Sulfonylureas and incretin mimetics (GLP-1 receptor agonists) are two fundamentally different classes of glucose-lowering medications used to manage type 2 diabetes mellitus. Whilst sulfonylureas such as gliclazide have been prescribed for over 50 years and work by continuously stimulating insulin release, incretin mimetics like semaglutide and liraglutide represent a newer approach, acting only when blood glucose is elevated. These classes differ markedly in their mechanisms of action, side effect profiles, effects on body weight, and hypoglycaemia risk. Understanding the difference between sulfonylureas and incretin mimetics enables clinicians and patients to make informed, individualised treatment decisions aligned with current NICE guidance and patient-specific clinical needs.

What Are Sulfonylureas and Incretin Mimetics?

Sulfonylureas and incretin mimetics (GLP-1 receptor agonists) are two distinct classes of glucose-lowering medications used in the management of type 2 diabetes mellitus. Understanding their fundamental differences helps clinicians and patients make informed treatment decisions.

Sulfonylureas have been used for over 50 years and include medications such as gliclazide, glimepiride, and glipizide. These oral agents work by stimulating the pancreatic beta cells to release more insulin, regardless of blood glucose levels. They bind to specific receptors (SUR1 receptors) on the beta cell membrane, causing closure of ATP-sensitive potassium channels. This triggers calcium influx and subsequent insulin secretion. Sulfonylureas are typically taken once or twice daily with meals. Individual agents differ in their metabolism and excretion: some are primarily hepatically metabolised, whilst others have significant renal excretion. Dose adjustment or agent selection is important in renal impairment—gliclazide is generally preferred in chronic kidney disease (CKD) where a sulfonylurea is indicated, and glibenclamide should be avoided due to prolonged hypoglycaemia risk.

Incretin mimetics, also known as GLP-1 receptor agonists, represent a newer therapeutic class introduced in the mid-2000s. Examples include exenatide, liraglutide, dulaglutide, and semaglutide. Most are administered via subcutaneous injection, ranging from twice daily to once weekly depending on the specific agent; oral semaglutide (Rybelsus) is also licensed in the UK as a once-daily tablet. These medications mimic the action of naturally occurring incretin hormones, particularly glucagon-like peptide-1 (GLP-1). Unlike sulfonylureas, incretin mimetics work in a glucose-dependent manner—they stimulate insulin secretion only when blood glucose levels are elevated. Additionally, they suppress glucagon release, slow gastric emptying, and promote satiety through central nervous system effects.

The fundamental distinction lies in their mechanism: sulfonylureas provide continuous insulin stimulation (carrying intrinsic hypoglycaemia risk), whilst incretin mimetics offer glucose-responsive action with additional metabolic benefits beyond glycaemic control. GLP-1 receptor agonists should not be used in combination with DPP-4 inhibitors (such as sitagliptin or linagliptin), as both act on the incretin pathway.

Comparing Side Effects: Sulfonylureas vs Incretin Mimetics

The adverse effect profiles of sulfonylureas and incretin mimetics differ substantially, influencing treatment selection for individual patients.

Sulfonylureas are generally well-tolerated but carry specific risks. The most significant concern is hypoglycaemia (low blood glucose), which occurs because these agents stimulate insulin release regardless of glucose levels. Severe hypoglycaemic episodes may require emergency treatment and are more common in elderly patients, those with renal impairment, or individuals with irregular eating patterns. Weight gain of 2–4 kg is commonly observed with sulfonylurea therapy, attributed to increased insulin levels promoting fat storage and potentially increased caloric intake to prevent hypoglycaemia. Other reported side effects include gastrointestinal disturbances (nausea, diarrhoea), skin reactions (including rare photosensitivity), and rarely, haematological abnormalities such as thrombocytopenia or agranulocytosis. Hyponatraemia has been reported rarely with some sulfonylureas.

Incretin mimetics present a different side effect spectrum. Gastrointestinal symptoms—particularly nausea, vomiting, and diarrhoea—are the most frequently reported adverse effects, especially during treatment initiation. These symptoms typically diminish over several weeks as tolerance develops. Gradual dose titration helps minimise gastrointestinal intolerance. Patients experiencing persistent vomiting or diarrhoea should maintain adequate hydration to reduce the risk of dehydration and acute kidney injury; those at renal risk may require monitoring. Injection site reactions (redness, itching) occur with injectable formulations but are usually mild and vary by agent.

There have been post-marketing reports of acute pancreatitis associated with incretin mimetics. The MHRA advises caution in patients with a history of pancreatitis. Patients should be advised to stop the medication and seek urgent medical attention (call 999 or attend A&E) if they experience severe, persistent abdominal pain. Cases of cholelithiasis and cholecystitis (gallbladder disease) have also been reported; patients should be counselled about symptoms such as severe upper abdominal pain, especially after meals. Additionally, rapid reduction in HbA1c with semaglutide has been associated with worsening of diabetic retinopathy in patients with pre-existing retinopathy; patients should be advised to report any visual symptoms promptly for ophthalmology review.

Unlike sulfonylureas, incretin mimetics carry minimal hypoglycaemia risk when used as monotherapy, though risk increases when combined with insulin or sulfonylureas. Dose reduction of these concomitant agents is usually required when starting a GLP-1 receptor agonist.

Patients and healthcare professionals are encouraged to report any suspected adverse reactions via the MHRA Yellow Card Scheme (available at yellowcard.mhra.gov.uk or via the Yellow Card app).

Weight Changes and Hypoglycaemia Risk

Weight trajectory and hypoglycaemia risk represent critical differentiating factors between sulfonylureas and incretin mimetics, significantly impacting treatment decisions in type 2 diabetes management.

Weight effects diverge markedly between these classes. Sulfonylureas typically cause weight gain averaging 2–4 kg over the first year of treatment. This occurs through multiple mechanisms: increased circulating insulin promotes lipogenesis and inhibits lipolysis, whilst patients may increase food intake to prevent or treat hypoglycaemic episodes. For individuals who are already overweight or obese—representing the majority of people with type 2 diabetes—this weight gain may worsen insulin resistance and cardiovascular risk factors. In contrast, incretin mimetics are associated with weight loss of 2–6 kg on average at licensed doses for type 2 diabetes. Weight loss occurs through delayed gastric emptying, enhanced satiety, and reduced caloric intake. Semaglutide is available in two formulations: Ozempic (for type 2 diabetes, up to 2 mg weekly) and Wegovy (licensed for weight management at 2.4 mg weekly); weight-loss effects differ by indication and dose. This makes incretin mimetics particularly attractive for patients where weight management is a therapeutic priority.

Hypoglycaemia risk differs substantially between classes. Sulfonylureas carry a moderate to high risk of hypoglycaemia because they stimulate insulin secretion continuously, independent of glucose levels. Elderly patients, those with irregular meal patterns, renal impairment, or taking multiple glucose-lowering agents face heightened risk. Severe hypoglycaemia can cause confusion, loss of consciousness, seizures, and cardiovascular events; patients experiencing severe hypoglycaemia should call 999 or attend A&E. Patients using sulfonylureas or insulin who drive must be aware of DVLA guidance on diabetes and hypoglycaemia, including requirements for blood glucose monitoring before and during driving.

Conversely, incretin mimetics have a very low intrinsic hypoglycaemia risk when used alone, as their glucose-lowering effect is glucose-dependent—insulin secretion ceases when glucose normalises. However, hypoglycaemia risk increases when incretin mimetics are combined with sulfonylureas or insulin; dose reduction of sulfonylureas or insulin is usually necessary when initiating a GLP-1 receptor agonist, as advised in the Summary of Product Characteristics (SmPC) for each agent.

NICE guidance (NG28) acknowledges these differences, recommending consideration of hypoglycaemia risk and weight effects when selecting glucose-lowering therapies. Patients at high risk of hypoglycaemia or those requiring weight loss may benefit more from incretin-based therapies.

Which Treatment Is Right for Type 2 Diabetes?

Selecting between sulfonylureas and incretin mimetics requires individualised assessment, considering clinical characteristics, patient preferences, and current NICE guidance (NG28) for type 2 diabetes management.

NICE recommendations position metformin as first-line therapy for most patients with type 2 diabetes. When metformin alone provides inadequate glycaemic control, treatment intensification is required. The choice of second-line agent depends on individual factors including cardiovascular disease, heart failure, chronic kidney disease, body weight, hypoglycaemia risk, and patient preference. SGLT2 inhibitors are prioritised in patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease due to proven benefits in reducing cardiovascular and renal outcomes.

Sulfonylureas represent a cost-effective option, particularly suitable for patients who:

• Cannot tolerate or have contraindications to other agents

• Require oral medication (needle-phobic or unable to self-inject)

• Have no significant hypoglycaemia risk factors

• Are not overweight or where weight gain is acceptable

• Need rapid glycaemic improvement

Incretin mimetics (GLP-1 receptor agonists) are recommended as second- or third-line options, particularly when:

• BMI ≥35 kg/m² (or appropriately lower thresholds for people from minority ethnic groups, as per NICE guidance) and weight-related comorbidities are present

• Significant hypoglycaemia risk exists (elderly, occupational hazards, driving requirements)

• Weight loss would provide substantial clinical benefit

• Cardiovascular protection is desired in patients with established ASCVD (liraglutide, dulaglutide, and injectable semaglutide have demonstrated cardiovascular outcome benefits in clinical trials)

NICE NG28 specifies that GLP-1 receptor agonists should be continued only if there is a beneficial metabolic response at 6 months, defined as a reduction of at least 11 mmol/mol (1.0%) in HbA1c and a weight loss of at least 3% of initial body weight. Treatment should be stopped if these criteria are not met.

Practical considerations influence choice. Sulfonylureas offer convenience (oral administration, low cost, once or twice daily dosing) but require consistent meal timing to minimise hypoglycaemia. Dose adjustment or agent selection is important in renal impairment. Incretin mimetics necessitate injection training for most formulations (oral semaglutide is an alternative), refrigerated storage for some agents, and higher costs, though once-weekly preparations improve convenience. Gastrointestinal side effects may limit tolerability initially. GLP-1 receptor agonists should not be combined with DPP-4 inhibitors.

Patient involvement in decision-making is essential. Discussing treatment goals (glycaemic control, weight management, hypoglycaemia avoidance, cardiovascular or renal protection), administration preferences, lifestyle factors, and potential side effects enables shared decision-making. Some patients prioritise avoiding injections; others prioritise weight loss or hypoglycaemia avoidance.

Regular monitoring of HbA1c (every 3–6 months), weight, and hypoglycaemia frequency guides ongoing therapy. Patients should contact their GP if experiencing recurrent hypoglycaemia, unexplained weight changes, persistent gastrointestinal symptoms, or inadequate glycaemic control. Treatment should be reviewed at least annually, with adjustment based on efficacy, tolerability, and evolving clinical circumstances. Both medication classes effectively lower blood glucose when appropriately selected for individual patient needs.

Frequently Asked Questions