Incretin therapies

What are incretin therapies?

Incretins are hormones released from the gastrointestinal tract following food intake. Two key incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Together, they influence glucose regulation, appetite, and energy balance in response to food.

GLP-1

• Glucose regulation - increases glucose-dependent insulin secretion and reduces glucagon secretion.

• Gastric emptying - delays gastric emptying, which can contribute to increased satiety.

• Appetite - acts on central pathways involved in appetite and satiety, reducing hunger and food intake.

GLP-1 receptor agonists mimic these effects but remain active for much longer than endogenous GLP-1. Depending on the drug and formulation, they are used in the management of type 2 diabetes, obesity and, increasingly, some of the diseases associated with them.

GIP

• Glucose regulation - stimulates glucose-dependent insulin secretion.

• Appetite and energy balance - GIP signalling may influence appetite and energy balance.

• Nutrient handling - GIP receptors are found in tissues including the brain and adipose tissue, where GIP signalling may influence nutrient handling.

Combining GIP and GLP-1 receptor activation appears to produce complementary metabolic effects. Tirzepatide is the first dual GIP/GLP-1 receptor agonist licensed in the UK.

How do incretin therapies work for weight loss?

Incretin therapies support weight management through several physiological effects, primarily by influencing appetite, satiety, and energy intake:

• Appetite regulation - incretin therapies reduce hunger and increase feelings of satiety and fullness, helping to reduce overall energy intake.

• Food-related thoughts - patients may experience a reduced preoccupation with food, sometimes described as a reduction in ‘food noise’.

• Weight regulation - weight loss triggers physiological adaptations that increase hunger and can promote weight regain. By reducing appetite and increasing satiety, incretin therapies can help counter these responses and support sustained weight loss.

• Lifestyle intervention - incretin therapies are generally used alongside dietary and physical activity interventions. Clinical trials of semaglutide and tirzepatide have typically included lifestyle support alongside pharmacological treatment, rather than evaluating medication as a replacement for lifestyle intervention.

Effects beyond glycaemic control and weight loss

Incretin therapies have a range of physiological effects beyond glycaemic control and weight loss, although the extent to which these are direct effects of receptor activation or secondary to weight loss remains an area of ongoing research:

• Vascular function and blood pressure - GLP-1 receptor activation has been associated with improvements in vascular function and reductions in blood pressure.

• Inflammation - incretin signalling may influence inflammatory pathways, potentially contributing to broader metabolic and cardiovascular effects.

• Renal effects - GLP-1 receptor activation may affect renal sodium handling, which could contribute to changes in blood pressure and cardiovascular risk.

• Visceral adiposity and insulin sensitivity - reductions in visceral adiposity and improvements in insulin sensitivity may contribute to the wider metabolic benefits observed with treatment.

• Liver health - reduced hepatic fat and improvements in metabolic and inflammatory signalling may contribute to improvements in metabolic dysfunction-associated steatotic liver disease (MASLD).

• Cardiovascular effects - changes in several of these pathways may contribute to the cardiovascular benefits observed in clinical trials, including effects relevant to heart failure.

• Direct and indirect effects - it remains difficult to distinguish the direct effects of incretin receptor activation from those mediated by weight loss, and their relative contribution is likely to vary between conditions.

Overall, the clinical effects of incretin therapies extend beyond appetite suppression, glycaemic control, and reductions in body weight.

Where do incretin therapies fit in UK clinical practice?

Type 2 diabetes

GLP-1 receptor agonists have been used in type 2 diabetes for considerably longer than they have been used for weight management.

Updated National Institute for Health and Care Excellence (NICE) guidance on the management of type 2 diabetes in adults encourages clinicians to individualise treatment according to factors including cardiovascular and renal disease, obesity, age at diagnosis, frailty, and the person's treatment priorities, rather than following a single sequential pathway.¹

Factors influencing treatment choice include:

• Cardiovascular and renal comorbidity.

• The presence and degree of obesity.

• Age at diagnosis.

• Frailty and overall clinical status.

• The person's treatment priorities and preferences.

• The potential effects of treatment beyond glycaemic control, including cardiovascular, renal, and hepatic outcomes in some patient groups.

Where weight reduction is the primary treatment aim, NICE advises clinicians to follow its guidance on overweight and obesity rather than the type 2 diabetes pathway.

Weight management

Our understanding of overweight and obesity as chronic diseases rather than a reflection of will-power has evolved at the same time as incretin-based treatments have become increasingly available.

The pharmacological options available for weight management in the UK have expanded considerably.

Semaglutide for weight management was initially available as a once-weekly injection. In June 2026, the MHRA also approved once-daily oral semaglutide (Wegovy® tablets), making this the first GLP-1 receptor agonist tablet licensed specifically for weight management in the UK.⁵

In practice, the same active drug may have different brands, formulations, doses, licensed indications, and NHS eligibility criteria depending on the condition being treated.

What does the clinical evidence show?

The evidence base for incretin therapies has expanded rapidly. While early studies focused largely on glycaemic control and weight loss, more recent trials have examined outcomes that matter directly to patients, including cardiovascular events, progression of kidney disease, heart failure, and complications of obesity.

Weight loss

The STEP and SURMOUNT trial programmes established the effectiveness of semaglutide and tirzepatide for weight management.

• In STEP 1, adults with overweight or obesity without diabetes receiving semaglutide 2.4 mg weekly lost an average of 14.9% of their initial body weight over 68 weeks, compared with 2.4% with placebo.⁶

• In SURMOUNT-1, weight loss with tirzepatide was dose-dependent, reaching an average of 20.9% with the 15 mg dose at 72 weeks, compared with 3.1% with placebo.⁷

More recently, the OASIS 4 trial demonstrated that clinically significant weight loss can also be achieved with oral semaglutide. Adults without diabetes receiving oral semaglutide 25 mg lost an average of 13.6% of their body weight at 64 weeks, compared with 2.2% with placebo.⁸

These are average figures, and individual responses vary considerably. Importantly, medication was not studied in isolation: participants in all three trials received structured lifestyle support alongside treatment, including dietary and physical activity interventions. The weight-loss outcomes should therefore be considered in this context.

Beyond weight loss

Perhaps more important than the amount of weight lost is the growing evidence that incretin therapies can improve clinically meaningful disease outcomes.

Cardiovascular disease

The SELECT trial stood out because it looked at cardiovascular outcomes in patients with overweight or obesity who did not have diabetes.

Key findings included:

• More than 17,000 adults aged 45 years or older with established cardiovascular disease and a BMI of at least 27 kg/m² were randomised to semaglutide 2.4 mg or placebo.

• Major adverse cardiovascular events occurred in 6.5% of the semaglutide group compared with 8.0% receiving placebo, representing a 20% relative risk reduction.

This demonstration that cardiovascular benefit was not confined to people with diabetes has led to significant changes in clinical practice.

Since May 2026, NICE has recommended semaglutide (Wegovy®), alongside a reduced-calorie diet and increased physical activity, as an option to reduce major adverse cardiovascular events in adults with established cardiovascular disease and a BMI of at least 27 kg/m².¹⁴

Kidney disease and heart failure

The FLOW trial extended the evidence into chronic kidney disease.¹⁰

Key findings included:

• In people with type 2 diabetes and CKD, subcutaneous semaglutide 1.0mg weekly reduced the risk of onset of renal failure.

• There was at least a 50% reduction in the eGFR from baseline, or death from cardiovascular or kidney related or cardiovascular causes by 24% compared with placebo.

Evidence has also emerged in heart failure associated with obesity in the SUMMIT trial.¹¹

Key findings included:

• People with obesity and heart failure with preserved ejection fraction (HFpEF) treated with tirzepatide had a lower risk of cardiovascular death or worsening heart failure than those receiving placebo.

• There were also improvements in symptoms and health-related quality of life.

Whilst this hasn’t been translated into a change in management guidance in the UK as yet, it further demonstrates the potential benefits of incretin therapies beyond their currently approved uses.

Obstructive sleep apnoea and metabolic liver disease

Evidence is also emerging in the SURMOUNT-OSA trial for the use of incretin therapies in obstructive sleep apnoea.¹²

Key findings included:

• Tirzepatide substantially reduced the severity of moderate-to-severe obstructive sleep apnoea in adults with obesity, both in people using positive airway pressure therapy and those who were not.

Whilst the use of tirzepatide as a specific treatment for obstructive sleep apnoea is not currently being advised, this knowledge may help guide individualised prescribing decisions when incretin therapies are being utilised with other primary end goals.

The ESSENCE trial has similarly strengthened the evidence in metabolic liver disease.¹³

Key findings included:

• Among people with metabolic dysfunction-associated steatohepatitis (MASH) and moderate or advanced fibrosis, semaglutide increased the likelihood of resolution of steatohepatitis without worsening fibrosis.

• Improvement in fibrosis without worsening steatohepatitis was also more common with semaglutide than placebo.

These findings have already translated into regulatory change in the UK, with the MHRA approving injectable semaglutide (Wegovy®) in July 2026 for the treatment of MASH in adults with moderate-to-advanced liver fibrosis.¹⁵

Taken together, these trials are changing how incretin therapies are viewed: not simply as treatments for glucose lowering or weight loss, but as therapies that may modify the course of obesity-related disease.

Practical considerations

Whether incretin therapy is initiated within primary care, a specialist NHS service, or by a private provider, clinicians are increasingly likely to encounter patients taking these medications.

It is important to distinguish marketing authorisation from NHS availability. A medicine may be licensed by the MHRA without being recommended or routinely funded for the same indication within the NHS. NICE eligibility criteria may also be narrower than the licensed indication, and local implementation pathways can vary.

Clinicians should therefore refer to current NICE guidance and local prescribing pathways when considering NHS treatment.

Dosing and dose escalation

Gastrointestinal adverse effects are common, particularly during treatment initiation and dose escalation. Semaglutide and tirzepatide are therefore started at a low dose and increased gradually.

The table below summarises the dosing for semaglutide and tirzepatide, as they compromise the bulk of incretin therapy in the UK. Other GLP-1 receptor agonists remain in use, particularly liraglutide and dulaglutide in type 2 diabetes; clinicians initiating or adjusting these should refer to the relevant SmPC and NICE guidance.

Dose escalation should not be regarded as a race to the maximum dose. If adverse effects are troublesome, escalation may need to be delayed or the dose reduced, depending on the medication and clinical circumstances.

Oral Wegovy® has specific administration requirements. It should be taken on an empty stomach following a fasting period of at least six hours, swallowed whole with a small amount of water (up to 120 mL), followed by a wait of at least 30 minutes before eating, drinking, or taking other oral medicines.⁽⁵⁾ Oral and injectable semaglutide should not be considered milligram-for-milligram equivalents.

Adverse effects and safety

• Gastrointestinal effects - nausea, vomiting, diarrhoea, constipation, and dyspepsia are the most common adverse effects. These are often most pronounced during treatment initiation or dose escalation and may improve over time.

  • Managing gastrointestinal symptoms - slower dose titration, smaller meals, avoiding large or rich meals, and maintaining adequate hydration may help reduce symptoms.

  • Persistent or severe symptoms - these should prompt clinical review to consider dose adjustment and exclude alternative causes. Vomiting or diarrhoea can cause dehydration and contribute to acute kidney injury, particularly in people taking medicines that affect renal function or fluid balance.

• Acute pancreatitis - this is uncommon but potentially serious. The MHRA strengthened warnings in January 2026 following rare reports of severe acute pancreatitis. Severe, persistent abdominal pain, particularly when radiating to the back, requires urgent medical assessment. Treatment should be stopped if pancreatitis is suspected.¹⁶

• Gallbladder disease - cholelithiasis and cholecystitis can occur, particularly in the context of substantial or rapid weight loss.¹⁷¹⁸

• Visual adverse effects - non-arteritic anterior ischaemic optic neuropathy (NAION) is a very rare adverse effect associated with semaglutide. Sudden visual loss or rapidly worsening eyesight requires urgent assessment. Semaglutide should be stopped if NAION is confirmed.¹⁹

Other practical considerations

• Hypoglycaemia - the risk of hypoglycaemia with incretin therapy alone is low but increases when used alongside insulin or a sulfonylurea. These medicines may therefore require review as glycaemic control improves.

• Pregnancy - incretin therapies should not be used during pregnancy or while trying to conceive. Semaglutide should be discontinued at least 2 months before a planned pregnancy and tirzepatide at least 1 month

  beforehand.¹⁹

• Contraception and HRT - tirzepatide may reduce the effectiveness of oral hormonal contraception and oral progestogens used as part of hormone replacement therapy during treatment initiation and dose escalation. Current MHRA guidance should be followed when counselling patients who may use these medicines.¹⁹

• Anaesthesia and sedation - delayed gastric emptying may have implications for procedures requiring sedation or anaesthesia. Patients should ensure their peri-operative team is aware that they are taking an incretin therapy.¹⁹

• Monitoring - monitoring should extend beyond weight alone and include treatment goals, nutritional intake, adverse effects, glycaemic control where relevant, and changes in obesity-related conditions.

• Preserving muscle mass and function - adequate protein intake and resistance-based physical activity are important components of weight management and may help preserve muscle mass and physical function during significant weight loss.

Future developments in incretin therapy

The incretin field continues to evolve rapidly. Developments are likely to include easier routes of administration, medications targeting multiple hormone pathways and a growing focus on treating obesity-related disease rather than weight alone.

Orforglipron is a non-peptide oral GLP-1 receptor agonist that can be taken without the fasting requirements associated with oral semaglutide. In the phase 3 ATTAIN-1 trial it produced clinically significant weight loss in adults with obesity, although orforglipron is not currently licensed in the UK.²⁰

Researchers are also investigating drugs that target several metabolic pathways simultaneously. Retatrutide is a triple agonist acting at the GIP, GLP-1 and glucagon receptors. It remains investigational and is not currently approved by the MHRA, but has exciting potential uses in managing patients with MASLD.²¹

Perhaps the more important change, however, is in how these medications are being used. Evidence from cardiovascular, renal, heart failure, sleep apnoea, and liver disease trials is shifting the focus away from weight loss as an isolated outcome and towards prevention and treatment of obesity-related disease.

For clinicians, this means incretin therapies are likely to become relevant across an increasingly broad range of clinical settings. As indications and NHS access continue to evolve, familiarity with their benefits, limitations and safety considerations will become an increasingly important part of everyday clinical practice.