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Rybelsus (semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist prescribed to improve blood glucose control in adults with type 2 diabetes mellitus. Some patients and clinicians observe that its glucose-lowering effect appears to diminish over time, raising concerns about whether the medication has stopped working. Understanding the difference between true drug failure and disease progression is essential. Type 2 diabetes is a progressive condition, and worsening glycaemic control may reflect advancing disease rather than reduced drug efficacy. This article examines why Rybelsus may seem less effective, how to recognise declining control, and what treatment options are available when intensification is needed.
Quick Answer: Rybelsus does not typically develop tolerance, but type 2 diabetes is progressive, so worsening glycaemic control often reflects disease advancement rather than the medication stopping working.
Rybelsus (semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist used to improve glycaemic control in adults with type 2 diabetes mellitus. Like many diabetes medications, patients and clinicians sometimes observe that its glucose-lowering effect appears to diminish over time—a phenomenon often referred to as secondary treatment failure.
It is important to distinguish between true pharmacological failure and other contributing factors. Type 2 diabetes is a progressive condition characterised by declining pancreatic beta-cell function and worsening insulin resistance. Even with optimal medication adherence, the underlying disease may advance, requiring treatment intensification. This natural progression does not mean the drug has "stopped working" in a pharmacological sense, but rather that the disease burden has increased beyond what the current regimen can manage.
Tolerance or tachyphylaxis—where the body becomes less responsive to a drug over time—is not a well-documented phenomenon with GLP-1 receptor agonists in clinical trials. The PIONEER trials, which studied Rybelsus for up to 78 weeks, did not show evidence of significant tolerance development. However, individual variation in drug response, changes in body weight, dietary habits, physical activity levels, and adherence can all influence perceived effectiveness. Additionally, gastrointestinal side effects may lead some patients to reduce their dose or take the medication inconsistently, inadvertently reducing its efficacy.
If glycaemic control deteriorates, a thorough clinical assessment is warranted to identify the underlying cause and guide appropriate management adjustments. It's important to note that Rybelsus is licensed for type 2 diabetes only and is not indicated for type 1 diabetes or diabetic ketoacidosis.
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Recognising when Rybelsus may no longer be providing adequate glycaemic control is essential for timely intervention. The most objective indicator is a rise in HbA1c levels on consecutive blood tests, particularly if HbA1c increases above the individualised target set by your healthcare team (commonly ≤53 mmol/mol or 7% for many patients, though targets vary according to NICE guidance).
Home blood glucose monitoring may reveal patterns of persistently elevated readings, especially fasting glucose levels or post-prandial (after-meal) spikes that were previously well controlled. Patients may notice:
Fasting blood glucose consistently above 7 mmol/L
Post-meal readings regularly exceeding 10 mmol/L
Greater variability in glucose levels despite consistent medication use
These thresholds should be interpreted in the context of your individualised targets as advised by your diabetes team.
Symptoms of hyperglycaemia may re-emerge or worsen, including increased thirst (polydipsia), frequent urination (polyuria), unexplained fatigue, blurred vision, or recurrent infections such as thrush or urinary tract infections. Some patients report increased hunger, which may also reflect inadequate glucose control.
It is crucial to consider non-pharmacological factors before concluding the medication has failed. Weight gain, reduced physical activity, dietary changes, intercurrent illness, or the introduction of other medications (such as corticosteroids) can all impair glycaemic control. Additionally, poor adherence—whether due to side effects, forgetfulness, or difficulty following the specific administration requirements—is a common and often overlooked cause of apparent treatment failure.
URGENT ADVICE: Seek same-day medical attention or call NHS 111 if you experience very high blood glucose (persistently above 20 mmol/L), positive ketones in your urine or blood, dehydration, abdominal pain, vomiting, drowsiness, breathlessness or confusion. These could indicate a serious condition requiring immediate treatment.
If you notice any of these signs, do not stop or adjust your medication independently. Contact your GP or diabetes specialist nurse for a comprehensive review, including assessment of adherence, lifestyle factors, and consideration of dose adjustment or additional therapy.
If you suspect Rybelsus is no longer controlling your blood glucose effectively, the first step is to schedule a review with your GP or diabetes care team. Do not discontinue or alter your medication without professional guidance, as abrupt changes can lead to worsening glycaemic control and increased risk of complications.
Your clinician will conduct a thorough assessment, which typically includes:
HbA1c measurement to objectively assess average glucose control over the preceding 2–3 months
Review of adherence: Rybelsus must be taken on an empty stomach with no more than 120 mL of water, and patients must wait at least 30 minutes before eating, drinking, or taking other medications. Tablets should be swallowed whole and not split or crushed. Non-adherence to these instructions significantly reduces absorption and efficacy
Medication review: Identifying any new drugs that may impair glucose control or interact with semaglutide (including levothyroxine, which may have increased exposure, and medications affected by delayed gastric emptying)
Lifestyle assessment: Changes in diet, physical activity, weight, alcohol consumption, or stress levels
Screening for intercurrent illness: Conditions such as infections, thyroid dysfunction, or Cushing's syndrome can worsen diabetes control
If you miss a dose of Rybelsus, skip that dose and take your next scheduled dose the following day. Do not take a double dose to make up for a missed dose.
If adherence and lifestyle factors are optimised, your clinician may consider dose escalation. Rybelsus is available in 3 mg, 7 mg, and 14 mg tablets. The usual starting dose is 3 mg once daily for 30 days, then 7 mg. If glycaemic targets are not met after at least 30 days on 7 mg, the dose may be increased to 14 mg once daily, which is the maximum recommended dose.
NICE guidance (NG28) recommends intensifying treatment if HbA1c rises to 58 mmol/mol (7.5%) or higher on lifestyle measures plus metformin. If Rybelsus at maximum dose is insufficient, combination therapy or switching to alternative agents should be considered. Your diabetes team will tailor the approach to your individual circumstances, comorbidities, and treatment goals.
When Rybelsus no longer provides adequate glycaemic control despite dose optimisation and adherence, several evidence-based treatment strategies are available, guided by NICE recommendations (NG28) and individual patient factors.
Combination therapy is often the preferred approach. Rybelsus is commonly prescribed alongside metformin, and additional agents can be considered:
SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin): These offer complementary glucose-lowering through increased urinary glucose excretion and provide cardiovascular and renal protection. NICE recommends SGLT2 inhibitors for patients with type 2 diabetes and established cardiovascular disease, high cardiovascular risk, chronic kidney disease, or heart failure. Usage depends on eGFR thresholds, and patients should receive sick-day guidance (temporarily stopping during acute illness)
Thiazolidinediones (e.g., pioglitazone): May improve insulin sensitivity but carry risks of weight gain, fluid retention, and fractures
Sulfonylureas (e.g., gliclazide): Effective but associated with hypoglycaemia and weight gain
Basal insulin: For patients with significant hyperglycaemia, especially if symptomatic or with very high HbA1c (≥75 mmol/mol or 9%), insulin therapy may be necessary
DPP-4 inhibitors (e.g., sitagliptin) are an alternative class of medication when GLP-1 receptor agonists are unsuitable. However, they should not be used concurrently with GLP-1 receptor agonists such as Rybelsus due to overlapping mechanisms and lack of additional benefit.
Switching to injectable GLP-1 agonists is another option. Subcutaneous formulations such as semaglutide injection (Ozempic), dulaglutide, or liraglutide may provide different efficacy profiles compared to oral Rybelsus. Some patients achieve better glycaemic control with injectable formulations, particularly at higher doses, though direct head-to-head comparisons are limited.
Lifestyle optimisation remains fundamental. Referral to a dietitian, structured education programmes (such as DESMOND), and support for physical activity can significantly improve outcomes. Weight loss of 5–10% can substantially enhance insulin sensitivity and medication effectiveness.
Your diabetes team will consider your cardiovascular and renal risk profile, hypoglycaemia risk, weight management goals, and personal preferences when recommending treatment intensification. Regular monitoring and ongoing support are essential to achieving and maintaining optimal glycaemic control whilst minimising complications.
If you experience side effects from any diabetes medication, report them to your healthcare professional and consider reporting via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or the Yellow Card app).
Rybelsus does not typically develop tolerance, but type 2 diabetes is a progressive condition. Worsening blood glucose control usually reflects disease advancement rather than the medication itself becoming less effective, though adherence issues and lifestyle factors can also reduce efficacy.
Contact your GP or diabetes care team for a comprehensive review. They will assess your adherence, lifestyle factors, and HbA1c levels, and may consider dose escalation, adding another medication, or switching to an alternative treatment.
Yes, switching to injectable GLP-1 receptor agonists such as semaglutide injection (Ozempic), dulaglutide, or liraglutide is an option. Some patients achieve better glycaemic control with injectable formulations, and your diabetes team can advise on the most appropriate choice for your circumstances.
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