Glucagon-like peptide-1 receptor agonists for type 2 diabetes are a class of injectable and oral medicines that help manage blood glucose levels in adults. These medicines mimic a natural gut hormone, stimulating insulin release only when blood sugar is elevated, which reduces the risk of dangerously low glucose levels. They also slow digestion, suppress unwanted glucose production, and often lead to weight loss—a valuable benefit for many people with type 2 diabetes. Available agents in the UK include semaglutide, dulaglutide, liraglutide, exenatide, and lixisenatide. This article explains how they work, who can use them, their benefits, side effects, and how they compare with other diabetes treatments.

What Are GLP-1 Receptor Agonists and How Do They Work?

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injectable (and one oral) medicines used to manage type 2 diabetes mellitus in adults. These medicines mimic the action of GLP-1, a naturally occurring hormone produced in the intestine that plays a crucial role in glucose regulation. Examples licensed and available in the UK include semaglutide (Ozempic for injection, Rybelsus tablets), dulaglutide (Trulicity), liraglutide (Victoza), exenatide (Byetta), and lixisenatide (Lyxumia).

The mechanism of action involves several complementary pathways. GLP-1 receptor agonists stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner—meaning they only promote insulin release when blood glucose levels are elevated, which significantly reduces the risk of hypoglycaemia compared with some other diabetes medicines. Simultaneously, these agents suppress glucagon secretion from pancreatic alpha cells, thereby reducing hepatic glucose production when it is not needed.

Additionally, GLP-1 receptor agonists slow gastric emptying, which moderates the rate at which glucose enters the bloodstream after meals. This contributes to improved postprandial (after-meal) glucose control. Many patients also experience reduced appetite and food intake, which can lead to weight loss—a particularly beneficial effect given that many people with type 2 diabetes are overweight or obese.

These medicines are administered by subcutaneous injection, with formulations available for twice-daily, once-daily, or once-weekly dosing depending on the specific agent. One oral formulation (semaglutide tablets, Rybelsus) is also available. The glucose-dependent mechanism means that when blood sugar levels are normal, insulin secretion is not excessively stimulated, providing a safer metabolic profile than some older diabetes treatments. For full prescribing details, refer to the electronic Medicines Compendium (eMC) Summary of Product Characteristics (SmPC) for each agent.

Who Can Use GLP-1 Receptor Agonists for Type 2 Diabetes?

NICE guidance (NG28) recommends GLP-1 receptor agonists for adults with type 2 diabetes in specific clinical circumstances. These medicines are typically considered when metformin and other therapies have not achieved adequate glycaemic control, or when certain patient characteristics make them particularly suitable—for example, where weight loss is beneficial or cardiovascular or renal protection is a priority.

GLP-1 receptor agonists may be appropriate for individuals who:

• Have a body mass index (BMI) of 35 kg/m² or higher (or lower thresholds—32.5 kg/m² or above—for people from Black, Asian, and other minority ethnic groups) and would benefit from weight loss

• Have established cardiovascular disease or are at high cardiovascular risk (certain GLP-1 receptor agonists have demonstrated cardiovascular benefits in clinical trials)

• Have chronic kidney disease (CKD) or heart failure, where specific agents may offer additional protection

• Require additional glucose-lowering therapy but wish to avoid weight gain associated with some other diabetes medicines

• Cannot tolerate or have contraindications to other glucose-lowering therapies

NICE NG28 continuation criteria: GLP-1 receptor agonist therapy should be continued beyond 6 months only if the person has had a beneficial metabolic response, 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.

These medicines are not suitable for everyone. They should not be used in people with type 1 diabetes or for the treatment of diabetic ketoacidosis. GLP-1 receptor agonists should not be used in combination with DPP-4 inhibitors (such as sitagliptin), as both act on the incretin system.

Animal studies have shown thyroid C-cell tumours (medullary thyroid carcinoma) with some GLP-1 receptor agonists, but there is no confirmed link in humans and this is not a formal contraindication in UK prescribing information. Nonetheless, caution and informed discussion are advised in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

Patients with severe gastrointestinal disease, including gastroparesis, may not tolerate these medicines well due to their effect on gastric emptying. Semaglutide has been associated with early worsening of diabetic retinopathy in clinical trials; patients should be advised to keep their diabetic eye screening appointments up to date. Caution is advised in those with a history of pancreatitis.

Renal impairment: Most GLP-1 receptor agonists do not require dose adjustment in renal impairment, but exenatide should be avoided in severe renal impairment (eGFR <30 mL/min/1.73 m²). Always refer to the individual SmPC for specific guidance.

Pregnancy and breastfeeding: GLP-1 receptor agonists are not recommended during pregnancy. Women of childbearing potential should use effective contraception, and semaglutide should be stopped at least 2 months before a planned pregnancy. These medicines are not recommended during breastfeeding. A thorough medical assessment by a GP or diabetes specialist is essential before initiating treatment to ensure the medicine is appropriate and safe for the individual patient.

Benefits and Effectiveness in Managing Type 2 Diabetes

Clinical trials have consistently demonstrated that GLP-1 receptor agonists are highly effective at improving glycaemic control in type 2 diabetes. Patients typically experience reductions in HbA1c (glycated haemoglobin) of approximately 1.0–1.5% (11–16 mmol/mol) when added to existing therapy, with some agents achieving even greater reductions. This improvement in long-term glucose control helps reduce the risk of diabetes-related complications including retinopathy, nephropathy, and neuropathy.

A particularly valuable benefit is weight loss, which distinguishes GLP-1 receptor agonists from many other glucose-lowering medicines. Patients commonly lose 3–5 kg on average, though individual responses vary considerably. It is important to note that higher-dose semaglutide (2.4 mg, marketed as Wegovy) is licensed specifically for weight management in obesity and has separate eligibility criteria and dosing from the diabetes indication; this article focuses on GLP-1 receptor agonists for glycaemic control in type 2 diabetes.

Cardiovascular benefits represent another significant advantage. Several large-scale cardiovascular outcome trials (including LEADER, SUSTAIN-6, and REWIND) have shown that certain GLP-1 receptor agonists—liraglutide, semaglutide, and dulaglutide—reduce the risk of major adverse cardiovascular events such as heart attack, stroke, and cardiovascular death in people with established cardiovascular disease or multiple cardiovascular risk factors. This makes them particularly valuable for patients with both diabetes and heart disease.

GLP-1 receptor agonists also have favourable effects on albuminuria and may slow eGFR decline, though the evidence for hard renal outcomes is less robust than for SGLT2 inhibitors. NICE NG28 recommends considering an SGLT2 inhibitor as the preferred option in adults with type 2 diabetes and chronic kidney disease or heart failure, unless contraindicated or not tolerated.

The low risk of hypoglycaemia when used as monotherapy or with metformin is another important benefit, as the glucose-dependent mechanism of insulin secretion means these medicines do not typically cause dangerously low blood sugar levels. However, when combined with insulin or sulphonylureas, dose adjustments of these other medicines may be necessary to prevent hypoglycaemia. Additionally, some patients report improved quality of life related to better glucose control, weight loss, and the convenience of once-weekly dosing options.

Common Side Effects and Safety Considerations

Gastrointestinal side effects are the most frequently reported adverse reactions with GLP-1 receptor agonists, affecting a substantial proportion of patients, particularly during treatment initiation. Common symptoms include:

• Nausea (affecting 10–40% of patients)

• Vomiting

• Diarrhoea

• Constipation

• Abdominal discomfort or pain

• Reduced appetite

These effects are usually mild to moderate and tend to diminish over several weeks as the body adjusts to the medicine. Starting with a lower dose and gradually increasing (dose titration) helps minimise these symptoms. Patients should be advised to eat smaller, more frequent meals and avoid high-fat foods, which may exacerbate nausea.

Injection site reactions—including redness, itching, or mild discomfort—can occur but are generally minor. Rotating injection sites helps reduce this risk. Some patients may experience headache or fatigue, particularly in the early stages of treatment.

More serious but less common adverse effects require careful monitoring. Acute pancreatitis has been reported, though a definitive causal relationship remains uncertain. Patients should be advised to seek urgent medical attention (via NHS 111, A&E, or 999 if severely unwell) if they experience severe, persistent abdominal pain, particularly if radiating to the back, with or without vomiting. Treatment should be discontinued if pancreatitis is suspected.

There have been reports of gallbladder disease, including cholelithiasis (gallstones) and cholecystitis, possibly related to rapid weight loss. Acute kidney injury has occurred, often in the context of severe dehydration from gastrointestinal side effects, emphasising the importance of maintaining adequate hydration.

Semaglutide has been associated with early worsening of diabetic retinopathy in clinical trials, particularly in patients with pre-existing retinopathy and rapid improvement in glycaemic control. Patients using semaglutide should be advised to attend regular diabetic eye screening appointments.

Patients should be counselled about recognising hypoglycaemia if GLP-1 receptor agonists are used in combination with insulin or sulphonylureas. Women of childbearing potential should discuss contraception and pregnancy planning, as these medicines are not recommended during pregnancy and should be stopped at least 2 months before a planned pregnancy (for semaglutide). GLP-1 receptor agonists are not recommended during breastfeeding.

Reporting side effects: Patients and healthcare professionals are encouraged to report any suspected adverse effects via the MHRA Yellow Card scheme at https://yellowcard.mhra.gov.uk/ or via the Yellow Card app. Any concerns about side effects should prompt consultation with a healthcare professional rather than abrupt discontinuation of treatment.

How to Use GLP-1 Receptor Agonists: Dosing and Administration

GLP-1 receptor agonists are primarily administered by subcutaneous injection into the abdomen, thigh, or upper arm. The injection technique is straightforward, and most formulations come in pre-filled pen devices designed for patient self-administration. Healthcare professionals should provide thorough training on injection technique, including proper storage, needle attachment, dose selection, and disposal of sharps in appropriate containers (available from pharmacies or local authority schemes).

Dosing schedules vary depending on the specific medicine:

• Once-weekly injections: Dulaglutide and semaglutide (Ozempic) offer the convenience of weekly dosing, which many patients prefer

• Once-daily injections: Liraglutide and lixisenatide require daily administration

• Twice-daily injections: Exenatide (Byetta) is administered twice daily, before morning and evening meals

• Oral formulation: Semaglutide tablets (Rybelsus) are taken once daily on an empty stomach with up to 120 mL of water only, at least 30 minutes before the first food, drink, or other oral medicines of the day. The tablet must be swallowed whole.

Dose titration is standard practice to improve tolerability. Treatment typically begins with a low starting dose, which is gradually increased every 1–4 weeks (depending on the agent) until the target maintenance dose is reached or the maximum tolerated dose is achieved. This stepwise approach significantly reduces gastrointestinal side effects.

Patients should be advised to:

• Rotate injection sites to prevent lipohypertrophy (lumps under the skin)

• Store unused pens in the refrigerator (2–8°C); in-use pens may often be kept at room temperature for a specified period (refer to the patient information leaflet)

• Never share injection pens, even if the needle is changed

• Administer weekly injections on the same day each week (the time of day can vary)

• For missed doses, follow the specific instructions in the patient information leaflet, as guidance varies by product. For example, Ozempic (semaglutide) can be taken within 5 days of the missed dose; Trulicity (dulaglutide) can be taken if there are at least 3 days until the next scheduled dose. If outside these windows, skip the missed dose and resume the regular schedule. Do not take a double dose.

For the oral formulation (Rybelsus), strict adherence to administration instructions is essential for optimal absorption. Patients should take the tablet with up to 120 mL of plain water only, on an empty stomach, and wait at least 30 minutes before eating, drinking anything other than water, or taking any other oral medicines. The tablet must be swallowed whole without crushing or chewing.

Always refer to the individual Summary of Product Characteristics (SmPC) and patient information leaflet for detailed, product-specific guidance on dosing, administration, storage, and missed doses.

Comparing GLP-1 Receptor Agonists with Other Diabetes Treatments

When considering treatment options for type 2 diabetes, GLP-1 receptor agonists offer distinct advantages compared with other glucose-lowering therapies, though the optimal choice depends on individual patient characteristics, preferences, and clinical circumstances.

Compared with metformin (the first-line treatment for most patients), GLP-1 receptor agonists generally produce similar or slightly greater HbA1c reductions but with the added benefit of weight loss rather than weight neutrality. However, metformin is oral, inexpensive, and has an extensive safety record, making it the preferred initial therapy. GLP-1 receptor agonists are typically added when metformin alone is insufficient.

Versus sulphonylureas (such as gliclazide), GLP-1 receptor agonists offer comparable glucose-lowering efficacy but with significantly lower hypoglycaemia risk and the advantage of weight loss rather than weight gain. NICE NG28 advises considering a GLP-1 receptor agonist in preference to a sulphonylurea when weight loss or avoidance of hypoglycaemia is a priority, though sulphonylureas remain appropriate options in selected patients.

Compared with SGLT2 inhibitors (such as dapagliflozin or empagliflozin), both classes offer cardiovascular benefits, low hypoglycaemia risk, and weight loss. However, SGLT2 inhibitors have stronger evidence for renal and heart failure outcomes and are generally preferred in adults with type 2 diabetes and chronic kidney disease or heart failure, unless contraindicated or not tolerated. The choice often depends on patient-specific factors: SGLT2 inhibitors are oral and may be preferred by those averse to injections, whilst GLP-1 receptor agonists may produce greater weight loss and are particularly valuable in established cardiovascular disease. Some patients benefit from combination therapy with both classes. GLP-1 receptor agonists should not be combined with DPP-4 inhibitors, as both act on the incretin pathway.

Versus insulin, GLP-1 receptor agonists generally cause less hypoglycaemia and promote weight loss rather than weight gain. However, insulin remains essential for some patients, particularly those with severe hyperglycaemia or significant beta-cell failure. Combination therapy with basal insulin and a GLP-1 receptor agonist can be highly effective, often allowing lower insulin doses. Fixed-ratio combination products (such as insulin degludec/liraglutide or insulin glargine/lixisenatide) are available and may be initiated by specialists in selected patients.

Versus DPP-4 inhibitors (such as sitagliptin), GLP-1 receptor agonists produce greater HbA1c reductions and weight loss, with some offering proven cardiovascular benefits. DPP-4 inhibitors are oral and weight-neutral but generally less potent. As noted, the two classes should not be used together.

The decision should be made collaboratively between patient and clinician, considering efficacy, safety, administration route, cost, and individual treatment goals, in line with NICE NG28 guidance. Regular review and adjustment of therapy is essential to maintain optimal diabetes control whilst minimising adverse effects. Refer to the British National Formulary (BNF) for detailed prescribing information and interactions.

Frequently Asked Questions