source at all times and ensure family members or colleagues know how to recognise and respond to hypoglycaemia. They should not drive if they feel hypoglycaemic or if their blood glucose is below 5.0 mmol/L, and should be aware of their DVLA obligations regarding diabetes and driving safety.

When to Seek Medical Advice About Rybelsus and Blood Sugar

While Rybelsus is generally well-tolerated with a favourable hypoglycaemia profile when used appropriately, certain situations warrant prompt medical review to ensure safe and effective diabetes management.

Contact your GP or diabetes specialist nurse if:

• You experience recurrent episodes of hypoglycaemia (two or more episodes per week), even if mild. This suggests your treatment regimen may need adjustment, particularly if you are taking Rybelsus alongside sulphonylureas or insulin. Dose reductions of these concomitant medications are often necessary.

• You develop impaired awareness of hypoglycaemia – if you no longer recognise the early warning signs of low blood sugar, you are at increased risk of severe episodes. This requires urgent specialist review and may necessitate changes to your diabetes management plan.

• Blood glucose readings are consistently outside your target range – whether persistently high (hyperglycaemia) or frequently low, this indicates your current treatment is not optimally controlling your diabetes.

• You experience troublesome side effects from Rybelsus, such as persistent nausea, vomiting, diarrhoea, or abdominal pain. Gastrointestinal symptoms are common when starting Rybelsus but usually improve over time. However, severe or persistent symptoms warrant medical assessment.

• You are planning pregnancy – Rybelsus should be discontinued at least 2 months before a planned pregnancy, as it is not recommended during pregnancy or breastfeeding. Seek specialist advice about alternative diabetes management.

• You are planning changes to your lifestyle that may affect blood glucose control, such as significantly increasing exercise or starting a weight-loss diet.

Seek immediate medical attention (call 999 or attend A&E) if:

• Severe hypoglycaemia occurs with loss of consciousness, seizures, or inability to swallow safely.

• You develop symptoms suggestive of pancreatitis, including severe, persistent abdominal pain (particularly if radiating to the back), with or without vomiting. If pancreatitis is suspected, stop taking Rybelsus and seek urgent medical assessment.

• Symptoms suggestive of diabetic ketoacidosis develop, including persistent vomiting, abdominal pain, rapid breathing, fruity-smelling breath, or confusion (though this is rare with type 2 diabetes and not specifically associated with GLP-1 receptor agonists).

• You experience symptoms of gallbladder disease such as severe right upper abdominal pain, fever, or yellowing of the skin or eyes (jaundice).

Regular follow-up with your diabetes care team, typically every 3–6 months, allows for ongoing monitoring of glycaemic control (HbA1c), medication review, and adjustment of treatment as needed. Never adjust or stop Rybelsus without consulting your healthcare professional, except in cases of suspected pancreatitis or severe adverse reactions requiring immediate medical attention.

If you suspect you are experiencing side effects from Rybelsus, you can report these through the MHRA Yellow Card Scheme (yellowcard.mhra.gov.uk or via the Yellow Card app).

Frequently Asked Questions