Rybelsus (semaglutide) is the first oral GLP-1 receptor agonist licensed in the UK for type 2 diabetes management. As a once-daily tablet, it offers an alternative to injectable therapies, supporting glycaemic control and weight management through glucose-dependent insulin secretion, glucagon suppression, and appetite regulation. Long-term use of Rybelsus requires careful monitoring to balance sustained therapeutic benefits—including HbA1c reduction and weight loss—with potential gastrointestinal side effects and other safety considerations. This article examines the evidence, benefits, risks, and practical guidance for extended Rybelsus therapy in line with NICE and UK clinical standards.

What Is Rybelsus and How Does It Work Long Term?

Rybelsus (semaglutide) is an oral glucagon-like peptide-1 receptor agonist (GLP-1 RA) licensed in the UK for the treatment of type 2 diabetes mellitus in adults. It is the first GLP-1 RA available in tablet form, offering an alternative to injectable formulations. Rybelsus is not indicated for type 1 diabetes or for treating diabetic ketoacidosis. It is typically prescribed when diet and exercise alone, or in combination with other glucose-lowering medications such as metformin, do not provide adequate glycaemic control.

The mechanism of action involves mimicking the naturally occurring incretin hormone GLP-1, which plays a crucial role in glucose homeostasis. Semaglutide binds to GLP-1 receptors, which are widely expressed throughout the body. The insulinotropic effects are mediated via pancreatic beta cells in a glucose-dependent manner, stimulating insulin secretion primarily when blood glucose levels are elevated. This reduces the risk of hypoglycaemia compared to some other diabetes medications. Additionally, Rybelsus suppresses glucagon secretion from pancreatic alpha cells, slows gastric emptying, and promotes satiety through central nervous system pathways.

With long-term use, these mechanisms continue to support glycaemic control and may contribute to sustained weight reduction—a beneficial effect for many individuals with type 2 diabetes who are overweight or obese. Clinical trial data extending beyond one year demonstrate that the glucose-lowering and weight-reducing effects of semaglutide are maintained over time, provided adherence remains consistent. However, individual responses vary, and ongoing monitoring is essential to assess efficacy and tolerability.

Rybelsus must be taken on an empty stomach with up to 120 mL of water, at least 30 minutes before food, drink, or other medications. Tablets should be swallowed whole and not split, crushed or chewed. Treatment starts with 3 mg daily for 30 days (a starter dose for tolerability, not for glycaemic control), then increases to 7 mg, and potentially to 14 mg if needed for glycaemic control. Long-term therapy requires careful consideration of patient-specific factors, including renal function, cardiovascular risk, and the presence of other comorbidities, in line with NICE guidance on individualised diabetes management.

Benefits of Long Term Rybelsus Use for Type 2 Diabetes

Sustained glycaemic control is one of the primary benefits of long-term Rybelsus therapy. Clinical trials, including the PIONEER programme, have demonstrated that semaglutide effectively reduces HbA1c levels over extended periods, with reductions typically ranging from about 1.0% to 1.5% in clinical studies when used as monotherapy or in combination with other antidiabetic agents. Individual results may vary. This durable effect helps reduce the risk of microvascular complications such as diabetic retinopathy, nephropathy, and neuropathy, which are closely linked to chronic hyperglycaemia.

Another significant advantage is weight management. Many patients with type 2 diabetes struggle with obesity, which exacerbates insulin resistance and cardiovascular risk. Rybelsus promotes weight loss through reduced appetite and delayed gastric emptying, with clinical data showing mean weight reductions of around 3–5 kg over 12–18 months in trials. Individual results may vary. This effect is particularly valuable given that weight loss can improve insulin sensitivity, blood pressure, and lipid profiles, contributing to overall cardiometabolic health.

Cardiovascular safety has been demonstrated for oral semaglutide in the PIONEER 6 trial, which showed non-inferiority to placebo for major adverse cardiovascular events. While Rybelsus is not specifically indicated for cardiovascular risk reduction in the UK, other GLP-1 RAs (such as injectable semaglutide, liraglutide, and dulaglutide) have proven cardiovascular benefits and may be preferred when cardiovascular risk reduction is a priority, in accordance with UK guidance.

Furthermore, the oral formulation offers practical advantages for patients who prefer not to use injections, potentially improving adherence and quality of life. Long-term adherence is critical for achieving and maintaining therapeutic goals, and the convenience of a once-daily tablet may support sustained engagement with treatment. NICE recommends considering patient preference and tolerability when selecting glucose-lowering therapies, and Rybelsus provides a valuable option within the GLP-1 RA class.

Potential Side Effects and Risks with Extended Rybelsus Treatment

Gastrointestinal side effects are the most commonly reported adverse events with Rybelsus, particularly during the initial weeks of treatment. These include nausea, vomiting, diarrhoea, abdominal pain, and constipation. While these symptoms often diminish over time as the body adapts to the medication, some patients experience persistent gastrointestinal discomfort that may affect adherence. Dose escalation should be gradual (starting at 3 mg daily for one month, then increasing to 7 mg, and potentially to 14 mg if needed) to minimise these effects.

Acute pancreatitis has been reported with GLP-1 receptor agonists including Rybelsus. Patients should be advised to seek urgent medical attention if they develop severe, persistent abdominal pain, particularly if radiating to the back, as this may indicate acute pancreatitis. Rybelsus should be discontinued if pancreatitis is suspected or confirmed, and alternative diabetes therapies should be considered.

Gallbladder disease including cholelithiasis and cholecystitis has been observed with GLP-1 RAs. Patients should be advised to seek medical attention for symptoms such as persistent upper abdominal pain, jaundice, or fever that could indicate gallbladder problems.

Animal studies have shown an increased incidence of thyroid C-cell tumours in rodents exposed to GLP-1 RAs, though the relevance to humans is unknown. Patients should be advised to seek medical advice if they experience symptoms such as a neck mass, dysphagia, or persistent hoarseness.

Other potential risks include hypoglycaemia when Rybelsus is used in combination with insulin or sulfonylureas, necessitating dose adjustments of these agents. Diabetic retinopathy complications have been reported in some trials, particularly in patients with pre-existing retinopathy who experience rapid improvements in glycaemic control.

Rybelsus is not recommended in patients with severe gastrointestinal disease, including severe gastroparesis, as experience is limited. Regarding drug interactions, Rybelsus should be taken at least 30 minutes before any other oral medicines. Monitor INR more frequently when initiating Rybelsus in patients on warfarin, and monitor thyroid function in patients taking levothyroxine, as its exposure may increase.

Patients should report suspected side effects via the MHRA Yellow Card scheme.

Monitoring and Safety Considerations During Long Term Use

Regular monitoring is essential to ensure the safe and effective long-term use of Rybelsus. NICE recommends that patients with type 2 diabetes have their HbA1c levels checked every 3–6 months once treatment is stable, with more frequent monitoring during dose adjustments or if glycaemic control deteriorates. Target HbA1c should be individualised based on factors such as age, comorbidities, risk of hypoglycaemia, and patient preference, typically aiming for 48–53 mmol/mol (6.5–7.0%) in most adults.

Renal function should be assessed at least annually, as diabetes is a leading cause of chronic kidney disease. While Rybelsus does not require dose adjustment for mild to moderate renal impairment, caution is advised in patients with severe renal impairment (eGFR <30 mL/min/1.73m²) due to limited clinical data. Gastrointestinal side effects such as vomiting and diarrhoea may lead to dehydration and acute kidney injury, particularly in vulnerable patients, so adequate hydration should be emphasised.

Body weight and BMI should be monitored regularly, as weight loss is both a therapeutic benefit and a marker of treatment response. Excessive or unintended weight loss may warrant dose adjustment or further investigation. Blood pressure and lipid profiles should also be reviewed periodically, as improvements in these parameters often accompany weight reduction and better glycaemic control.

Specific monitoring is required for certain co-prescribed medications. For patients taking warfarin, more frequent INR monitoring is recommended when starting Rybelsus. Those on levothyroxine should have thyroid function tests, as semaglutide may increase levothyroxine exposure. Patients with pre-existing diabetic retinopathy should be monitored closely, particularly during periods of rapid improvement in glycaemic control.

Patient education is a cornerstone of safe long-term therapy. Individuals should be counselled on the correct administration of Rybelsus—taken on an empty stomach with no more than 120 mL of water, at least 30 minutes before food, drink, or other medications, and swallowed whole (not split, crushed or chewed)—to ensure optimal absorption. Patients should also be informed about recognising symptoms of pancreatitis, gallbladder disease, dehydration, and hypoglycaemia (if taking concomitant insulin or sulfonylureas), and when to seek medical advice. Annual diabetes reviews, including foot examinations and retinal screening, remain important components of comprehensive care.

When to Review or Stop Long Term Rybelsus Therapy

Treatment review should occur at regular intervals to assess efficacy, tolerability, and the ongoing appropriateness of Rybelsus therapy. NICE guidance recommends reviewing glucose-lowering treatments if HbA1c targets are not achieved within 6 months, or if there are concerns about side effects, adherence, or changes in clinical circumstances.

NICE continuation criteria for GLP-1 receptor agonists specify that treatment should only be continued if the person has had a beneficial metabolic response (a reduction of at least 11 mmol/mol [1%] in HbA1c and weight loss of at least 3% of initial body weight) after 6 months. If these targets are not met, the treatment should be reviewed and potentially discontinued.

If Rybelsus fails to provide adequate glycaemic control despite dose optimisation, intensification with additional agents or switching to alternative therapies, including injectable GLP-1 RAs or insulin, may be necessary. Rybelsus should not be used concurrently with other GLP-1 RAs, and combining with DPP-4 inhibitors is generally not recommended per NICE guidance.

Discontinuation should be considered if patients experience intolerable side effects that do not resolve with dose adjustment or supportive measures. Persistent gastrointestinal symptoms, suspected or confirmed pancreatitis, or significant weight loss beyond therapeutic goals are valid reasons to stop treatment.

Changes in renal function may also prompt treatment review. While mild to moderate renal impairment does not preclude Rybelsus use, progression to severe renal impairment or end-stage kidney disease may necessitate switching to therapies with more robust safety data in this population.

If a patient is planning pregnancy, Rybelsus should be stopped at least 2 months before planned conception. It should not be used during pregnancy and is generally not recommended during breastfeeding unless the benefit outweighs the risk.

Patient preference and quality of life are important considerations. If the burden of daily administration, dietary restrictions around dosing, or ongoing side effects significantly impair quality of life, a shared decision-making approach should be adopted to explore alternative options. Regular dialogue between patients and healthcare professionals ensures that treatment remains aligned with individual goals, values, and clinical needs. Ultimately, long-term Rybelsus therapy should be part of a holistic, patient-centred diabetes management plan that includes lifestyle modification, cardiovascular risk reduction, and ongoing support.

Frequently Asked Questions