GLP-1 receptor agonists are a class of medications licensed in the UK for type 2 diabetes and, in some formulations, weight management. Whilst leptin resistance—a condition where the brain fails to respond to satiety signals—is commonly associated with obesity, GLP-1 agonists are not specifically indicated for treating this phenomenon. However, these agents promote weight loss through mechanisms that appear to function independently of leptin signalling, including appetite suppression, delayed gastric emptying, and glucose-dependent insulin secretion. This article explores how GLP-1 agonists work, their availability in the UK, safety considerations, and NHS guidance for appropriate use.

Understanding Leptin Resistance and Its Impact on Weight Management

Leptin is a hormone produced primarily by adipose (fat) tissue that plays a crucial role in regulating energy balance and body weight. Often referred to as the 'satiety hormone', leptin signals to the brain—specifically the hypothalamus—when the body has sufficient energy stores, thereby reducing appetite and increasing energy expenditure. In individuals with healthy leptin signalling, this feedback mechanism helps maintain a stable body weight.

Leptin resistance describes a condition where the brain no longer responds appropriately to leptin signals, despite elevated circulating levels of the hormone. This phenomenon is commonly observed in individuals with obesity, where high levels of body fat produce abundant leptin, yet the brain fails to register satiety. Consequently, affected individuals continue to experience hunger and reduced metabolic rate, making weight loss particularly challenging. The exact mechanisms underlying leptin resistance remain under investigation, but chronic inflammation, endoplasmic reticulum stress, and disrupted leptin transport across the blood-brain barrier are thought to contribute.

It's important to note that leptin resistance is not a formal clinical diagnosis with validated diagnostic criteria in UK practice, and routine leptin measurement is not recommended to guide therapy. This differs from rare congenital leptin deficiency, a distinct condition that may respond to specific treatment with metreleptin.

The clinical implications of leptin resistance are significant. Patients may struggle with persistent hunger, reduced energy expenditure, and difficulty achieving meaningful weight loss through conventional dietary and lifestyle interventions alone. This creates a frustrating cycle where obesity perpetuates leptin resistance, which in turn makes weight management increasingly difficult. While GLP-1 receptor agonists are not specifically indicated for treating leptin resistance, they produce weight loss benefits via mechanisms that appear to work independently of leptin signalling pathways. There is currently no evidence that GLP-1 agonists directly treat or reverse leptin resistance itself.

How GLP-1 Agonists Work in the Body

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of medications that mimic the action of the naturally occurring incretin hormone GLP-1. This hormone is released from intestinal L-cells in response to food intake and plays multiple roles in glucose homeostasis and appetite regulation. GLP-1 agonists bind to and activate GLP-1 receptors located throughout the body, including the pancreas, gastrointestinal tract, and central nervous system.

The primary mechanism of action involves several complementary pathways:

• Glucose-dependent insulin secretion: GLP-1 agonists stimulate pancreatic beta cells to release insulin only when blood glucose levels are elevated, reducing the risk of hypoglycaemia compared to some other diabetes medications.

• Glucagon suppression: These agents inhibit the release of glucagon from pancreatic alpha cells, thereby reducing hepatic glucose production.

• Delayed gastric emptying: By slowing the rate at which food leaves the stomach, GLP-1 agonists promote earlier and more sustained feelings of fullness after meals. This effect may attenuate over time (tachyphylaxis) and can affect the absorption of concomitant oral medicines, necessitating review of medication timing.

• Central appetite regulation: GLP-1 receptors in the hypothalamus and other brain regions involved in appetite control are activated, leading to reduced hunger and food intake.

Whilst GLP-1 agonists were initially developed for type 2 diabetes management, their weight loss effects have become increasingly recognised. Some agents in this class have also demonstrated cardiovascular and renal outcome benefits in clinical trials. The appetite-suppressing properties appear to work through pathways that function independently of leptin signalling, potentially offering benefits even in individuals with obesity. However, it is important to emphasise that GLP-1 agonists are not specifically licensed for treating leptin resistance as a distinct condition. Their effects on weight management result from multiple mechanisms that collectively improve energy balance.

Available GLP-1 Agonist Medications in the UK

Several GLP-1 receptor agonists are currently licensed and available in the UK, each with distinct characteristics regarding administration, dosing frequency, and approved indications. The Medicines and Healthcare products Regulatory Agency (MHRA) has approved these medications for specific uses, primarily type 2 diabetes management and, in some cases, weight management.

Medications licensed for type 2 diabetes include:

• Exenatide (Byetta, Bydureon): Available as twice-daily injections or once-weekly extended-release formulation

• Liraglutide (Victoza): Administered as a once-daily subcutaneous injection at doses up to 1.8 mg for diabetes

• Dulaglutide (Trulicity): Once-weekly injection with pre-filled pen devices

• Semaglutide (Ozempic): Once-weekly injection for diabetes management

• Oral semaglutide (Rybelsus): The first oral GLP-1 agonist, taken daily

For weight management specifically, two formulations have received UK marketing authorisation:

• Liraglutide 3.0 mg (Saxenda): Licensed for weight management in adults with a BMI ≥30 kg/m², or ≥27 kg/m² with weight-related comorbidities

• Semaglutide 2.4 mg (Wegovy): Once-weekly injection approved for chronic weight management under similar BMI criteria

It is crucial to understand that whilst these medications demonstrate efficacy in promoting weight loss, they are not specifically indicated for leptin resistance. Importantly, Ozempic (semaglutide 1 mg) and Rybelsus are not licensed for weight management and should not be used off-label for this purpose, particularly during ongoing supply shortages.

NHS access to these medications is governed by specific NICE guidance. For weight management, NICE Technology Appraisal TA875 (semaglutide 2.4 mg) and TA664 (liraglutide 3 mg) stipulate that treatment must be initiated and monitored by specialist weight management services, with specific eligibility criteria and a maximum treatment duration of 2 years. Due to supply constraints and commissioning restrictions, many patients currently access these medications through private prescription. The MHRA and NHS England have issued advisories prioritising diabetes indications during the current supply disruption.

Safety Considerations and Side Effects of GLP-1 Agonists

Whilst GLP-1 receptor agonists are generally well-tolerated, patients and prescribers must be aware of potential adverse effects and important safety considerations. Understanding these risks enables informed decision-making and appropriate monitoring during treatment.

Common gastrointestinal side effects are the most frequently reported adverse reactions, particularly during treatment initiation and dose escalation:

• Nausea (affecting 20–40% of patients initially)

• Vomiting and diarrhoea

• Constipation

• Abdominal discomfort or bloating

These symptoms typically diminish over several weeks as tolerance develops. Gradual dose titration, as recommended in the Summary of Product Characteristics, helps minimise gastrointestinal disturbance. Patients should be advised to eat smaller, more frequent meals and avoid high-fat foods during the adjustment period.

Serious but rare adverse effects require particular vigilance:

• Acute pancreatitis: Patients should be counselled to seek immediate medical attention if they experience severe, persistent abdominal pain radiating to the back. GLP-1 agonists should be discontinued if pancreatitis is suspected.

• Gallbladder disease: Rapid weight loss may increase the risk of cholelithiasis (gallstones) and cholecystitis.

• Hypoglycaemia: Risk is low when used as monotherapy but increases when combined with insulin or sulphonylureas.

• Thyroid concerns: Medullary thyroid carcinoma has been observed in rodent studies. UK SmPCs advise caution in patients with personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2.

• Diabetic retinopathy complications: Rapid improvement in blood glucose control may temporarily worsen retinopathy. Patients with pre-existing retinopathy should have appropriate monitoring.

• Intestinal obstruction: Rare cases of ileus have been reported; patients with severe and persistent abdominal symptoms should seek urgent medical assessment.

Contraindications and cautions include severe gastrointestinal disease, previous pancreatitis, and severe renal impairment (depending on the specific agent). GLP-1 agonists are contraindicated in pregnancy and breastfeeding. Women of childbearing potential should use effective contraception, and some agents (notably semaglutide) require a washout period of at least 2 months before planned conception.

Patients should contact their GP promptly if they experience persistent vomiting, signs of dehydration, severe abdominal pain, or any concerning symptoms. Any suspected adverse reactions should be reported through the MHRA Yellow Card Scheme (yellowcard.mhra.gov.uk).

NHS Guidance on GLP-1 Agonist Treatment Options

NICE guidance provides the framework for GLP-1 agonist prescribing within the NHS, balancing clinical effectiveness with cost-effectiveness considerations. Current recommendations address both type 2 diabetes management and weight management in specific populations.

For type 2 diabetes, NICE guideline NG28 recommends considering GLP-1 agonists as an option when:

• Triple therapy with metformin and two other oral drugs is ineffective, not tolerated, or contraindicated

• The person has a BMI ≥35 kg/m² (or ≥32.5 kg/m² in people of South Asian or related ethnicity) and specific psychological or medical problems associated with obesity

• Insulin therapy would have significant occupational implications or weight loss would benefit other obesity-related comorbidities

Treatment should be continued only if there is a beneficial metabolic response (HbA1c reduction of at least 11 mmol/mol [1.0%] and weight loss of at least 3% of initial body weight at 6 months).

Regarding weight management, NICE Technology Appraisals provide specific guidance:

• TA875 recommends semaglutide 2.4 mg (Wegovy) as an option for managing overweight and obesity alongside a reduced-calorie diet and increased physical activity. Treatment must be initiated and monitored by specialist weight management services, with specific BMI thresholds and comorbidity requirements. Treatment should not continue beyond 2 years.

• TA664 similarly recommends liraglutide 3 mg (Saxenda) with comparable specialist service requirements and eligibility criteria.

Access considerations are important for patients to understand:

• Referral to Tier 3 or 4 specialist weight management services is required for NHS-funded weight management treatment with GLP-1 agonists

• Local formularies may restrict which GLP-1 agonists are available

• Supply shortages have affected availability, particularly for higher-dose formulations

• Private prescriptions may be necessary for those not meeting NHS criteria

• Ongoing monitoring and specialist input are typically required

Patients interested in GLP-1 agonist therapy should discuss their individual circumstances with their GP, who can advise on local referral pathways to specialist services if appropriate. A comprehensive assessment including BMI, metabolic parameters, comorbidities, and previous treatment responses will inform whether these medications represent an appropriate option. It is important to emphasise that GLP-1 agonists are not a standalone solution but should form part of a comprehensive approach including dietary modification, physical activity, and behavioural support for optimal outcomes.

Frequently Asked Questions