Incretin-based therapies for obesity treatment represent a transformative approach to weight management, harnessing medications that mimic naturally occurring gut hormones to achieve substantial, sustained weight loss. Originally developed for type 2 diabetes, these treatments—including GLP-1 receptor agonists such as liraglutide (Saxenda®) and semaglutide (Wegovy®)—work by suppressing appetite, delaying gastric emptying, and improving metabolic regulation. In the UK, the National Institute for Health and Care Excellence (NICE) recommends their use within specialist weight management services, alongside dietary modifications and increased physical activity, for eligible adults with obesity and weight-related comorbidities. Understanding how these therapies work, their effectiveness, and access pathways is essential for patients and healthcare professionals considering this treatment option.

What Are Incretin-Based Therapies for Obesity?

Incretin-based therapies represent a significant advancement in the medical management of obesity, utilising medications originally developed for type 2 diabetes to achieve substantial weight loss. These treatments work by mimicking naturally occurring hormones in the body called incretins, which play crucial roles in regulating appetite, food intake, and glucose metabolism.

The two main classes of incretin-based medications are glucagon-like peptide-1 (GLP-1) receptor agonists and dual GIP/GLP-1 receptor agonists. GLP-1 is an incretin hormone produced in the intestine that stimulates insulin secretion, suppresses glucagon release, and importantly for weight management, slows gastric emptying and reduces appetite. When pharmaceutical versions of these hormones are administered, they produce more sustained effects than the body's natural incretins, which are rapidly broken down by enzymes.

In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) has licensed two GLP-1 receptor agonists specifically for weight management: liraglutide 3.0 mg (Saxenda®) and semaglutide 2.4 mg (Wegovy®). These should not be confused with diabetes-only formulations such as Ozempic® (semaglutide 1 mg). Both weight-management medicines are administered via subcutaneous injection—liraglutide daily and semaglutide once weekly. The National Institute for Health and Care Excellence (NICE) has issued guidance on their use within the NHS, recommending them only as adjuncts to a reduced-calorie diet and increased physical activity, delivered within specialist weight management services (typically tier 3 services).

The emergence of incretin therapies has transformed obesity treatment by offering a pharmacological option that addresses the underlying biological mechanisms driving excessive weight gain. Unlike older weight-loss medications that primarily worked through appetite suppression or fat absorption inhibition, incretin-based treatments target multiple pathways involved in energy balance and metabolic regulation, making them particularly effective for long-term weight management when combined with lifestyle modifications. For full prescribing information, healthcare professionals and patients should consult the Summary of Product Characteristics (SmPC) for each medicine via the electronic Medicines Compendium (EMC) or MHRA website.

How Incretin Therapies Work to Reduce Weight

Incretin-based therapies achieve weight loss through multiple complementary mechanisms that address both the physiological and behavioural aspects of obesity. Understanding these mechanisms helps explain why these medications produce more substantial and sustained weight loss compared to previous pharmacological approaches. The principal driver of weight loss is reduced energy intake.

The primary mechanisms include:

• Appetite suppression and satiety enhancement: GLP-1 receptor agonists act on receptors in the hypothalamus and brainstem, regions of the brain that regulate hunger and fullness. This reduces appetite and increases feelings of satiety after eating, leading to decreased caloric intake without the intense hunger often experienced with calorie restriction alone.

• Delayed gastric emptying: These medications slow the rate at which food leaves the stomach and enters the small intestine. This prolonged gastric retention contributes to earlier and longer-lasting feelings of fullness after meals, naturally reducing portion sizes and snacking behaviour. It should be noted that this effect may diminish over time (tachyphylaxis), though appetite suppression and reduced energy intake are maintained.

• Effects on food preferences: Clinical studies suggest that patients treated with incretin therapies may report decreased cravings for high-calorie, palatable foods, particularly those high in fat and sugar. The mechanisms are not fully understood but may involve alterations in reward pathways in the brain. Further research is ongoing to clarify these effects.

• Improved glucose regulation: By enhancing insulin secretion in a glucose-dependent manner and suppressing inappropriate glucagon release, these medications help stabilise blood glucose levels, which may reduce hunger signals triggered by glucose fluctuations.

Weight loss achieved with incretin therapies includes both fat mass and lean body mass. Whilst fat mass reduction predominates, some loss of lean tissue also occurs, as with any substantial weight loss. To help preserve muscle mass, patients are advised to engage in resistance exercise and ensure adequate protein intake alongside their treatment. The medications work synergistically with lifestyle interventions—patients who combine incretin therapy with dietary modifications and increased physical activity typically achieve greater weight loss than those relying on medication alone. The effects are dose-dependent, with higher doses generally producing more substantial weight reduction.

NICE-Recommended Incretin Medicines for Weight Management

The National Institute for Health and Care Excellence (NICE) has evaluated incretin-based medications licensed by the MHRA for obesity treatment, with specific guidance on their use within the NHS. Currently, NICE recommends liraglutide (Saxenda®) and semaglutide (Wegovy®), both GLP-1 receptor agonists, under defined criteria.

Liraglutide (Saxenda®) was the first GLP-1 receptor agonist licensed specifically for weight management in the UK. It is administered as a daily subcutaneous injection, with doses gradually increased from 0.6 mg to a maintenance dose of 3.0 mg. NICE recommends liraglutide only as part of specialist weight management services, and treatment should be discontinued if patients do not achieve at least 5% weight loss after 12 weeks at the maintenance dose.

Semaglutide (Wegovy®) represents a more recent addition to NHS weight management options. Administered as a once-weekly subcutaneous injection, semaglutide is initiated at 0.25 mg weekly and gradually escalated to a maintenance dose of 2.4 mg. Clinical trials have demonstrated superior weight loss with semaglutide compared to liraglutide. NICE guidance (TA875, published March 2023) recommends semaglutide for adults with at least one weight-related comorbidity and a body mass index (BMI) of ≥35 kg/m², or ≥30 kg/m² in certain circumstances (such as recent type 2 diabetes diagnosis within 10 years). Importantly, NICE recommends semaglutide for a maximum of 2 years and only within specialist tier 3 weight management services that provide multidisciplinary support including dietetic input, psychological support, and physical activity guidance.

Both medications are recommended only as adjuncts to a reduced-calorie diet and increased physical activity. Treatment continuation requires patients to achieve at least 5% weight loss after 6 months of treatment; if this threshold is not met, the medication should be discontinued.

Tirzepatide, a dual GIP/GLP-1 receptor agonist showing promising weight loss in clinical trials, is currently undergoing NICE appraisal for obesity treatment in the UK (as of early 2024). Until NICE guidance is published, its availability for weight management within the NHS remains uncertain. Availability of incretin therapies on the NHS has been affected by supply constraints, leading to prioritisation for patients with greatest clinical need, and there is significant regional variation in access depending on local commissioning decisions. Patients should discuss their individual circumstances with their GP to determine eligibility and local availability of incretin-based obesity treatments. Full details are available in NICE technology appraisal TA875 and the respective SmPCs via the EMC.

Effectiveness and Expected Weight Loss Outcomes

Clinical trial evidence demonstrates that incretin-based therapies produce substantial and clinically meaningful weight loss, significantly exceeding results achieved with lifestyle interventions alone or older anti-obesity medications. Understanding realistic expectations is important for both patients and healthcare professionals.

Liraglutide 3.0 mg (Saxenda®) produces an average weight loss of approximately 5–10% of initial body weight over 56 weeks when combined with lifestyle intervention. In the pivotal SCALE Obesity and Prediabetes trial, 63% of participants achieved at least 5% weight loss, and 33% achieved at least 10% weight loss, compared to 27% and 11% respectively in the placebo group receiving lifestyle intervention alone.

Semaglutide 2.4 mg (Wegovy®) demonstrates superior efficacy, with average weight loss of approximately 12–15% of initial body weight over 68 weeks. The STEP clinical trial programme (including STEP 1, 3, and 4) showed that nearly 70% of participants achieved at least 10% weight loss, and approximately 50% achieved at least 15% weight loss. Some individuals experience even greater reductions, with around 35% losing 20% or more of their starting weight. The SELECT cardiovascular outcomes trial demonstrated that semaglutide 2.4 mg also reduces the risk of major adverse cardiovascular events in people with established cardiovascular disease and overweight or obesity.

Tirzepatide, though not yet widely available for obesity treatment in the UK pending NICE appraisal, has shown average weight loss reaching 15–22% of body weight in the SURMOUNT-1 trial, depending on the dose used.

Weight loss typically occurs gradually over 12–18 months, with the most rapid reduction in the first 6 months. Beyond weight reduction, incretin therapies produce significant improvements in cardiovascular risk factors including blood pressure, lipid profiles, and glycaemic control. Quality of life measures, physical functioning, and obesity-related comorbidities also show meaningful improvements.

It is important to note that substantial weight regain commonly occurs after discontinuation of treatment. For example, in the STEP 1 extension study, participants regained approximately two-thirds of their lost weight within one year of stopping semaglutide. This highlights that obesity is a chronic condition requiring long-term management. Within the NHS, NICE recommends semaglutide for a maximum of 2 years within specialist services; maintenance strategies and long-term safety and cost-effectiveness data continue to be evaluated.

Side Effects and Safety Considerations

Whilst incretin-based therapies are generally well-tolerated, patients should be informed about potential adverse effects and safety considerations before commencing treatment. Most side effects are gastrointestinal in nature and tend to be most pronounced during dose escalation.

Common gastrointestinal side effects affect the majority of patients to some degree and include:

• Nausea (reported by 40–50% of patients, usually mild to moderate)

• Diarrhoea (approximately 30% of patients)

• Constipation (20–25% of patients)

• Vomiting (15–25% of patients)

• Abdominal pain and dyspepsia

These effects typically diminish over time as the body adjusts to the medication. Gradual dose escalation, eating smaller meals, and avoiding high-fat foods can help minimise gastrointestinal symptoms. Most patients find these effects manageable, though approximately 5–10% discontinue treatment due to tolerability issues.

Serious but rare adverse effects require awareness:

• Pancreatitis: Patients should be counselled to seek immediate medical attention if they experience severe, persistent abdominal pain radiating to the back. Treatment should be discontinued if pancreatitis is confirmed.

• Gallbladder disease: Rapid weight loss increases the risk of gallstones and cholecystitis. Patients experiencing right upper quadrant pain, fever, or jaundice should contact their GP promptly.

• Dehydration and acute kidney injury: Severe or persistent gastrointestinal side effects (nausea, vomiting, diarrhoea) can lead to dehydration and, in susceptible individuals, acute kidney injury. Patients should be advised to maintain adequate fluid intake and seek medical advice if symptoms are severe. Renal function should be monitored in at-risk patients, particularly those with pre-existing renal impairment or taking medications affecting renal function.

• Hypoglycaemia: Risk is low when used as monotherapy for obesity, but increases if combined with insulin or sulfonylureas in patients with diabetes.

• Diabetic retinopathy complications: In people with type 2 diabetes and pre-existing diabetic retinopathy, rapid improvement in glycaemic control has been associated with temporary worsening of retinopathy. Ophthalmic monitoring may be considered in this group.

• Thyroid concerns: GLP-1 receptor agonists have been associated with thyroid C-cell tumours in rodent studies, though the relevance to humans is unknown. Patients should be advised to report symptoms of thyroid tumours (e.g., a lump in the neck, hoarseness, difficulty swallowing, or shortness of breath). In the United States, these medicines carry a boxed warning regarding medullary thyroid carcinoma (MTC) and Multiple Endocrine Neoplasia syndrome type 2 (MEN2), but this is not a formal contraindication in UK or EU prescribing information.

Contraindications and cautions include:

• Pregnancy and breastfeeding: These medicines are contraindicated. Women of childbearing potential should use effective contraception. Semaglutide should be discontinued at least 2 months before a planned pregnancy due to its long half-life. For tirzepatide, there is a potential interaction with oral contraceptives due to delayed gastric emptying; women using oral contraceptives should consider additional non-oral contraception for 4 weeks after starting treatment and after each dose escalation.

• Severe gastrointestinal disease: Use is not recommended in patients with severe gastrointestinal disease (e.g., severe gastroparesis) due to limited data and the risk of exacerbating symptoms.

Patients and healthcare professionals are encouraged to report any suspected adverse drug reactions via the MHRA Yellow Card Scheme at yellowcard.mhra.gov.uk or through the Yellow Card app. Regular monitoring and specialist supervision ensure early identification and management of any complications. Full safety information is available in the SmPC for each medicine via the EMC.

Eligibility and Accessing Treatment in the UK

Access to incretin-based therapies for obesity through the NHS is governed by NICE guidance and local commissioning decisions, with specific eligibility criteria that patients must meet. Understanding the pathway to treatment helps set realistic expectations about availability.

NICE eligibility criteria for semaglutide (NICE TA875, March 2023) specify that treatment should be offered to adults who:

• Have a body mass index (BMI) of at least 35 kg/m² with at least one weight-related comorbidity (such as hypertension, type 2 diabetes, dyslipidaemia, obstructive sleep apnoea, or cardiovascular disease), OR

• Have a BMI of 30–34.9 kg/m² in specific circumstances, such as recent type 2 diabetes diagnosis (within 10 years)

• Are receiving treatment within a specialist tier 3 weight management service providing multidisciplinary support (dietetic input, psychological support, physical activity guidance)

• Have demonstrated engagement with lifestyle interventions (diet and physical activity modifications)

For people of South Asian, Chinese, other Asian, Middle Eastern, Black African, or African-Caribbean family background, BMI thresholds are adjusted downward by 2.5 kg/m² to reflect increased metabolic risk at lower BMI levels, in line with NICE guidance on obesity (CG189).

Treatment continuation and duration: NICE recommends that semaglutide should be continued only if patients achieve at least 5% weight loss after 6 months of treatment. If this threshold is not met, the medication should be discontinued. Importantly, NICE recommends semaglutide for a maximum of 2 years within specialist services. Similar principles apply to liraglutide, with stopping rules based on response at 12 weeks on the maintenance dose.

Accessing treatment typically requires:

1. GP referral to a tier 3 specialist weight management service
2. Comprehensive assessment including medical history, comorbidities, previous weight loss attempts, and psychological evaluation
3. Engagement with lifestyle modification programme before or alongside medication initiation
4. Regular monitoring with the specialist service throughout treatment, adhering to local protocols and formulary policies

Current challenges: Significant supply constraints have affected the availability of both liraglutide and semaglutide, leading to prioritisation for patients with greatest clinical need, as communicated by NHS England. Regional variation exists in NHS commissioning of specialist weight management services, and waiting times can be substantial. Patients should discuss their individual circumstances with their GP to determine eligibility and local availability of incretin-based obesity treatments. Some patients choose to access these medications privately, though costs are considerable and vary.

For full details, refer to NICE TA875 (semaglutide), NICE guidance on obesity (CG189), and local NHS specialist weight management service pathways.

Frequently Asked Questions