Incretins are gut hormones that regulate blood glucose, but emerging research suggests they may also benefit blood vessel health. Endothelial dysfunction—impaired function of the cells lining blood vessels—is common in type 2 diabetes and contributes to cardiovascular disease. Studies indicate that incretin-based therapies, particularly GLP-1 receptor agonists, may improve endothelial function through mechanisms including enhanced nitric oxide production, reduced inflammation, and decreased oxidative stress. Whilst certain GLP-1 receptor agonists have demonstrated cardiovascular benefits in major trials, the precise contribution of improved endothelial function to these outcomes remains an active area of investigation.

What Are Incretins and How Do They Work?

Incretins are naturally occurring hormones produced in the gastrointestinal tract in response to food intake. The two principal incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones play a crucial role in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in a glucose-dependent manner, meaning they only promote insulin release when blood glucose levels are elevated.

The incretin effect accounts for approximately 50–70% of postprandial insulin secretion in healthy individuals. Beyond their glucose-lowering properties, incretins also suppress glucagon release from pancreatic alpha cells, slow gastric emptying, and promote satiety through central nervous system pathways. In people with type 2 diabetes, the incretin effect is significantly diminished, contributing to impaired glucose regulation.

Incretin-based therapies have been developed to exploit these physiological mechanisms. GLP-1 receptor agonists (such as semaglutide, dulaglutide, and liraglutide) mimic the action of native GLP-1 but are resistant to enzymatic degradation. Dipeptidyl peptidase-4 (DPP-4) inhibitors (including sitagliptin and linagliptin) work by preventing the breakdown of endogenous incretins, thereby prolonging their activity.

According to NICE guidance (NG28), DPP-4 inhibitors may be considered as second-line therapy when metformin alone does not achieve glycaemic targets. GLP-1 receptor agonists are generally reserved for specific scenarios, such as triple therapy (often with metformin and another agent) when BMI criteria are met, or when a GLP-1 receptor agonist with proven cardiovascular benefit may be considered for people with established cardiovascular disease or high cardiovascular risk. It is important to note that GLP-1 receptor agonists and DPP-4 inhibitors should not be used together.

An important distinction exists between these two drug classes: certain GLP-1 receptor agonists (specifically liraglutide, semaglutide subcutaneous, and dulaglutide) have demonstrated reductions in major adverse cardiovascular events (MACE) in large outcome trials, whereas DPP-4 inhibitors have shown cardiovascular neutrality in similar studies. Recent research has expanded our understanding of incretin actions beyond glycaemic control, with emerging evidence suggesting beneficial effects on cardiovascular and vascular health, including potential improvements in endothelial function.

Understanding Endothelial Function and Cardiovascular Health

The endothelium is a single-cell layer lining the interior surface of blood vessels throughout the body. Far from being a passive barrier, the endothelium is a highly active organ that regulates vascular tone, inflammation, thrombosis, and vascular permeability. Endothelial function refers to the ability of these cells to maintain vascular homeostasis, primarily through the production of nitric oxide (NO), a potent vasodilator and anti-inflammatory mediator.

Healthy endothelial function is characterised by:

• Vasodilation in response to physiological stimuli

• Anti-inflammatory properties that prevent leucocyte adhesion

• Antithrombotic effects that inhibit platelet aggregation

• Regulation of vascular permeability and smooth muscle cell proliferation

Endothelial dysfunction represents an early, often reversible stage of atherosclerosis and is a key predictor of future cardiovascular events. It is characterised by reduced nitric oxide bioavailability, increased oxidative stress, enhanced inflammatory responses, and a prothrombotic state. Common causes include diabetes, hypertension, dyslipidaemia, smoking, and obesity.

In people with type 2 diabetes, endothelial dysfunction is particularly prevalent and contributes significantly to their elevated cardiovascular risk. Hyperglycaemia, insulin resistance, and associated metabolic abnormalities promote oxidative stress and inflammation, which impair endothelial nitric oxide production. This vascular impairment precedes the development of macrovascular complications such as coronary artery disease, stroke, and peripheral arterial disease.

Assessment of endothelial function in clinical research typically involves flow-mediated dilatation (FMD) of the brachial artery, measured using high-resolution ultrasound. This non-invasive technique provides a surrogate marker for systemic endothelial health and cardiovascular risk. It is important to note that FMD is primarily a research tool and is not part of routine NHS clinical assessment or risk stratification for individual patients.

Mechanisms Behind Incretin Effects on Blood Vessel Health

Emerging evidence from preclinical and small human studies suggests that incretin-based therapies may exert beneficial effects on endothelial function through multiple mechanisms, independent of their glucose-lowering actions. GLP-1 receptors have been identified in vascular endothelial cells, cardiomyocytes, and vascular smooth muscle in some studies, providing a potential biological basis for direct cardiovascular effects, though the extent and functional significance of vascular GLP-1 receptor expression in humans remains an area of ongoing investigation.

Several proposed mechanisms include:

• Enhanced nitric oxide production: Preclinical studies suggest that GLP-1 receptor activation may stimulate endothelial nitric oxide synthase (eNOS), potentially increasing NO bioavailability and promoting vasodilation. Some small human studies have reported improvements in endothelial function markers.

• Reduction in oxidative stress: Laboratory and early clinical research indicates that incretin therapies may reduce the generation of reactive oxygen species (ROS) and enhance antioxidant defences, potentially protecting endothelial cells from oxidative damage.

• Anti-inflammatory effects: GLP-1 receptor agonists have been associated with reductions in circulating inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α), which contribute to endothelial dysfunction.

• Improved lipid metabolism: Some GLP-1 receptor agonists may reduce postprandial lipaemia and favourably affect lipid profiles, potentially reducing atherogenic lipoproteins that damage the endothelium.

• Blood pressure reduction: Modest reductions in systolic blood pressure observed with GLP-1 receptor agonists may contribute to improved endothelial function and reduced vascular stress.

Some clinical studies measuring flow-mediated dilatation have reported improvements in endothelial function following treatment with GLP-1 receptor agonists in patients with type 2 diabetes. However, these findings should be interpreted cautiously, as weight loss and blood pressure reduction may confound observed endothelial improvements. Evidence for endothelial effects with DPP-4 inhibitors is more limited and inconsistent compared with GLP-1 receptor agonists.

It is important to emphasise that whilst these mechanistic findings are of scientific interest, the extent to which improved endothelial function contributes to the cardiovascular benefits observed in major outcome trials with specific GLP-1 receptor agonists remains uncertain. Multiple factors likely contribute to cardiovascular risk reduction, and further research is needed to fully characterise the magnitude and clinical significance of these vascular effects.

Clinical Implications for Patients with Type 2 Diabetes

The potential vascular benefits of incretin-based therapies have important implications for the management of type 2 diabetes, particularly given the elevated cardiovascular risk in this population. Cardiovascular outcome trials have demonstrated that certain GLP-1 receptor agonists—specifically liraglutide, semaglutide (subcutaneous), and dulaglutide—significantly reduce major adverse cardiovascular events (MACE) in people with established cardiovascular disease or multiple risk factors. In contrast, DPP-4 inhibitors have shown cardiovascular neutrality in similar outcome trials.

According to NICE guidance (NG28), treatment decisions should be individualised. DPP-4 inhibitors may be considered as second-line therapy when metformin alone does not achieve HbA1c targets. GLP-1 receptor agonists are generally considered in specific scenarios, including:

• Triple therapy (often with metformin and another agent) when BMI criteria are met or when insulin therapy is unacceptable or inappropriate

• People with established cardiovascular disease or high cardiovascular risk, where a GLP-1 receptor agonist with proven cardiovascular benefit may be considered (often alongside metformin and an SGLT2 inhibitor where appropriate)

• When weight management is a priority, as GLP-1 receptor agonists promote weight loss

• When avoidance of hypoglycaemia is important, given their glucose-dependent mechanism

For patients, the potential endothelial and cardiovascular benefits represent an additional rationale for using GLP-1 receptor agonists with proven cardiovascular benefit beyond glucose control alone. However, it is essential to emphasise that whilst improvements in endothelial function have been demonstrated in research settings, there is no established causal link between this specific mechanism and the cardiovascular benefits observed in clinical trials. Multiple factors likely contribute to cardiovascular risk reduction.

Patient safety considerations include monitoring for gastrointestinal side effects (nausea, vomiting, diarrhoea), which are common but typically diminish over time. Patients should be advised to seek urgent medical attention if they experience severe, persistent abdominal pain, which may rarely indicate pancreatitis. Other important safety considerations include:

• Hypoglycaemia risk when GLP-1 receptor agonists are combined with insulin or sulfonylureas; dose adjustments of these agents may be necessary

• Gallbladder disease, including cholelithiasis and cholecystitis, has been reported

• Diabetic retinopathy complications have been observed with semaglutide, particularly in people with existing retinopathy and rapid improvement in glycaemic control

• Dehydration and acute kidney injury may occur in the context of significant gastrointestinal fluid losses; patients should be advised to maintain adequate hydration

Animal studies have shown thyroid C-cell tumours with GLP-1 receptor agonists, though the relevance to humans is uncertain. Patients should be advised to report symptoms such as a lump in the neck, hoarseness, or difficulty swallowing. Product-specific information is available in the Summary of Product Characteristics (SmPC) for each medicine via the MHRA/EMC website.

Patients should be advised to report any suspected side effects via the MHRA Yellow Card Scheme at yellowcard.mhra.gov.uk or through the Yellow Card app.

Regular cardiovascular risk assessment, blood pressure monitoring, and lipid management remain essential components of comprehensive diabetes care. Incretin-based therapies should be viewed as part of a holistic approach that includes lifestyle modification, optimal glycaemic control, and management of other cardiovascular risk factors to protect vascular health and reduce long-term complications.

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