Incretin glucagon-like peptide-1 (GLP-1) is a naturally occurring hormone that plays a pivotal role in regulating blood glucose levels after meals. Produced by specialised cells in the gut, GLP-1 enhances insulin secretion, suppresses glucagon release, and slows gastric emptying—mechanisms that collectively improve glucose control. Its discovery has revolutionised diabetes management, leading to the development of GLP-1 receptor agonists and DPP-4 inhibitors, now established treatments for type 2 diabetes under NICE guidance. Understanding how GLP-1 works as an incretin hormone is essential for healthcare professionals and patients navigating modern diabetes and obesity therapies.

What Is Glucagon-Like Peptide-1 (GLP-1)?

Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin hormone produced primarily by specialised L-cells in the distal small intestine and colon. As a member of the incretin family, GLP-1 plays a crucial role in glucose homeostasis by enhancing insulin secretion in response to food intake. The hormone is released within minutes of eating, particularly following meals containing carbohydrates and fats, and acts as a key physiological regulator of postprandial (after-meal) blood glucose levels.

GLP-1 belongs to the glucagon superfamily of peptide hormones and is derived from the proglucagon gene through tissue-specific post-translational processing. In its active form, native GLP-1 has a very short half-life of approximately 1–2 minutes in circulation, as it is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). This brief duration of action is one reason why therapeutic GLP-1 receptor agonists have been developed with modifications to resist enzymatic breakdown.

The discovery of GLP-1's glucose-lowering properties has led to important advances in diabetes management over the past two decades. Beyond its role in stimulating insulin secretion, GLP-1 exerts multiple metabolic effects that contribute to improved glycaemic control. Understanding GLP-1 as an incretin hormone has led to the development of two major drug classes: GLP-1 receptor agonists (such as semaglutide, liraglutide, and dulaglutide) and DPP-4 inhibitors (such as sitagliptin). More recently, dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonists (such as tirzepatide) have also become available. These incretin-based therapies are now established treatments for type 2 diabetes mellitus according to NICE guidance (NICE NG28). For further information, see the NHS medicines pages for semaglutide, liraglutide, and dulaglutide, and the European Medicines Agency (EMA) European Public Assessment Reports (EPARs) for these agents.

How GLP-1 Works as an Incretin Hormone

GLP-1 functions through several complementary mechanisms that collectively improve glucose regulation. The primary action occurs via binding to GLP-1 receptors on pancreatic beta cells, which triggers glucose-dependent insulin secretion. This glucose-dependency is a critical safety feature: GLP-1 stimulates insulin release only when blood glucose levels are elevated, significantly reducing the risk of hypoglycaemia compared to some other diabetes medications such as sulphonylureas.

Simultaneously, GLP-1 suppresses the secretion of glucagon from pancreatic alpha cells. Glucagon normally raises blood glucose by promoting hepatic glucose production, so its suppression during the postprandial period helps prevent excessive glucose elevation. This dual action—enhancing insulin whilst reducing glucagon—creates a coordinated response that maintains glucose within physiological ranges.

Beyond the pancreas, GLP-1 exerts important effects on gastric emptying and appetite regulation. The hormone slows gastric emptying, which moderates the rate at which nutrients enter the bloodstream and helps prevent sharp postprandial glucose spikes. It should be noted that this slowing of gastric emptying may lessen over time with continued therapy and can affect tolerability, particularly during treatment initiation. GLP-1 receptors in the central nervous system, particularly in the hypothalamus and brainstem, mediate effects on satiety and food intake. Activation of these receptors promotes feelings of fullness and reduces appetite, contributing to weight loss—an effect that has proven particularly valuable in managing type 2 diabetes and obesity.

Additional effects include:

• Potential effects on beta-cell function: preclinical and observational studies suggest GLP-1 may support beta-cell survival and potentially stimulate beta-cell proliferation, though the clinical relevance of these findings in humans remains uncertain and is not yet established in routine clinical outcomes

• Cardiovascular benefits: GLP-1 receptors are present in cardiac tissue and blood vessels, and some GLP-1 receptor agonists have demonstrated cardiovascular risk reduction in clinical trials

• Anti-inflammatory properties: emerging evidence suggests GLP-1 may have modest anti-inflammatory effects; however, these remain investigational and their clinical significance requires further study

For detailed pharmacology and mechanism of action, refer to the MHRA Electronic Medicines Compendium (EMC) Summaries of Product Characteristics (SmPCs) for individual GLP-1 receptor agonists (e.g., semaglutide [Ozempic/Wegovy], liraglutide [Victoza/Saxenda], dulaglutide [Trulicity]) and the corresponding EMA EPARs.

Benefits and Effects of GLP-1 Therapy

GLP-1-based therapies have demonstrated substantial clinical benefits in managing type 2 diabetes and, more recently, obesity. Glycaemic control improvements are well-established, with GLP-1 receptor agonists typically reducing HbA1c (a measure of average blood glucose over 2–3 months) by approximately 1.0–1.5 percentage points when added to existing diabetes treatment, though the magnitude of reduction varies by agent, dose, and baseline glycaemic control. NICE recommends GLP-1 receptor agonists as second- or third-line options for type 2 diabetes when metformin alone or in combination with other agents fails to achieve adequate glycaemic targets (NICE NG28).

Weight reduction represents another significant benefit. Clinical trials have shown that GLP-1 receptor agonists can produce weight loss, with the magnitude depending on the specific agent, dose, and indication. In type 2 diabetes, typical diabetes-licensed doses (e.g., semaglutide 1 mg weekly, liraglutide 1.8 mg daily) generally result in modest weight loss of 3–5 kg. Higher-dose formulations licensed specifically for weight management in obesity (e.g., semaglutide 2.4 mg weekly [Wegovy], liraglutide 3 mg daily [Saxenda]) can produce greater weight loss, often 10–15% of body weight in clinical trials. In the UK, access to these higher-dose obesity treatments is typically via specialist weight management services and requires meeting specific criteria, including body mass index (BMI) thresholds (usually BMI ≥30 kg/m² or ≥27 kg/m² with weight-related comorbidities) and participation in a structured weight management programme. This effect is particularly valuable given that many people with type 2 diabetes are overweight or obese, and weight loss itself improves insulin sensitivity and glycaemic control.

Cardiovascular outcome trials (CVOTs) have revealed that certain GLP-1 receptor agonists—specifically liraglutide (LEADER trial), semaglutide (SUSTAIN-6 trial), and dulaglutide (REWIND trial)—reduce major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in people with type 2 diabetes and established cardiovascular disease or high cardiovascular risk. NICE NG28 recommends considering these agents for adults with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular risk, whilst also emphasising that sodium-glucose co-transporter-2 (SGLT2) inhibitors should be prioritised for their proven cardio-renal protective benefits. The choice between these drug classes should be individualised based on patient characteristics, comorbidities, and treatment goals. For detailed cardiovascular outcome data, refer to the EMA EPARs for liraglutide, semaglutide, and dulaglutide.

Additional potential benefits under investigation include:

• Renal protection: some evidence suggests beneficial effects on kidney function and albuminuria, though SGLT2 inhibitors remain the preferred agents for renal protection in type 2 diabetes

• Non-alcoholic fatty liver disease: GLP-1 therapy may reduce hepatic fat content

• Blood pressure reduction: modest decreases in systolic blood pressure have been observed

These multifaceted benefits extend beyond simple glucose lowering, addressing several components of cardiometabolic risk simultaneously. For UK-specific guidance on treatment positioning and eligibility criteria, consult NICE NG28 (Type 2 diabetes in adults: management), relevant NICE Technology Appraisals (e.g., semaglutide for weight management), and NHS weight management service pages.

Side Effects and Safety Considerations

Whilst GLP-1-based therapies are generally well-tolerated, patients and healthcare professionals should be aware of potential adverse effects. The most common side effects are gastrointestinal, including nausea, vomiting, diarrhoea, and constipation. These symptoms typically occur during treatment initiation or dose escalation and often diminish over several weeks as tolerance develops. Starting with lower doses and gradually titrating upwards, as recommended in product literature, can minimise these effects. Patients experiencing persistent or severe gastrointestinal symptoms should contact their GP or diabetes specialist nurse for advice. Severe vomiting or diarrhoea can lead to dehydration and, in rare cases, acute kidney injury; patients should be advised to maintain adequate hydration and seek medical attention if they are unable to tolerate fluids.

Hypoglycaemia risk with GLP-1 receptor agonists alone is low due to their glucose-dependent mechanism of action. However, when combined with insulin or sulphonylureas, the risk increases, and dose adjustments of these concomitant medications may be necessary. Patients should be educated about hypoglycaemia symptoms (tremor, sweating, confusion, palpitations) and appropriate management.

There has been concern regarding pancreatitis risk. Whilst extensive post-marketing surveillance and meta-analyses have not established a definitive causal link, UK Summaries of Product Characteristics (SmPCs) advise caution in patients with a history of pancreatitis. GLP-1 receptor agonists should be discontinued if pancreatitis is suspected or confirmed and should not be restarted. Patients should be advised to seek immediate medical attention if they develop severe, persistent abdominal pain, which may radiate to the back, as this could indicate pancreatitis.

Thyroid considerations warrant attention: GLP-1 receptor agonists carry a warning regarding thyroid C-cell tumours (medullary thyroid carcinoma) based on rodent studies. There is no confirmed evidence of this risk in humans, and medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2) are not listed as contraindications in UK/EU SmPCs, though the product information includes a warning. Patients with a personal or family history of these conditions should discuss the risks and benefits with their healthcare provider.

Pregnancy and breastfeeding: GLP-1 receptor agonists are not recommended during pregnancy or breastfeeding due to limited safety data. Women of childbearing potential should use effective contraception during treatment. If pregnancy is planned or occurs, GLP-1 receptor agonists should be discontinued; for semaglutide, a washout period of at least two months is recommended before conception due to its long half-life. Women should discuss contraception and pregnancy planning with their healthcare provider.

Renal function: Most GLP-1 receptor agonists do not require dose adjustment in renal impairment. However, some agents have specific restrictions: for example, exenatide (Byetta) is not recommended and may be contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²). Prescribers should consult individual product SmPCs for agent-specific guidance.

Other safety considerations include:

• Injection site reactions: redness, itching, or lumps may occur with subcutaneous formulations

• Gallbladder disease: increased risk of cholelithiasis (gallstones) and cholecystitis (gallbladder inflammation) has been reported

• Diabetic retinopathy: rapid improvement in glycaemic control may temporarily worsen retinopathy in susceptible individuals, particularly those with pre-existing retinopathy who are also using insulin. Eye screening and, where feasible, gradual glycaemic improvement are recommended

Regular monitoring, including HbA1c, renal function, and assessment for adverse effects, should follow NICE guidance and manufacturer recommendations to ensure safe, effective use of GLP-1-based therapies. Patients should be advised to report any suspected side effects via the MHRA Yellow Card Scheme (yellowcard.mhra.gov.uk). For detailed safety information, refer to the MHRA/EMC SmPCs for semaglutide (Ozempic/Wegovy), liraglutide (Victoza/Saxenda), dulaglutide (Trulicity), and exenatide (Byetta/Bydureon), as well as the corresponding NHS medicines pages and EMA EPARs.

Frequently Asked Questions