Saxenda (liraglutide 3.0 mg) is a prescription medicine licensed in the UK for weight management in adults and adolescents with obesity. Understanding the mechanism of action of Saxenda is essential for healthcare professionals and patients considering this treatment option. Saxenda belongs to a class of medications called glucagon-like peptide-1 (GLP-1) receptor agonists, which work by mimicking a naturally occurring hormone that regulates appetite and food intake. This article explores how Saxenda works at a molecular level, its clinical effectiveness, and who may benefit from treatment under UK guidance.

What Is Saxenda and How Does It Work?

Saxenda (liraglutide 3.0 mg) is a prescription medicine licensed in the UK for weight management in adults with obesity or overweight with weight-related health conditions, and in adolescents aged 12-17 years with obesity and body weight above 60 kg.

Saxenda belongs to a class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists. Originally developed for the treatment of type 2 diabetes at lower doses (marketed as Victoza), liraglutide at the higher 3.0 mg dose has been shown to produce significant weight loss when combined with a reduced-calorie diet and increased physical activity.

The medication works by mimicking the action of a naturally occurring hormone in the body that regulates appetite and food intake. It influences areas of the brain involved in appetite regulation, slows gastric emptying to promote feelings of fullness, and helps regulate blood glucose levels.

While Saxenda is licensed for use in the UK, NHS provision through NICE guidance (TA664) is more restricted. NICE recommends Saxenda only for adults within specialist weight management services (Tier 3 or 4), with specific BMI thresholds and conditions. Treatment should be discontinued if at least 5% weight loss is not achieved after 12 weeks on the maintenance dose (3.0 mg).

It is important to note that Saxenda is not a standalone solution for weight management. The medication is most effective when used as part of a comprehensive weight management programme that includes dietary changes, regular physical activity, and behavioural support. Patients prescribed Saxenda should be under the care of a healthcare professional experienced in weight management.

Mechanism of Action of Saxenda: GLP-1 Receptor Activation

The mechanism of action of Saxenda centres on its ability to activate GLP-1 receptors throughout the body, particularly in key areas that regulate appetite, satiety, and glucose metabolism. Liraglutide is a synthetic analogue of human GLP-1, sharing 97% structural similarity with the naturally occurring hormone.

Liraglutide has been modified with a C16 fatty acid side chain that enables albumin binding. This structural modification protects it from rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of approximately 13 hours, compared to minutes for endogenous GLP-1.

When administered, Saxenda binds to and activates GLP-1 receptors in several critical locations:

• Hypothalamus and brainstem: Activation of GLP-1 receptors in these appetite-regulating centres of the brain reduces hunger signals and increases feelings of satiety. This leads to decreased food intake and reduced cravings between meals.

• Gastrointestinal tract: Saxenda slows gastric emptying, meaning food remains in the stomach for longer periods. This effect is most pronounced early in treatment and may attenuate over time. The delayed gastric emptying contributes to enhanced feelings of fullness after eating, helping patients feel satisfied with smaller portion sizes.

• Pancreas: GLP-1 receptor activation stimulates glucose-dependent insulin secretion from pancreatic beta cells whilst suppressing inappropriate glucagon release. This helps regulate blood glucose levels, particularly after meals.

The weight loss effect of Saxenda is primarily attributed to reduced caloric intake resulting from decreased appetite and increased satiety, rather than increased energy expenditure or malabsorption. Clinical studies have demonstrated that patients treated with Saxenda consume fewer calories throughout the day compared to those receiving placebo. This appetite-modulating effect has been observed in clinical trials lasting up to 56 weeks, although individual responses may vary.

Clinical Evidence Supporting Saxenda's Effectiveness

The efficacy of Saxenda for weight management has been extensively evaluated through the SCALE (Satiety and Clinical Adiposity – Liraglutide Evidence) clinical trial programme, which included over 5,000 participants across multiple international studies.

In the pivotal SCALE Obesity and Prediabetes trial (Pi-Sunyer et al., NEJM 2015), adults with obesity or overweight with comorbidities who received Saxenda 3.0 mg daily alongside lifestyle intervention achieved an average weight loss of 8.0% of initial body weight at 56 weeks, compared to 2.6% in the placebo group. Notably, 63.2% of patients treated with Saxenda lost at least 5% of their body weight (considered clinically meaningful), and 33.1% achieved weight loss of 10% or more.

The SCALE Maintenance trial demonstrated that Saxenda is effective not only for initial weight loss but also for weight loss maintenance. Participants who had already lost weight through a low-calorie diet maintained significantly more of their weight loss and achieved additional reductions compared to the placebo group.

Beyond weight reduction, clinical trials have shown that Saxenda treatment is associated with improvements in certain cardiometabolic risk factors, including reductions in waist circumference, blood pressure, and markers of glycaemic control in patients with prediabetes.

NICE guidance (TA664) recommends Saxenda as a treatment option for weight management in adults within specialist weight management services (Tier 3 or 4) who have:

• A BMI of at least 35 kg/m² (or at least 32.5 kg/m² in people from certain minority ethnic groups)

• A BMI of at least 30 kg/m² (or at least 27.5 kg/m² in people from certain minority ethnic groups) and weight-related comorbidities

Treatment should be discontinued if patients do not lose at least 5% of their initial body weight after 12 weeks at the maintenance dose of 3.0 mg. NHS treatment is typically provided for up to 2 years.

Who Can Benefit from Saxenda Treatment in the UK?

In the UK, Saxenda is licensed for weight management in adults with a BMI of 30 kg/m² or greater (obesity), or 27 kg/m² or greater (overweight) with at least one weight-related comorbidity. It is also licensed for adolescents aged 12-17 years with body weight above 60 kg and obesity (BMI corresponding to ≥30 kg/m² in adults).

However, NHS provision through NICE guidance (TA664) is more restricted, recommending Saxenda only for adults who meet specific criteria and are being treated within specialist weight management services (Tier 3 or 4).

Patients most likely to benefit from Saxenda are those who have made serious attempts to lose weight through diet and exercise but have been unable to achieve or maintain clinically significant weight loss. The medication is particularly suitable for individuals with obesity-related health complications that would improve with weight reduction.

Saxenda is not suitable for everyone. According to the UK SmPC, it should not be used in patients with:

• Hypersensitivity to liraglutide or any of the excipients

• Pregnancy or breastfeeding

Caution is advised in patients with:

• History of pancreatitis (stop treatment if pancreatitis is suspected)

• Gallbladder disease (risk of cholelithiasis or cholecystitis)

• Thyroid disease

• Risk of dehydration that could lead to acute kidney injury

• Type 2 diabetes treated with insulin or sulfonylureas (dose adjustments may be needed to reduce hypoglycaemia risk)

Saxenda should not be used together with other GLP-1 receptor agonists.

Common adverse effects include nausea, diarrhoea, constipation, vomiting, and injection site reactions. These gastrointestinal symptoms are usually mild to moderate and tend to diminish over time as the dose is gradually increased.

Before prescribing Saxenda, healthcare professionals should conduct a thorough assessment including medical history, current medications, and baseline measurements. Patients should contact their healthcare provider if they experience severe or persistent abdominal pain (which could indicate pancreatitis), or symptoms of dehydration due to gastrointestinal side effects.

Patients should report any suspected side effects to the MHRA Yellow Card Scheme (yellowcard.mhra.gov.uk). Regular monitoring and review are essential to assess treatment response, tolerability, and the need for continuation or discontinuation of therapy.

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