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Rybelsus (semaglutide) is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist licensed in the UK for treating type 2 diabetes mellitus in adults. Unlike injectable GLP-1 therapies, Rybelsus offers a convenient once-daily tablet option for patients whose blood glucose remains inadequately controlled with lifestyle measures alone. By mimicking a natural hormone that regulates blood sugar, Rybelsus enhances insulin secretion, suppresses glucagon release, and slows gastric emptying—helping to improve glycaemic control whilst reducing the risk of hypoglycaemia when used as monotherapy. Understanding how Rybelsus works can help patients and clinicians optimise its use within a comprehensive diabetes management plan.
Quick Answer: Rybelsus works by mimicking the natural hormone GLP-1 to enhance insulin secretion, suppress glucagon release, and slow gastric emptying, thereby improving blood glucose control in adults with type 2 diabetes.
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, which work by mimicking the action of a naturally occurring hormone in the body that helps regulate blood sugar levels.
Unlike many other GLP-1 receptor agonists that require injection, Rybelsus is available as a tablet for oral administration. It is typically prescribed when diet and exercise alone are insufficient to control blood glucose, and may be used alongside other diabetes medications such as metformin or as monotherapy when metformin is not tolerated. Importantly, Rybelsus should not be used in combination with DPP-4 inhibitors or other GLP-1 receptor agonists.
The primary mechanism involves enhancing insulin secretion from the pancreas in response to elevated blood glucose levels, whilst simultaneously suppressing the release of glucagon (a hormone that raises blood sugar). Rybelsus also slows gastric emptying, which helps reduce post-meal glucose spikes, and may promote a feeling of fullness that can support weight management.
Rybelsus is available in three strengths—3 mg, 7 mg, and 14 mg—with treatment usually starting at the lowest dose and gradually increasing to minimise gastrointestinal side effects. The medication must be taken on an empty stomach with a small amount of water (up to 120 ml), at least 30 minutes before food or other medications, to ensure optimal absorption. The tablet should be swallowed whole and not split, crushed or chewed. This specific dosing requirement is essential for the tablet's effectiveness and distinguishes it from most other oral diabetes treatments.
Semaglutide, the active pharmaceutical ingredient in Rybelsus, is a modified GLP-1 analogue designed to resist rapid breakdown by the enzyme dipeptidyl peptidase-4 (DPP-4). Natural GLP-1 has a very short half-life of only a few minutes, but semaglutide's molecular modifications extend its duration of action, with a systemic half-life of approximately one week. Despite this long half-life, Rybelsus requires once-daily dosing due to its oral absorption characteristics and as established in clinical trials.
The drug works by binding to GLP-1 receptors found throughout the body, particularly in the pancreas, brain, and gastrointestinal tract. When blood glucose levels rise after eating, semaglutide stimulates pancreatic beta cells to release insulin in a glucose-dependent manner. Crucially, this means insulin secretion occurs primarily when blood sugar is elevated, which significantly reduces the risk of hypoglycaemia when used alone. However, the risk of hypoglycaemia increases when Rybelsus is used in combination with sulfonylureas or insulin.
Simultaneously, semaglutide suppresses glucagon secretion from pancreatic alpha cells. Glucagon normally signals the liver to release stored glucose, so reducing its activity helps prevent excessive glucose production between meals. This dual action on insulin and glucagon creates a more physiological pattern of glucose regulation.
Another important mechanism involves the central nervous system. GLP-1 receptors in the hypothalamus and other brain regions influence appetite and satiety signals. Semaglutide's action on these receptors can reduce hunger and food intake, which often leads to modest weight loss—a beneficial effect for many people with type 2 diabetes who are overweight.
The delayed gastric emptying caused by semaglutide means food moves more slowly from the stomach into the small intestine, resulting in a more gradual rise in post-meal blood glucose levels and contributing to improved overall glycaemic control.
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When starting Rybelsus, patients typically begin with the 3 mg dose once daily for 30 days. This initial period allows the body to adjust to the medication and helps minimise gastrointestinal side effects. After one month, the dose is usually increased to 7 mg daily, and if additional glycaemic control is needed after a further 30 days, it may be increased to the maximum dose of 14 mg daily.
Proper administration is critical for Rybelsus to work effectively. The tablet must be taken first thing in the morning on an empty stomach with no more than 120 ml (half a glass) of plain water. The tablet should be swallowed whole—do not split, crush or chew it. Patients must then wait at least 30 minutes before eating, drinking, or taking any other oral medications. If a dose is missed, the next scheduled dose should be taken the following day as usual; do not take a double dose. This strict timing requirement is necessary because food, beverages (other than water), and other medicines can significantly reduce the absorption of semaglutide from the gastrointestinal tract.
Common side effects, particularly during the initial weeks, include nausea, vomiting, diarrhoea, abdominal pain, and reduced appetite. These gastrointestinal symptoms are usually mild to moderate and tend to improve over time as the body adjusts. Taking the medication consistently and following the dosing instructions carefully can help minimise these effects.
Patients should monitor their blood glucose levels as advised by their healthcare team, as Rybelsus will gradually improve glycaemic control over several weeks. HbA1c levels (a measure of average blood sugar over 2–3 months) typically show improvement within 12–16 weeks of treatment. Many patients also experience modest weight loss, though this varies individually.
Important safety advice: Contact your GP promptly if you experience severe or persistent abdominal pain (which could indicate pancreatitis), signs of dehydration from vomiting or diarrhoea (which could lead to acute kidney injury), or any visual changes (particularly if you have pre-existing diabetic retinopathy). If you develop symptoms of hypoglycaemia (shakiness, sweating, confusion) whilst taking Rybelsus with other diabetes medications such as sulfonylureas or insulin, seek medical advice about dose adjustments of these medications. Also be aware that Rybelsus may increase the risk of gallbladder problems such as gallstones.
If you are taking warfarin or other coumarin anticoagulants, more frequent INR monitoring is recommended when starting Rybelsus. Similarly, if you take levothyroxine, your thyroid function should be monitored as semaglutide may affect thyroid hormone levels.
Report any suspected side effects to the MHRA Yellow Card scheme at www.mhra.gov.uk/yellowcard or via the Yellow Card app.
Rybelsus is licensed for adults with type 2 diabetes mellitus whose blood glucose levels are inadequately controlled despite lifestyle modifications. According to NICE guidance (NG28), GLP-1 receptor agonists like semaglutide may be considered when other treatments have not achieved target HbA1c levels or when weight loss would be particularly beneficial.
The medication is particularly suitable for patients who:
Prefer oral medication over injectable treatments
Have struggled to achieve glycaemic targets with metformin or other oral diabetes medications
Would benefit from weight loss alongside glucose control
Have a high risk of hypoglycaemia with other treatments (as Rybelsus carries a low intrinsic risk when used alone)
Cannot tolerate or have contraindications to other diabetes medications
NICE recommends considering GLP-1 receptor agonists for people with type 2 diabetes who have a BMI of 35 kg/m² or higher and specific psychological or medical problems associated with obesity. NICE advises that lower BMI thresholds should be considered for people from certain ethnic groups, such as those of South Asian or Chinese family origin. The medication may also be appropriate for those with lower BMI if insulin therapy would have significant occupational implications or weight loss would benefit other obesity-related comorbidities.
Treatment should be continued only if there is a beneficial metabolic response at around 6 months, defined by NICE as a reduction in HbA1c of at least 11 mmol/mol (1 percentage point) and weight loss of at least 3% of initial body weight.
Rybelsus is not suitable for people with type 1 diabetes, diabetic ketoacidosis, or severe gastroparesis. It should be used with caution in patients with a history of pancreatitis. The UK SmPC notes that semaglutide caused C-cell tumours in rodent studies, though the relevance to humans is unknown. Women who are pregnant, planning pregnancy, or breastfeeding should not use Rybelsus. Due to its long half-life, semaglutide should be discontinued at least 2 months before a planned pregnancy.
Patients with severe renal impairment (eGFR <15 ml/min/1.73m²) or end-stage renal disease have limited data on Rybelsus use, and specialist advice should be sought. Patients with pre-existing diabetic retinopathy should be monitored closely, as rapid improvement in glucose control may be associated with temporary worsening of retinopathy.
Remember that Rybelsus should not be used in combination with DPP-4 inhibitors or other GLP-1 receptor agonists.
Rybelsus begins to lower blood glucose levels within days, but significant improvements in HbA1c (average blood sugar over 2–3 months) typically become evident within 12–16 weeks of consistent treatment.
Food, beverages other than water, and other oral medications significantly reduce the absorption of semaglutide from the gastrointestinal tract. Taking Rybelsus on an empty stomach with up to 120 ml of water, at least 30 minutes before eating or taking other medicines, ensures optimal absorption and effectiveness.
Rybelsus has a low intrinsic risk of hypoglycaemia when used alone because it stimulates insulin secretion only when blood glucose is elevated. However, the risk increases when Rybelsus is combined with sulfonylureas or insulin, and dose adjustments of these medications may be necessary.
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