If you've been taking Rybelsus (semaglutide) for type 2 diabetes and notice your blood glucose levels rising again, you're not alone. Some patients find that Rybelsus stops working as effectively over time, a phenomenon that can occur with many diabetes medications. This reduced effectiveness may stem from the progressive nature of type 2 diabetes itself, incorrect dosing or administration, lifestyle changes, or the natural evolution of your condition. Understanding why this happens and what steps to take is essential for maintaining good glycaemic control and preventing complications.

Why Rybelsus May Stop Working Over Time

Rybelsus (semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist used to improve glycaemic control in adults with type 2 diabetes mellitus. It works by enhancing insulin secretion in response to meals, suppressing glucagon release, and slowing gastric emptying. Whilst Rybelsus is effective for many patients, some individuals may notice a reduction in its efficacy over time—a phenomenon that can occur with various diabetes medications.

Progressive beta-cell dysfunction is a key factor in type 2 diabetes. The condition is characterised by ongoing deterioration of pancreatic beta-cell function, meaning that over months or years, the pancreas produces less insulin. As this natural disease progression continues, medications that rely on stimulating insulin secretion may become less effective. This is not a failure of the medication itself, but rather reflects the underlying pathophysiology of diabetes.

Some patients may experience a diminished response to GLP-1 receptor agonists like Rybelsus, though it's important to note that while attenuation of gastric emptying effects may occur, the glycaemic benefits generally persist. Additionally, lifestyle factors play a significant role: weight gain, reduced physical activity, poor dietary adherence, or increased stress can all contribute to worsening glycaemic control, making it appear as though Rybelsus is no longer working.

Other factors include inadequate dosing—the 3 mg dose is only for initial 30-day treatment to improve gastrointestinal tolerability and is not intended for ongoing glycaemic control. Patients may need to titrate to 7 mg or 14 mg for effective treatment. Poor medication adherence is another factor, particularly incorrect administration. Rybelsus must be taken on an empty stomach with no more than 120 ml of water, at least 30 minutes before food, drink, or other oral medications. The tablet should be swallowed whole (not split, crushed or chewed). Concurrent illnesses, new medications (especially corticosteroids), or undiagnosed conditions such as thyroid disorders can also impact blood glucose control. Notably, Rybelsus may increase exposure to levothyroxine, requiring additional monitoring.

Signs That Rybelsus Is No Longer Effective

Recognising when Rybelsus may no longer be providing adequate glycaemic control is essential for timely intervention. Elevated blood glucose readings are the most direct indicator. If you monitor your blood glucose at home (typically recommended for those on insulin, sulfonylureas, or experiencing hypoglycaemia), you may notice:

• Fasting glucose levels consistently above your individualised target (often around 7.0 mmol/L)

• Post-prandial (after-meal) glucose readings regularly exceeding your target range

• Increased variability in glucose readings throughout the day

Another important marker is a rising HbA1c level. HbA1c reflects average blood glucose control over the preceding 8–12 weeks. According to NICE guidance, the target HbA1c for most adults with type 2 diabetes is 48 mmol/mol (6.5%), though individualised targets may be higher based on factors such as age, duration of diabetes, and risk of hypoglycaemia. If HbA1c rises above your agreed target despite good adherence to Rybelsus, this suggests the medication is no longer sufficient.

Return of diabetes symptoms can also signal inadequate control. These may include:

• Increased thirst (polydipsia) and frequent urination (polyuria)

• Unexplained fatigue or lethargy

• Blurred vision

• Recurrent infections, particularly thrush or urinary tract infections

• Unintentional weight loss (in cases of severe hyperglycaemia)

Weight regain after initial weight loss may be another indicator. Many patients experience weight reduction when starting Rybelsus due to its effects on appetite and gastric emptying. If weight begins to increase again, this warrants reassessment, though it's not definitive evidence of medication failure.

Patients should maintain regular contact with their diabetes care team and report any of these changes promptly. Seek urgent medical attention if you experience marked hyperglycaemia with symptoms of dehydration, or if you develop symptoms that could suggest diabetic ketoacidosis (particularly if you also take an SGLT2 inhibitor).

What to Do When Rybelsus Stops Working

If you suspect Rybelsus is no longer controlling your diabetes effectively, do not stop taking the medication without consulting your GP or diabetes specialist. Abrupt discontinuation can lead to worsening glycaemic control and potential complications. Instead, take the following steps:

Review your current dose and adherence. Ensure you are taking Rybelsus correctly: on an empty stomach, with no more than 120 ml of water, at least 30 minutes before food, drink, or other medications. The tablet should be swallowed whole, not split, crushed or chewed. Incorrect administration significantly reduces absorption and efficacy. If you are on 3 mg, note this is only an initial 30-day dose to improve tolerability. According to the SmPC, patients should titrate to 7 mg daily and then to 14 mg daily if needed and tolerated for optimal glycaemic control.

Assess lifestyle factors that may be contributing to reduced effectiveness. Work with your healthcare team to evaluate:

• Dietary habits: Are you following a balanced, carbohydrate-controlled diet?

• Physical activity: Are you meeting recommended activity levels (at least 150 minutes of moderate-intensity exercise weekly)?

• Weight management: Has your weight increased since starting treatment?

• Stress and sleep: Both can significantly impact blood glucose control

Schedule a comprehensive diabetes review with your GP or diabetes nurse. This should include:

• HbA1c measurement to objectively assess glycaemic control

• Review of home blood glucose monitoring data (if applicable)

• Assessment for diabetes complications (retinopathy, nephropathy, neuropathy)

• Evaluation of cardiovascular risk factors

• Screening for other conditions affecting glucose control (such as thyroid dysfunction) if clinically indicated

Consider medication intensification. NICE guidance supports a stepwise approach to diabetes management. If Rybelsus monotherapy is insufficient, your clinician may recommend adding a second agent, such as metformin (if not already prescribed) or an SGLT2 inhibitor. Note that DPP-4 inhibitors should not be used concurrently with GLP-1 receptor agonists due to overlapping mechanisms. Alternatively, switching to a different GLP-1 receptor agonist or transitioning to injectable semaglutide may be considered, as higher doses can be achieved via subcutaneous administration.

Seek urgent medical attention if you develop significant hyperglycaemia with dehydration, or if you have symptoms that could suggest diabetic ketoacidosis (particularly if also taking an SGLT2 inhibitor).

Alternative Treatments When Rybelsus Loses Effectiveness

When Rybelsus no longer provides adequate glycaemic control, several evidence-based alternatives are available. Treatment decisions should be individualised based on HbA1c levels, cardiovascular and renal risk, patient preferences, and tolerability.

Injectable GLP-1 receptor agonists represent a logical next step. Switching from oral semaglutide (Rybelsus) to subcutaneous semaglutide (Ozempic) allows for higher doses (up to 2.0 mg weekly) and may restore glycaemic control. Other injectable GLP-1 agonists include dulaglutide (Trulicity) and liraglutide (Victoza). These agents offer similar mechanisms of action with proven cardiovascular benefits and some renal benefits, though SGLT2 inhibitors have stronger evidence for kidney outcomes.

SGLT2 inhibitors (sodium-glucose co-transporter-2 inhibitors) such as dapagliflozin, empagliflozin, or canagliflozin work via a complementary mechanism—promoting glucose excretion through the kidneys. NICE recommends SGLT2 inhibitors for patients with type 2 diabetes and established cardiovascular disease, heart failure, or chronic kidney disease. These agents can be used in combination with GLP-1 receptor agonists for additive glycaemic benefit and cardiorenal protection. Common adverse effects include genital and urinary tract infections and a small risk of diabetic ketoacidosis. Report any suspected side effects to the MHRA Yellow Card Scheme.

Dual combination therapy may involve adding metformin (if not already prescribed) or a thiazolidinedione (pioglitazone). DPP-4 inhibitors (such as sitagliptin or linagliptin) should not be used concurrently with GLP-1 receptor agonists due to overlapping mechanisms.

Insulin therapy may be necessary for patients who are symptomatic with hyperglycaemia or when HbA1c remains above target despite optimised non-insulin therapy. Basal insulin (such as insulin glargine or insulin degludec) can be initiated alongside existing medications. Some patients may benefit from combination products such as insulin degludec/liraglutide (Xultophy) or insulin glargine/lixisenatide (Suliqua), which combine basal insulin with a GLP-1 agonist.

Tirzepatide (Mounjaro), a dual GLP-1/GIP receptor agonist, has received NICE approval for type 2 diabetes. Availability may vary by local NHS formulary. Your diabetes team will guide you towards the most appropriate treatment based on current NICE guidance, clinical evidence, and your individual circumstances. Regular follow-up and ongoing medication review remain essential to achieving and maintaining optimal glycaemic control whilst minimising the risk of diabetes-related complications.

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