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. Understanding the mechanism of action of Rybelsus is essential for healthcare professionals and patients alike, as it explains how this innovative tablet works to improve blood glucose control. By mimicking the natural hormone GLP-1, Rybelsus enhances insulin secretion, suppresses glucagon release, and delays gastric emptying—all contributing to better glycaemic management. This article explores the detailed pharmacological actions of Rybelsus, its clinical benefits, and important safety considerations for optimal diabetes care.

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 belongs to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists. Unlike many other GLP-1 agonists that require subcutaneous injection, Rybelsus is the first oral formulation of semaglutide, offering a convenient tablet option for patients who prefer not to inject.

Rybelsus works by mimicking the action of a naturally occurring hormone called GLP-1, which is released by the intestines in response to food intake. This hormone plays a crucial role in regulating blood glucose levels by enhancing insulin secretion from the pancreas when blood sugar is elevated. By activating GLP-1 receptors throughout the body, Rybelsus helps to improve glycaemic control in people with type 2 diabetes.

The medication is typically prescribed when diet and exercise alone are insufficient to control blood sugar levels, and it may be used as monotherapy or in combination with other antidiabetic agents such as metformin or insulin. It is not indicated for type 1 diabetes, diabetic ketoacidosis, or for weight loss, and is not recommended for use in people under 18 years of age.

Rybelsus is available in three tablet strengths—3 mg, 7 mg, and 14 mg. Treatment begins with 3 mg once daily for 30 days, then increases to 7 mg once daily. After at least 30 days on the 7 mg dose, it may be increased to 14 mg if needed for better glycaemic control and if tolerated. It is important to take Rybelsus correctly: on an empty stomach with up to 120 ml of water only, swallow the tablet whole (do not split, crush or chew), and wait at least 30 minutes before consuming any food, drink, or other oral medications to ensure adequate absorption.

When used with insulin or sulfonylureas, there is an increased risk of hypoglycaemia, and dose adjustments of these medications may be needed.

The Mechanism of Action of Rybelsus Explained

The mechanism of action of Rybelsus centres on its role as a GLP-1 receptor agonist. Semaglutide, the active ingredient, is a modified version of human GLP-1 with a prolonged half-life, allowing for once-daily oral dosing. When Rybelsus is absorbed into the bloodstream, it binds to and activates GLP-1 receptors located on pancreatic beta cells, the gastrointestinal tract, and various regions of the brain.

Glucose-dependent insulin secretion is the primary mechanism by which Rybelsus lowers blood glucose. Upon activation of GLP-1 receptors on pancreatic beta cells, insulin release is stimulated in a glucose-dependent manner. This means that insulin secretion occurs predominantly when blood glucose levels are elevated, reducing the risk of hypoglycaemia compared to some other antidiabetic medications. However, hypoglycaemia can still occur when Rybelsus is used in combination with insulin or sulfonylureas.

Simultaneously, Rybelsus suppresses glucagon secretion from pancreatic alpha cells. Glucagon is a hormone that raises blood glucose by promoting hepatic glucose production. By reducing inappropriate glucagon release, particularly in the postprandial (after-meal) state, Rybelsus helps to prevent excessive glucose output from the liver, further contributing to improved glycaemic control.

Another key aspect of Rybelsus's mechanism is delayed gastric emptying. Activation of GLP-1 receptors in the stomach slows the rate at which food leaves the stomach and enters the small intestine. This delay reduces the speed at which glucose is absorbed into the bloodstream after meals, leading to lower postprandial glucose spikes. Patients may notice increased satiety and reduced appetite as a result of this effect, which can support weight management efforts—a valuable benefit for many individuals with type 2 diabetes who are overweight or obese. It should be noted that this gastric emptying delay may diminish with continued treatment.

Additional Effects of Rybelsus on the Body

Beyond its primary glucose-lowering effects, Rybelsus exerts several additional physiological actions that contribute to its overall therapeutic profile. One of the most clinically significant is its effect on body weight. Many patients taking Rybelsus experience modest weight loss, which is thought to result from a combination of delayed gastric emptying, increased satiety, and reduced appetite. GLP-1 receptors in the hypothalamus and other brain regions involved in appetite regulation are activated by semaglutide, leading to decreased food intake. Although this weight-reducing effect can be beneficial, it's important to note that Rybelsus is not licensed for weight loss in the UK.

This weight-reducing effect is particularly beneficial in type 2 diabetes, where excess body weight is a common comorbidity and contributes to insulin resistance. NICE guidelines recognise the importance of weight management in diabetes care, and GLP-1 receptor agonists like Rybelsus are often favoured when weight loss is a therapeutic priority alongside glycaemic control.

Regarding cardiovascular effects, the PIONEER 6 trial demonstrated that oral semaglutide was non-inferior to placebo for cardiovascular safety in high-risk patients with type 2 diabetes. While injectable semaglutide has shown cardiovascular benefits in separate trials, clinicians should refer to the current SmPC and regulatory guidance when considering cardiovascular risk reduction, as indications may differ between formulations.

Common adverse effects of Rybelsus include gastrointestinal symptoms such as nausea, vomiting, diarrhoea, and abdominal discomfort. These are typically mild to moderate and often diminish over time as the body adjusts to the medication. Patients should be counselled about these potential side effects and advised to report persistent or severe symptoms to their healthcare provider. Severe gastrointestinal symptoms may lead to dehydration and potentially acute kidney injury, so maintaining adequate hydration is important.

Other important safety considerations include the risk of diabetic retinopathy complications, particularly in patients with pre-existing retinopathy who are also on insulin, and the potential for gallbladder disease. Rybelsus should not be used during pregnancy or breastfeeding, and women of childbearing potential should use contraception. Treatment should be discontinued well in advance of a planned pregnancy.

In animal studies, semaglutide caused thyroid C-cell tumours, but the relevance to humans is unknown. If you experience any suspected side effects, report them via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or the Yellow Card app).

Clinical Evidence Supporting Rybelsus Mechanism

The clinical efficacy of Rybelsus has been demonstrated in a comprehensive programme of randomised controlled trials known as the PIONEER studies. These trials evaluated oral semaglutide across various patient populations and treatment regimens, consistently showing significant reductions in HbA1c (a marker of long-term blood glucose control) and body weight compared to placebo and active comparators.

In the PIONEER 1 trial, Rybelsus monotherapy resulted in HbA1c reductions of up to 1.4% (approximately 15 mmol/mol) from baseline, with the 14 mg dose demonstrating superior efficacy. The PIONEER 4 trial compared Rybelsus to injectable liraglutide (another GLP-1 agonist) and showed non-inferior glycaemic control, confirming that the oral formulation is a viable alternative to injectable therapies for many patients.

Weight loss observed in the PIONEER trials ranged from approximately 2 to 4 kg on average, depending on the dose and study population. These findings support the mechanistic understanding that Rybelsus not only improves glucose metabolism through its effects on insulin and glucagon but also influences energy balance and body weight through central and peripheral appetite regulation.

The PIONEER 6 cardiovascular outcomes trial demonstrated that Rybelsus was non-inferior to placebo regarding major adverse cardiovascular events in high-risk patients with type 2 diabetes, supporting its cardiovascular safety profile.

NICE guidance (NG28) on the management of type 2 diabetes in adults supports the use of GLP-1 receptor agonists when certain criteria are met, including inadequate glycaemic control on other therapies and a body mass index (BMI) ≥35 kg/m² (adjusted to ≥30 kg/m² in people of South Asian and related ethnic groups), or lower in specific clinical circumstances where weight loss would benefit other significant obesity-related comorbidities. The evidence base for Rybelsus aligns with these recommendations, making it a suitable option for appropriately selected patients.

Patient safety is paramount when prescribing Rybelsus. Patients should be advised to take the medication correctly to ensure absorption, report any persistent gastrointestinal symptoms, and seek urgent medical attention if they experience severe abdominal pain (which could indicate pancreatitis). Regular monitoring of HbA1c, renal function, body weight, and retinopathy status (especially in those with pre-existing diabetic retinopathy) is recommended to assess treatment response and tolerability. Patients should be warned about the risk of hypoglycaemia when Rybelsus is used with insulin or sulfonylureas. If glycaemic targets are not achieved or side effects are intolerable, alternative therapies should be considered in consultation with a diabetes specialist or GP.

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