Sulfonylureas are a well-established class of oral medications used to manage type 2 diabetes by stimulating the pancreas to produce more insulin. For over six decades, these glucose-lowering agents have helped millions of people achieve better blood sugar control when lifestyle changes alone prove insufficient. Commonly prescribed options in the UK include gliclazide and glimepiride, which may be used alongside metformin or as an alternative when metformin is unsuitable. Understanding how sulfonylureas work, their benefits, potential side effects, and who should use them is essential for making informed decisions about your diabetes treatment plan.

What Are Sulfonylureas and How Do They Work in Type 2 Diabetes?

Sulfonylureas are a class of oral glucose-lowering medications that have been used to treat type 2 diabetes for over 60 years. They belong to the group of insulin secretagogues, meaning they work by stimulating the pancreas to produce more insulin. These medications may be prescribed when lifestyle modifications such as diet and exercise alone are insufficient to achieve adequate blood glucose control.

The mechanism of action of sulfonylureas involves binding to specific receptors on the beta cells of the pancreas, known as sulfonylurea receptors (SUR1). This binding closes ATP-sensitive potassium channels on the cell membrane, leading to depolarisation of the beta cell. The resulting influx of calcium ions triggers the release of insulin granules into the bloodstream. This process is glucose-independent, meaning sulfonylureas stimulate insulin secretion regardless of blood glucose levels, which explains both their effectiveness and their potential to cause hypoglycaemia.

According to NICE guidance (NG28), sulfonylureas have several roles in type 2 diabetes management. They may be used as first-line therapy if metformin is contraindicated or not tolerated, or when rapid glucose reduction is needed in patients with symptomatic hyperglycaemia. More commonly, they are added as second-line or third-line therapy when metformin alone does not achieve target HbA1c levels, or as part of dual or triple therapy combinations. Metformin remains the usual first-line pharmacological treatment for most people with type 2 diabetes.

These medications are particularly useful in patients who still have reasonable pancreatic beta-cell function. They are less effective in advanced type 2 diabetes where beta-cell reserve is significantly depleted. Understanding how sulfonylureas work helps both patients and healthcare professionals make informed decisions about their role in diabetes management. It is important to note that the risk of hypoglycaemia with sulfonylureas is higher than with glucose-dependent agents such as GLP-1 receptor agonists or DPP-4 inhibitors.

Common Sulfonylureas Used in the UK for Type 2 Diabetes

Several sulfonylureas are licensed and available in the UK, though prescribing patterns have evolved over recent decades. The most commonly prescribed sulfonylureas include gliclazide, glimepiride, and to a lesser extent glipizide. Older agents such as glibenclamide (known internationally as glyburide) and tolbutamide are now prescribed less frequently due to their higher risk of hypoglycaemia and longer duration of action.

Gliclazide is the most widely used sulfonylurea in the UK. It is available in standard (immediate-release) and modified-release formulations. The modified-release version (gliclazide MR) is often preferred as it provides more stable blood glucose control throughout the day and may be associated with a lower risk of hypoglycaemia. Typical doses range from 30 mg to 120 mg once daily for the modified-release preparation, or 40 mg to 320 mg daily (in divided doses) for standard immediate-release gliclazide.

Glimepiride is another commonly prescribed option, typically given as a once-daily dose ranging from 1 mg to 4 mg (maximum 6 mg). It has a relatively rapid onset of action and intermediate duration, making it convenient for many patients. Some evidence suggests glimepiride may have a slightly lower hypoglycaemia risk compared to older sulfonylureas such as glibenclamide.

Glipizide is less commonly used in current UK practice but remains available in some areas, usually prescribed in doses of 2.5 mg to 20 mg daily. Local formulary guidance may vary regarding its availability.

The choice between different sulfonylureas often depends on individual patient factors, prescriber familiarity, local formulary guidance, renal and hepatic function, and cost considerations. All sulfonylureas in current use are available as generic medications, making them relatively inexpensive treatment options. Your GP or diabetes specialist will select the most appropriate agent based on your specific circumstances, kidney and liver function, and other medications. Always refer to the British National Formulary (BNF) or the Summary of Product Characteristics (SmPC) for detailed dosing, cautions, and contraindications for each agent.

Benefits and Effectiveness of Sulfonylureas in Blood Sugar Control

Sulfonylureas have demonstrated significant effectiveness in lowering blood glucose levels and reducing HbA1c in people with type 2 diabetes. Clinical trials and meta-analyses have shown that sulfonylureas typically reduce HbA1c by approximately 1.0–1.5% (11–16 mmol/mol) when used as monotherapy or added to metformin. This degree of glucose reduction is clinically meaningful and can help reduce the risk of diabetes-related complications over time.

One of the key advantages of sulfonylureas is their rapid onset of action. Patients often notice improvements in blood glucose levels within days to weeks of starting treatment, which can be encouraging and help with treatment adherence. This contrasts with some other diabetes medications that may take longer to demonstrate their full effect.

Sulfonylureas are also cost-effective compared to many newer glucose-lowering agents. As generic medications, they represent an affordable option for the NHS and for patients who pay prescription charges. This economic consideration remains important in healthcare resource allocation, particularly when multiple treatment options are available.

The UK Prospective Diabetes Study (UKPDS) provided important evidence that intensive blood glucose control with sulfonylureas reduced the risk of microvascular complications such as retinopathy and nephropathy in people with newly diagnosed type 2 diabetes. This landmark study helped establish sulfonylureas as an effective treatment option for long-term diabetes management.

However, it is important to note that sulfonylureas do not address the underlying insulin resistance that characterises type 2 diabetes, nor do they provide the cardiovascular or renal protective benefits demonstrated by some newer medication classes such as SGLT2 inhibitors or GLP-1 receptor agonists. NICE guidance (NG28) now recommends considering SGLT2 inhibitors alongside metformin for adults with type 2 diabetes who have established atherosclerotic cardiovascular disease or are at high cardiovascular risk, and for those with chronic kidney disease. These agents may be preferred over sulfonylureas in such patients.

Side Effects and Risks of Sulfonylureas

The most significant and common adverse effect of sulfonylureas is hypoglycaemia (low blood sugar). Because these medications stimulate insulin release regardless of blood glucose levels, there is a risk of blood sugar dropping too low, particularly if meals are delayed or skipped, during increased physical activity, or if alcohol is consumed. Symptoms of hypoglycaemia include sweating, trembling, confusion, palpitations, and hunger. Severe hypoglycaemia can lead to loss of consciousness and requires urgent treatment.

The risk of hypoglycaemia varies between different sulfonylureas, with older agents like glibenclamide carrying a higher risk than newer options such as gliclazide or glimepiride. Patients prescribed sulfonylureas should be educated about recognising and treating hypoglycaemia. UK guidance recommends treating hypoglycaemia with 15–20 g of fast-acting carbohydrate such as glucose tablets, glucose gel, or sugary drinks (not diet versions). Recheck blood glucose after 10–15 minutes and repeat treatment if still low. Follow with a longer-acting carbohydrate such as a slice of bread or a normal meal. If you are unconscious, having a seizure, or unable to swallow safely, this is a medical emergency—call 999 immediately. If you experience frequent hypoglycaemic episodes, contact your GP or diabetes team for medication review.

Weight gain is another common side effect, typically ranging from 2–4 kg over the first year of treatment. This occurs because increased insulin levels promote glucose uptake and storage in tissues. Weight gain can be problematic as many people with type 2 diabetes are already overweight, and additional weight may worsen insulin resistance. Combining sulfonylurea treatment with dietary advice and physical activity can help minimise weight gain.

Other less common side effects include:

• Gastrointestinal symptoms such as nausea, diarrhoea, or constipation

• Skin reactions including rash, itching, or photosensitivity (increased sensitivity to sunlight)

• Hyponatraemia (low blood sodium), which may present as confusion, nausea, or headache—your doctor may check your sodium levels if you develop these symptoms

• Liver enzyme abnormalities and rarely cholestatic jaundice—liver function tests should be checked if you develop symptoms such as jaundice, dark urine, or persistent abdominal pain

• Blood disorders such as thrombocytopenia or agranulocytosis (very rare)

Important drug interactions can occur with sulfonylureas. Certain medications can increase the risk of hypoglycaemia, including azole antifungals (e.g., fluconazole), quinolone antibiotics (e.g., ciprofloxacin), sulfonamide antibiotics, and warfarin. Beta-blockers may mask the warning symptoms of hypoglycaemia, making it harder to recognise low blood sugar. Alcohol can also increase the risk of hypoglycaemia. Always inform your doctor or pharmacist of all medications you are taking.

Some patients may experience secondary failure to sulfonylureas, where the medications become less effective over time due to progressive loss of pancreatic beta-cell function. This is a natural progression of type 2 diabetes rather than a side effect per se, but it may necessitate treatment intensification or switching to alternative therapies. Regular HbA1c monitoring helps identify when treatment adjustments are needed.

If you experience any side effects, including those not listed here, you should report them via the MHRA Yellow Card Scheme at yellowcard.mhra.gov.uk or by searching for MHRA Yellow Card in the Google Play or Apple App Store. Reporting helps improve the safety of medicines for everyone.

Who Should and Shouldn't Take Sulfonylureas for Type 2 Diabetes?

Sulfonylureas are generally suitable for adults with type 2 diabetes who have inadequate glucose control despite lifestyle modifications, either as an alternative to metformin when metformin is contraindicated or not tolerated, or added to metformin or other glucose-lowering therapies. They are most effective in patients who still have reasonable pancreatic beta-cell function; effectiveness depends on individual beta-cell reserve and response to treatment.

Sulfonylureas may be particularly appropriate for:

• Patients who cannot tolerate metformin due to gastrointestinal side effects

• Those requiring rapid glucose reduction, including symptomatic hyperglycaemia

• Individuals for whom cost is a significant consideration

• Patients without established cardiovascular disease or chronic kidney disease (where SGLT2 inhibitors or GLP-1 receptor agonists may be preferred according to NICE NG28)

However, there are several important contraindications and situations where sulfonylureas should be avoided or used with caution. They are contraindicated in type 1 diabetes, as these patients lack beta-cell function, and in diabetic ketoacidosis (DKA). Sulfonylureas should not be used during pregnancy or breastfeeding. According to NICE guidance (NG3), metformin and/or insulin are the treatments used in pregnancy for type 2 diabetes; insulin is preferred if additional glucose-lowering therapy is needed. If you are planning pregnancy or become pregnant, contact your diabetes team urgently for medication review.

Severe renal impairment requires careful consideration, as sulfonylureas and their metabolites are primarily excreted by the kidneys. Accumulation can increase hypoglycaemia risk. Glibenclamide should be avoided in chronic kidney disease (CKD) due to high risk of prolonged hypoglycaemia. Gliclazide is often preferred in mild to moderate renal impairment, but dose adjustments may be necessary as kidney function declines. Specific eGFR thresholds and dose adjustments vary by agent—always refer to the BNF or the Summary of Product Characteristics (SmPC) for detailed renal dosing guidance. Your doctor will assess your kidney function before prescribing and monitor it regularly.

Caution is advised in:

• Elderly patients, who are at higher risk of hypoglycaemia and may have reduced awareness of warning symptoms or impaired counter-regulatory responses

• People with irregular meal patterns or those at risk of missing meals

• Patients with significant hepatic impairment, as metabolism may be impaired

• Those taking multiple medications that may interact with sulfonylureas (see Side Effects section)

• Individuals with a history of severe hypoglycaemia

• Patients who drive or operate machinery, particularly professionally, due to hypoglycaemia risk (see DVLA guidance below)

• People with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as sulfonylureas (particularly gliclazide) may cause haemolytic anaemia; alternative treatments should be considered

DVLA driving precautions: If you drive, you must be aware that sulfonylureas can cause hypoglycaemia, which may impair your ability to drive safely. You are legally required to inform the DVLA if you are treated with medication that can cause hypoglycaemia and you hold a Group 2 licence (bus, coach, or lorry). Group 1 (car/motorcycle) licence holders must inform the DVLA if they have had severe hypoglycaemia (requiring assistance from another person) or impaired awareness of hypoglycaemia. Always check your blood glucose before driving and carry fast-acting carbohydrate in your vehicle. Refer to GOV.UK guidance on 'Assessing fitness to drive' for full details.

According to current NICE guidance (NG28), for patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, medications with proven cardiovascular or renal benefits (such as SGLT2 inhibitors or GLP-1 receptor agonists) should be considered before or instead of sulfonylureas. Your diabetes team will assess your individual circumstances, comorbidities, cardiovascular and renal risk, and treatment goals to determine whether a sulfonylurea is the most appropriate choice for you.

Frequently Asked Questions