Rybelsus (semaglutide) is an oral medication licensed in the UK for managing type 2 diabetes mellitus. As a glucagon-like peptide-1 (GLP-1) receptor agonist, it helps regulate blood sugar levels and appetite. Whilst emerging research suggests potential benefits for liver health in patients with non-alcoholic fatty liver disease (NAFLD), it is crucial to understand that Rybelsus is not currently licensed for treating fatty liver disease in the UK. This article examines the evidence, safety considerations, and NHS guidance surrounding Rybelsus use in patients with fatty liver.

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. 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 regulates blood sugar levels and appetite.

The mechanism of action involves several key processes. Rybelsus stimulates insulin secretion from the pancreas when blood glucose levels are elevated, whilst simultaneously suppressing the release of glucagon, a hormone that raises blood sugar. This dual action helps maintain more stable glycaemic control throughout the day. Additionally, semaglutide slows gastric emptying, which means food moves more slowly from the stomach into the small intestine, leading to increased satiety and reduced appetite.

One of the notable effects of Rybelsus is weight loss, which occurs as a secondary benefit in many patients. This weight reduction is achieved through decreased caloric intake due to enhanced feelings of fullness and reduced hunger. It is important to note that Rybelsus is not licensed for weight loss in the UK.

Rybelsus must be taken once daily on an empty stomach with up to 120 ml of water only. The tablet should be swallowed whole and patients must wait at least 30 minutes before consuming any food, drink, or other oral medications. Treatment typically starts with 3 mg daily for 30 days, then increases to 7 mg daily, with a possible further increase to 14 mg if needed for glycaemic control.

It is important to emphasise that Rybelsus is not currently licensed for the treatment of fatty liver disease in the UK. The Medicines and Healthcare products Regulatory Agency (MHRA) has approved it solely for type 2 diabetes management. While researchers have observed potential benefits for liver health in studies of injectable semaglutide, particularly in patients who have both diabetes and non-alcoholic fatty liver disease (NAFLD), evidence specific to the oral formulation remains limited.

Understanding Fatty Liver Disease and Treatment Options

Non-alcoholic fatty liver disease (NAFLD) is a common condition characterised by excessive fat accumulation in the liver in people who drink little or no alcohol. It exists on a spectrum, ranging from simple steatosis (fat accumulation without inflammation) to non-alcoholic steatohepatitis (NASH), which involves inflammation and liver cell damage that can progress to fibrosis, cirrhosis, and even liver failure.

NAFLD is strongly associated with metabolic syndrome, a cluster of conditions including obesity, type 2 diabetes, high blood pressure, and dyslipidaemia. In the UK, NAFLD affects an estimated 20–30% of the general population, with higher prevalence among those with obesity or diabetes. Many individuals remain asymptomatic until advanced liver disease develops, making early detection and management crucial. Importantly, liver function tests can be normal in NAFLD, and diagnosis often requires ultrasound imaging alongside assessment of metabolic risk factors.

Current treatment approaches focus primarily on lifestyle modification. NICE guidance emphasises that weight loss of 7–10% of body weight can significantly reduce liver fat and improve inflammation. Key recommendations include:

• Dietary changes: Adopting a balanced, calorie-controlled diet with reduced intake of refined carbohydrates and saturated fats

• Regular physical activity: At least 150 minutes of moderate-intensity exercise weekly

• Management of comorbidities: Optimising control of diabetes, hypertension, and cholesterol levels

• Alcohol guidance: Staying within UK low-risk drinking guidelines (no more than 14 units per week, spread over several days with alcohol-free days); complete abstinence may be advised for those with advanced liver disease

Assessment of NAFLD severity typically involves calculating risk scores such as the FIB-4 index or NAFLD Fibrosis Score. Those with intermediate or high scores may require an Enhanced Liver Fibrosis (ELF) test and referral to specialist hepatology services if advanced fibrosis is suspected.

Currently, no medications are specifically licensed in the UK for treating NAFLD or NASH. Vitamin E may be considered by specialists for adults with biopsy-proven NASH who don't have diabetes. Pioglitazone might be offered to some patients with NASH, particularly those with type 2 diabetes, but requires specialist supervision. Both treatments remain off-label for this indication. The absence of approved pharmacological treatments has driven research into repurposing existing diabetes medications, including GLP-1 receptor agonists like semaglutide.

Clinical Evidence for Rybelsus in Liver Health

Emerging clinical evidence suggests that semaglutide may offer benefits for liver health in patients with NAFLD or NASH, though it is important to emphasise that there is no official licence for this indication in the UK. The potential hepatic benefits appear to be mediated through multiple mechanisms, including weight loss, improved insulin sensitivity, reduced inflammation, and direct effects on liver metabolism.

Several clinical trials have investigated GLP-1 receptor agonists in NAFLD. A notable phase 2 study published in the New England Journal of Medicine examined subcutaneous semaglutide (injectable form, not Rybelsus) in patients with NASH and found that a significantly higher proportion of patients achieved resolution of NASH without worsening of fibrosis compared to placebo. However, the study did not demonstrate significant improvement in fibrosis stage. Participants experienced substantial weight loss and improvements in liver enzyme levels, particularly alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

It is crucial to understand that most robust evidence comes from studies of injectable semaglutide, not the oral formulation (Rybelsus). While oral semaglutide effectively reduces body weight and improves glycaemic control in type 2 diabetes—both key factors in managing fatty liver disease—its specific effects on liver histology remain largely unproven. It would be premature to assume identical liver benefits between the oral and injectable formulations without direct evidence.

Important limitations must be acknowledged:

• Direct evidence for oral Rybelsus on liver histology is limited

• Long-term data on liver-specific outcomes remain sparse

• The medication's effects on advanced fibrosis and cirrhosis require further investigation

• Individual responses vary considerably

Patients should understand that whilst the evidence is promising, Rybelsus should not be considered a standalone treatment for fatty liver disease. It may be prescribed for eligible patients with type 2 diabetes who also have NAFLD, where it could potentially provide dual benefits. Any decision to use Rybelsus must be made by a qualified healthcare professional after comprehensive assessment.

Safety Considerations and Side Effects

Like all medications, Rybelsus carries potential side effects that patients and healthcare professionals must consider carefully. The most commonly reported adverse effects are gastrointestinal in nature and typically occur during the initial weeks of treatment as the body adjusts to the medication.

Common side effects (affecting more than 1 in 10 people) include:

• Nausea: Often the most troublesome symptom, usually improving over time

• Diarrhoea: May be persistent in some individuals

• Vomiting: Particularly during dose escalation

• Abdominal pain or discomfort: Generally mild to moderate

• Decreased appetite: Whilst this contributes to weight loss, it may be excessive in some patients

• Constipation: Can occur alongside other digestive symptoms

• Dyspepsia and reflux: Including heartburn and regurgitation

These gastrointestinal symptoms can often be managed by following the recommended dose titration schedule (starting at 3 mg daily for 30 days before increasing to 7 mg), eating smaller meals, and avoiding high-fat foods. If symptoms persist or become severe, patients should consult their GP or diabetes specialist.

Serious but less common risks include:

• Hypoglycaemia: Particularly when used with insulin or sulfonylureas; dose adjustments of other diabetes medications may be necessary

• Acute pancreatitis: Patients should seek immediate medical attention if experiencing severe, persistent abdominal pain

• Diabetic retinopathy complications: Rapid improvement in blood glucose control may temporarily worsen diabetic eye disease

• Gallbladder problems: Including gallstones and cholecystitis

• Dehydration and acute kidney injury: Due to fluid loss from gastrointestinal side effects

According to the UK product information, hypersensitivity to semaglutide or any of the excipients is the only formal contraindication. However, Rybelsus should be used with caution in patients with:

• History of pancreatitis

• Severe gastrointestinal disease including gastroparesis

• Type 1 diabetes (not indicated)

• Diabetic ketoacidosis (not indicated)

Rybelsus should not be used during pregnancy or breastfeeding. Women of childbearing potential should use effective contraception and discontinue the medication at least two months before planned conception.

Important drug interactions include potential effects on absorption of other oral medications (take other medicines at least 30 minutes after Rybelsus), possible increased effect of levothyroxine (monitor thyroid function), and potential changes in warfarin effect (monitor INR).

Patients with existing liver disease require careful monitoring, though current evidence suggests semaglutide is generally well-tolerated in this population. If you experience any side effects, report them to your healthcare professional and consider using the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or the Yellow Card app).

NHS Guidance and When to Speak With Your GP

NHS prescribing of Rybelsus is currently restricted to patients with type 2 diabetes who meet specific criteria. According to NICE guidance (NG28), GLP-1 receptor agonists like semaglutide may be considered when:

• Triple therapy is needed (with metformin and another oral diabetes medication) when glycaemic control remains inadequate

• The patient has a BMI ≥35 kg/m² (or lower in certain ethnic groups) with specific psychological or medical problems associated with obesity

• The patient has a BMI <35 kg/m² and insulin would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities

• As part of a treatment strategy with insulin when other treatments have not achieved adequate glycaemic control

Importantly, NICE recommends continuing GLP-1 receptor agonist treatment only if the patient 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.

It is crucial to understand that Rybelsus is not currently prescribed by the NHS specifically for fatty liver disease alone. If you have NAFLD without diabetes, lifestyle modification remains the primary recommended approach. However, if you have both conditions, your healthcare team may consider Rybelsus as part of your diabetes management, which could potentially benefit your liver health as well.

You should speak with your GP if you:

• Have been diagnosed with fatty liver disease and want to discuss treatment options

• Have type 2 diabetes with poor glycaemic control despite current medications

• Experience unexplained fatigue, abdominal discomfort, or other symptoms that might indicate liver problems

• Are taking Rybelsus and develop severe or persistent side effects

• Notice signs of hypoglycaemia (shakiness, sweating, confusion, rapid heartbeat)

• Develop severe abdominal pain that could indicate pancreatitis

Seek urgent medical attention if you develop:

• Yellowing of the skin or eyes (jaundice)

• Vomiting blood or passing black, tarry stools

• Confusion or drowsiness

• Severe abdominal swelling (ascites)

• Fever with severe abdominal pain

Monitoring and follow-up are essential. If prescribed Rybelsus, you should expect regular reviews to assess:

• Blood glucose control (HbA1c levels)

• Weight changes and BMI

• Liver function tests (if indicated)

• Tolerability and side effects

• Overall cardiovascular risk factors

If you have NAFLD, your GP may calculate risk scores such as FIB-4 or NAFLD Fibrosis Score to assess the likelihood of advanced fibrosis. Those with intermediate or high scores may need an Enhanced Liver Fibrosis (ELF) test and possible referral to a liver specialist.

Your GP or diabetes specialist will determine whether Rybelsus is appropriate for your individual circumstances, considering your medical history, current medications, and treatment goals. Self-medication or obtaining Rybelsus without proper medical supervision is not safe and could lead to serious complications. Always engage with NHS services and qualified healthcare professionals for evidence-based, personalised advice regarding fatty liver disease and diabetes management.

Frequently Asked Questions