Do incretin mimetics cause hypoglycaemia? This is a common concern for patients starting GLP-1 receptor agonists such as semaglutide, liraglutide, or dulaglutide for type 2 diabetes. The short answer is that these medications carry a low intrinsic risk of hypoglycaemia when used alone, thanks to their glucose-dependent mechanism of action. However, the risk increases significantly when they are combined with other diabetes treatments, particularly sulphonylureas or insulin. Understanding how incretin mimetics work, recognising risk factors, and knowing when to seek medical advice are essential for safe and effective diabetes management. This article provides evidence-based guidance aligned with NICE, MHRA, and NHS recommendations.

What Are Incretin Mimetics and How Do They Work?

Incretin mimetics, also known as glucagon-like peptide-1 (GLP-1) receptor agonists, are a class of medications used primarily in the management of type 2 diabetes mellitus. These medicines include drugs such as exenatide, liraglutide, dulaglutide, and semaglutide. Most are given by injection, though semaglutide is also available as an oral tablet (Rybelsus) in the UK. This article focuses on GLP-1 receptor agonists; a related class, DPP-4 inhibitors (such as sitagliptin), are incretin enhancers and work differently. Tirzepatide is a newer dual GIP/GLP-1 receptor agonist with a similar low intrinsic hypoglycaemia risk when used alone.

GLP-1 receptor agonists work by mimicking the action of naturally occurring incretin hormones that are released from the gut in response to food intake. The mechanism of action is glucose-dependent, which is a crucial characteristic that influences their safety profile. When blood glucose levels are elevated, these medications stimulate the pancreatic beta cells to release insulin. Simultaneously, they suppress the release of glucagon from pancreatic alpha cells (also in a glucose-dependent manner), a hormone that raises blood glucose. This dual action helps to lower blood sugar levels effectively after meals. Additionally, GLP-1 receptor agonists slow gastric emptying, which moderates the rate at which glucose enters the bloodstream, and they may reduce appetite, contributing to weight loss in many patients. Some GLP-1 receptor agonists (liraglutide 3 mg, semaglutide 2.4 mg) are also licensed in the UK for weight management; their intrinsic hypoglycaemia risk remains low when used without insulin or sulphonylureas.

The glucose-dependent nature of GLP-1 receptor agonists is particularly important when considering hypoglycaemia risk. Unlike some other diabetes medications, such as sulphonylureas or insulin, GLP-1 receptor agonists generally do not cause hypoglycaemia when used alone. This is because their insulin-stimulating and glucagon-suppressing effects diminish as blood glucose levels fall towards normal, providing an inherent safety mechanism. According to NICE guidance (NG28), GLP-1 receptor agonists are considered to have a low intrinsic risk of hypoglycaemia, making them a valuable option for many patients with type 2 diabetes who require glucose-lowering therapy without the added concern of frequent low blood sugar episodes. This safety profile is supported by MHRA-approved Summaries of Product Characteristics (SmPCs) for semaglutide (Ozempic, Rybelsus), dulaglutide (Trulicity), liraglutide (Victoza), and exenatide (Byetta, Bydureon).

Risk Factors That May Increase Hypoglycaemia Risk

Whilst GLP-1 receptor agonists carry a low intrinsic risk of hypoglycaemia when used as monotherapy, certain circumstances and combinations can increase the likelihood of low blood sugar episodes. Understanding these risk factors is essential for both patients and healthcare professionals to optimise diabetes management safely.

Combination therapy represents the most significant risk factor. When GLP-1 receptor agonists are prescribed alongside other glucose-lowering medications—particularly sulphonylureas (such as gliclazide or glimepiride) or insulin—the risk of hypoglycaemia increases substantially. Both sulphonylureas and insulin stimulate insulin release or provide exogenous insulin regardless of blood glucose levels, and when combined with the glucose-lowering effects of GLP-1 receptor agonists, blood sugar can drop too low. NICE NG28 recommends considering dose reductions of sulphonylureas or insulin when initiating GLP-1 receptor agonist therapy, and increasing blood glucose monitoring to mitigate this risk.

Other important risk factors include:

• Irregular meal patterns or missed meals: Since GLP-1 receptor agonists affect appetite and gastric emptying, skipping meals whilst taking other diabetes medications can precipitate hypoglycaemia

• Increased physical activity: Unplanned or vigorous exercise increases glucose utilisation and may require medication adjustments

• Renal impairment: The impact varies by drug. Exenatide is contraindicated or requires caution in severe renal impairment (eGFR <30 mL/min/1.73 m²) due to reduced clearance and increased exposure. In contrast, dulaglutide, liraglutide, and semaglutide generally do not require dose adjustment in renal impairment, according to their SmPCs. Always check individual product information and discuss with your diabetes team

• Alcohol consumption: Alcohol inhibits gluconeogenesis and can prolong hypoglycaemia, particularly when combined with other glucose-lowering agents

• Elderly patients: Older adults may have impaired counter-regulatory responses and may not recognise hypoglycaemia symptoms as readily

• Driving and operating machinery: Those at risk of hypoglycaemia (especially when taking insulin or sulphonylureas) should not drive if blood glucose is below 5 mmol/L. DVLA guidance requires that drivers with diabetes on treatments that can cause hypoglycaemia must be able to recognise warning signs and manage episodes safely. Severe hypoglycaemia requiring third-party assistance mandates stopping driving and notifying the DVLA

Patients should discuss these risk factors with their diabetes care team, who can provide individualised advice on medication timing, dosing adjustments, and blood glucose monitoring strategies to minimise hypoglycaemia risk whilst maintaining effective glycaemic control. Those taking GLP-1 receptor agonists with insulin or sulphonylureas should carry fast-acting carbohydrates at all times.

Recognising and Managing Low Blood Sugar Symptoms

Recognising the signs and symptoms of hypoglycaemia is crucial for prompt management and prevention of serious complications. Hypoglycaemia is generally defined as a blood glucose level below 4.0 mmol/L ('4 is the floor'), though symptoms can vary between individuals and may occur at different thresholds.

Early warning symptoms of hypoglycaemia include:

• Trembling or shakiness

• Sweating (often profuse)

• Anxiety or irritability

• Palpitations or rapid heartbeat

• Hunger

• Tingling lips or tongue

• Pallor (pale appearance)

If hypoglycaemia progresses without treatment, more severe symptoms may develop, including confusion, difficulty concentrating, blurred vision, weakness, drowsiness, and in extreme cases, loss of consciousness or seizures. Some patients, particularly those with long-standing diabetes, may develop impaired awareness of hypoglycaemia, where warning symptoms are diminished or absent, increasing the risk of severe episodes.

Immediate management of hypoglycaemia follows the "Rule of 15" (NHS and Diabetes UK guidance):

1. Test blood glucose if possible to confirm hypoglycaemia (below 4.0 mmol/L)
2. Consume 15–20 grams of fast-acting carbohydrate, such as:
3. 150–200 ml of fruit juice or non-diet fizzy drink
4. 4–5 glucose tablets
5. 5–6 sweets (such as jelly babies)
6. Wait 15 minutes and retest blood glucose
7. Repeat treatment if blood glucose remains below 4.0 mmol/L
8. Follow with a longer-acting carbohydrate (such as a sandwich or biscuits) once blood glucose has recovered, especially if the next meal is not due soon

Patients taking GLP-1 receptor agonists in combination with sulphonylureas or insulin should be educated about hypoglycaemia management and must carry glucose tablets or a fast-acting carbohydrate source at all times. Those experiencing recurrent hypoglycaemia should contact their diabetes care team for medication review and dose adjustments. Structured education programmes, recommended by NICE for all people with type 2 diabetes, include training on recognising and managing hypoglycaemia, even when using medications with low intrinsic risk such as GLP-1 receptor agonists.

When to Seek Medical Advice About Blood Glucose Levels

Whilst GLP-1 receptor agonists generally pose a low risk of hypoglycaemia when used alone, certain situations warrant prompt medical attention to ensure patient safety and optimise diabetes management.

Seek urgent medical attention (call 999 or attend A&E) if:

• The person becomes unconscious or has a seizure due to suspected hypoglycaemia

• Severe hypoglycaemia does not respond to initial treatment

• There is persistent confusion or altered mental state

• The person is unable to swallow safely or take oral treatment

For these emergencies, glucagon (injection or nasal spray) should be administered by a trained family member or carer if available. Always call 999 for severe or unresponsive hypoglycaemia; intravenous glucose may be required in hospital.

Contact your GP or diabetes specialist nurse within 24 hours if:

• You experience recurrent hypoglycaemia (two or more episodes of blood glucose below 4.0 mmol/L in a week)

• You have hypoglycaemia without clear cause or despite following your treatment plan

• You develop impaired awareness of hypoglycaemia (reduced or absent warning symptoms)

• Your blood glucose readings are consistently outside your target range

• You experience side effects from GLP-1 receptor agonists that affect your ability to eat regularly (such as persistent nausea or vomiting). You should also report suspected side effects via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk or through the Yellow Card app

Arrange a routine review if:

• You are starting or stopping other medications that may affect blood glucose

• Your lifestyle has changed significantly (diet, exercise, work patterns)

• You are planning pregnancy or have become pregnant

• You have concerns about your diabetes management or medication regimen

Driving safety: If you have experienced severe hypoglycaemia requiring third-party assistance, you must stop driving and notify the DVLA as per DVLA guidance on assessing fitness to drive with diabetes. Do not drive if your blood glucose is below 5 mmol/L. Those on insulin or sulphonylureas must be able to recognise hypoglycaemia warning signs and manage episodes safely to continue driving.

The NHS recommends that all patients with diabetes have regular structured reviews, typically annually, but more frequent monitoring may be appropriate when medications are adjusted. Your diabetes care team can provide personalised advice on blood glucose targets, medication adjustments, and self-management strategies. According to NICE NG28, structured education programmes should be offered to all people with type 2 diabetes, which include training on recognising and managing hypoglycaemia, even when using medications with low intrinsic risk such as GLP-1 receptor agonists.

Frequently Asked Questions