Rybelsus (semaglutide) is the first oral GLP-1 receptor agonist licensed in the UK for type 2 diabetes mellitus. Whilst it offers an alternative to injectable formulations and can support glycaemic control and weight management, several problems limit its use. Common issues include gastrointestinal side effects such as nausea, vomiting, and diarrhoea, which can affect tolerability. Serious risks include pancreatitis, thyroid concerns, and gallbladder disease. Additionally, Rybelsus has strict dosing requirements due to poor oral bioavailability, which can challenge adherence. Understanding these problems is essential for patients and healthcare professionals when considering Rybelsus as a treatment option.

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 in combination with other diabetes medications. It belongs to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists. Rybelsus is notable as the first GLP-1 receptor agonist available in tablet form, offering an alternative to injectable formulations such as Ozempic (also semaglutide) and other GLP-1 analogues.

The mechanism of action centres on mimicking the effects of the naturally occurring hormone GLP-1. Semaglutide binds to and activates GLP-1 receptors in the pancreas, which stimulates insulin secretion in a glucose-dependent manner. This means insulin is released primarily when blood glucose levels are elevated, reducing the risk of hypoglycaemia compared to some other diabetes medications. Additionally, semaglutide suppresses glucagon secretion, slows gastric emptying, and promotes satiety, which can contribute to weight loss—a beneficial effect for many patients with type 2 diabetes.

Rybelsus is initiated at 3 mg once daily for 30 days as a starting dose (this dose is not effective for glycaemic control). After 30 days, the dose is increased to 7 mg once daily, and may be further increased to 14 mg once daily if needed for improved glycaemic control. According to NICE guidance (NG28), GLP-1 receptor agonists like Rybelsus may be considered when triple therapy with metformin and two other oral drugs is not effective, not tolerated or contraindicated, and where weight loss would be beneficial (typically in patients with a BMI ≥35 kg/m² or BMI <35 kg/m² with weight-related comorbidities).

Despite its therapeutic advantages, Rybelsus is associated with several tolerability and safety concerns that can limit its use in certain patient populations. Understanding these issues is essential for both healthcare professionals and patients considering this treatment option.

Common Side Effects and Tolerability Issues with Rybelsus

The most frequently reported adverse effects of Rybelsus are gastrointestinal in nature. Clinical trials and post-marketing surveillance have consistently identified nausea, vomiting, diarrhoea, abdominal pain, and constipation as common complaints, particularly during the initial weeks of treatment or following dose escalation. These symptoms are related to the drug's mechanism—slowed gastric emptying and effects on the gastrointestinal tract.

Nausea is the most prevalent side effect, affecting a significant proportion of patients. For many, this is mild to moderate and tends to diminish over time as the body adjusts to the medication. However, in some individuals, persistent or severe nausea can lead to treatment discontinuation. Healthcare professionals often advise patients to take Rybelsus on an empty stomach first thing in the morning with a small amount of water (up to 120 mL), to swallow the tablet whole (not split, crushed or chewed), and to wait at least 30 minutes before eating, drinking, or taking other oral medicines. These instructions are primarily to ensure adequate absorption of the medication.

Decreased appetite and early satiety are also common, which, while contributing to weight loss, may be problematic for patients who are already at risk of malnutrition or unintentional weight loss. Other tolerability issues include headache, dizziness, and fatigue, which are generally mild but can affect quality of life.

It is important to note that gastrointestinal side effects do not necessarily indicate a serious problem, but they are a key reason why some patients find Rybelsus difficult to tolerate. Patients experiencing persistent or worsening symptoms, particularly severe vomiting or diarrhoea that could lead to dehydration, should contact their GP or diabetes specialist nurse for advice. Dose adjustments, slower titration schedules, or switching to an alternative medication may be considered to improve tolerability while maintaining glycaemic control.

Patients are encouraged to report any suspected adverse reactions to Rybelsus via the MHRA Yellow Card Scheme.

Serious Risks and Safety Concerns Associated with Rybelsus

While most adverse effects of Rybelsus are mild and self-limiting, there are serious risks that require careful consideration and monitoring. One of the most significant concerns is the potential for acute pancreatitis. GLP-1 receptor agonists, including semaglutide, have been associated with cases of pancreatitis in clinical practice. Patients should be advised to seek urgent medical attention if they develop severe, persistent abdominal pain that may radiate to the back, often accompanied by nausea and vomiting. If pancreatitis is suspected, Rybelsus should be discontinued and not restarted.

Another safety concern relates to thyroid C-cell tumours. In rodent studies, semaglutide was associated with an increased incidence of thyroid C-cell tumours, including medullary thyroid carcinoma (MTC). Although there is no established causal link in humans, the MHRA advises caution. Patients should be counselled to report symptoms such as a lump in the neck, hoarseness, difficulty swallowing, or shortness of breath. Patients with a personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2) should be carefully evaluated regarding the benefit-risk balance of using semaglutide.

Gallbladder disease including cholelithiasis and cholecystitis has been reported with GLP-1 receptor agonists. Patients should be advised to seek medical attention for symptoms such as right upper quadrant pain, fever, or jaundice.

Diabetic retinopathy complications have been observed in some patients, particularly those with pre-existing retinopathy who experience rapid improvements in glycaemic control. Careful monitoring is recommended for patients with a history of diabetic retinopathy.

Additionally, there have been reports of acute kidney injury, often in the context of severe gastrointestinal side effects leading to dehydration. Patients with renal impairment or those taking other nephrotoxic medications should be monitored closely. Hypoglycaemia risk is generally low with Rybelsus monotherapy but increases when used in combination with insulin or sulfonylureas; dose adjustments of these agents may be necessary. Patients should be educated on recognising and managing hypoglycaemic episodes and advised to contact their healthcare provider if recurrent episodes occur.

Absorption Problems and Dosing Challenges

One of the unique challenges with Rybelsus is its poor oral bioavailability. Semaglutide is a peptide that would normally be degraded in the gastrointestinal tract. To overcome this, Rybelsus is co-formulated with an absorption enhancer called sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which facilitates absorption across the gastric mucosa. Even with this technology, the bioavailability of oral semaglutide is approximately 1%, which is substantially lower than the bioavailability of subcutaneous semaglutide.

This low bioavailability necessitates strict dosing instructions to maximise absorption and therapeutic effect. Patients must take Rybelsus on an empty stomach with no more than 120 mL of water, swallow the tablet whole (not split, crushed or chewed), and must wait at least 30 minutes before consuming any food, drink (other than water), or other oral medications. Failure to adhere to these instructions can significantly reduce drug absorption and compromise glycaemic control.

These requirements can be challenging for patients to incorporate into daily routines, particularly for those with complex medication regimens, shift workers, or individuals with cognitive impairment. Non-adherence—whether intentional or unintentional—can lead to suboptimal diabetes control and may be mistakenly attributed to treatment failure rather than absorption issues.

Drug interactions related to absorption are also a consideration. Because Rybelsus must be taken alone, patients taking multiple morning medications may find the regimen cumbersome. Importantly, Rybelsus can increase the exposure of levothyroxine, so thyroid function should be monitored in patients taking both medications. Additionally, when initiating Rybelsus in patients on warfarin, more frequent INR monitoring is advised. According to the SmPC, medicines that affect gastric pH (such as proton pump inhibitors) do not have clinically relevant effects on semaglutide absorption.

Healthcare professionals should provide clear written and verbal instructions on how to take Rybelsus and assess patient understanding and ability to adhere to the regimen. For patients who struggle with these requirements, alternative GLP-1 receptor agonists (injectable formulations) or other oral diabetes medications may be more appropriate.

Who Should Avoid Rybelsus? Contraindications and Precautions

According to the UK SmPC, Rybelsus is contraindicated in patients with a known hypersensitivity to semaglutide or any excipients in the formulation.

There are several important precautions and warnings to consider. Due to findings of thyroid C-cell tumours in rodent studies, patients with a personal or family history of medullary thyroid carcinoma (MTC) or those with multiple endocrine neoplasia syndrome type 2 (MEN 2) should be carefully evaluated regarding the benefit-risk balance of using semaglutide.

Rybelsus is not licensed for use in type 1 diabetes or for the treatment of diabetic ketoacidosis. It should not be used in patients under 18 years of age, as safety and efficacy have not been established in this population. Additionally, Rybelsus is not recommended during pregnancy or breastfeeding. Current guidance suggests that Rybelsus should be discontinued at least two months before a planned pregnancy, and alternative treatments (such as insulin) should be considered for women who are pregnant or breastfeeding.

Caution is advised in patients with a history of pancreatitis, gallbladder disease, severe gastrointestinal disease (including inflammatory bowel disease or gastroparesis), or diabetic retinopathy. Patients with renal impairment should be monitored, particularly if experiencing gastrointestinal side effects that could lead to dehydration and acute kidney injury. There is no need for dose adjustment in mild to moderate renal impairment, but caution is warranted in severe impairment due to limited clinical experience.

Patients taking insulin or sulfonylureas concurrently with Rybelsus are at increased risk of hypoglycaemia; dose reductions of these agents may be necessary. Generally, combining a GLP-1 receptor agonist with a DPP-4 inhibitor is not recommended due to limited additive benefit.

Older adults and those with multiple comorbidities should be assessed individually, considering the potential for polypharmacy, adherence challenges, and increased vulnerability to adverse effects. A thorough medication review and patient-centred discussion are essential before initiating Rybelsus to ensure it is safe and appropriate for the individual.

Alternatives to Rybelsus for Type 2 Diabetes Management

For patients who cannot tolerate Rybelsus or for whom it is contraindicated, several alternative treatment options are available for type 2 diabetes management. The choice of therapy should be individualised based on factors including glycaemic control, cardiovascular and renal risk, body weight, hypoglycaemia risk, patient preference, and cost-effectiveness, in line with NICE guideline NG28.

Metformin remains the first-line oral agent for most patients with type 2 diabetes, unless contraindicated. It is effective, generally well-tolerated, and has a long safety record. For patients requiring additional therapy, options include SGLT2 inhibitors (such as dapagliflozin, empagliflozin, or canagliflozin), which offer cardiovascular and renal protective benefits and promote weight loss, though they carry risks such as genital infections and, rarely, diabetic ketoacidosis. NICE recommends prioritising SGLT2 inhibitors for patients with chronic kidney disease, heart failure, or established cardiovascular disease. DPP-4 inhibitors (such as sitagliptin or linagliptin) are weight-neutral, well-tolerated, and have a low hypoglycaemia risk, making them suitable for older adults or those with complex comorbidities.

Injectable GLP-1 receptor agonists (such as dulaglutide, liraglutide, or subcutaneous semaglutide) offer similar or superior efficacy to Rybelsus without the strict dosing requirements related to oral absorption. Many patients find once-weekly injections (e.g., dulaglutide, semaglutide) convenient and preferable to daily oral tablets with complex administration rules. Some injectable GLP-1 receptor agonists (liraglutide, dulaglutide, and subcutaneous semaglutide) have demonstrated cardiovascular benefits in high-risk patients in clinical trials.

For patients with inadequate control on oral agents, basal insulin (such as insulin glargine or insulin detemir) may be introduced, often in combination with metformin. Sulfonylureas (such as gliclazide) are effective and inexpensive but carry a higher risk of hypoglycaemia and weight gain. Thiazolidinediones (pioglitazone) may be considered in specific circumstances but are associated with weight gain, fluid retention, and bone fracture risk.

Patients experiencing problems with Rybelsus should be encouraged to discuss their concerns with their GP or diabetes care team. A medication review can identify the most suitable alternative, taking into account individual circumstances, comorbidities, and treatment goals. Shared decision-making and patient education are key to achieving optimal diabetes control and quality of life.

Frequently Asked Questions