The history of incretin mimetics traces a remarkable journey from early 20th-century observations of the 'incretin effect' to the development of a transformative class of medicines for type 2 diabetes. These GLP-1 receptor agonists, which mimic naturally occurring gut hormones, have evolved from twice-daily injections to once-weekly formulations and, most recently, oral tablets. Their story encompasses serendipitous discoveries—including a peptide isolated from Gila monster venom—rigorous clinical trials demonstrating cardiovascular benefits, and regulatory milestones that have reshaped UK diabetes management. Understanding this history provides valuable context for their current role in clinical practice and ongoing evolution.

What Are Incretin Mimetics and How Do They Work?

Incretin mimetics, also known as GLP-1 receptor agonists or glucagon-like peptide-1 analogues, represent a class of glucose-lowering medicines used primarily in the management of type 2 diabetes mellitus. These agents mimic the action of naturally occurring incretin hormones, particularly GLP-1, which are released from the intestine in response to food intake.

The mechanism of action centres on several complementary pathways. GLP-1 receptor agonists bind to and activate GLP-1 receptors on pancreatic beta cells, stimulating glucose-dependent insulin secretion. Crucially, this effect is glucose-dependent, meaning insulin release occurs only when blood glucose levels are elevated. When used alone, GLP-1 receptor agonists have a low intrinsic risk of hypoglycaemia. However, when combined with insulin or sulfonylureas, the risk of hypoglycaemia increases; dose reduction of these agents should be considered according to the Summary of Product Characteristics (SmPC) and NICE guidance. Additionally, these medicines suppress glucagon secretion from pancreatic alpha cells, further contributing to glycaemic control.

Beyond pancreatic effects, incretin mimetics slow gastric emptying, which moderates the postprandial rise in blood glucose and promotes satiety. This mechanism contributes to weight reduction, a beneficial effect observed in many patients. Central nervous system effects include reduced appetite and food intake through actions on hypothalamic centres regulating energy balance.

Cardiovascular benefits have emerged as an important feature for certain agents in this class. Liraglutide (LEADER trial), semaglutide subcutaneous (SUSTAIN-6), and dulaglutide (REWIND) have demonstrated reductions in major adverse cardiovascular events in cardiovascular outcome trials, leading to their recommendation in patients with type 2 diabetes and established cardiovascular disease. The precise mechanisms underlying these cardioprotective effects remain under investigation but may involve improvements in endothelial function, blood pressure reduction, and favourable effects on lipid metabolism.

Important safety considerations include the risk of acute pancreatitis (patients should be advised to seek immediate medical attention if they experience severe, persistent abdominal pain), gallbladder disease, and acute kidney injury secondary to dehydration from severe gastrointestinal adverse effects. With semaglutide, a signal for early worsening of diabetic retinopathy was observed in SUSTAIN-6; patients with pre-existing retinopathy or those experiencing rapid improvement in glycaemic control should be monitored appropriately. Rodent studies have shown thyroid C-cell tumours; whilst the relevance to humans is unknown, patients should be advised to report symptoms of a thyroid mass (e.g., persistent lump in the neck, difficulty swallowing, persistent hoarseness).

Discovery and Early Development of Incretin-Based Therapies

The story of incretin mimetics begins with observations made over a century ago. In the early 1900s, researchers noted that oral glucose administration produced a greater insulin response than intravenous glucose, suggesting the existence of intestinal factors that enhanced insulin secretion. This phenomenon, termed the 'incretin effect', remained poorly understood for decades.

The breakthrough came in the 1970s and 1980s when two key incretin hormones were identified: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Researchers discovered that these peptides were rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), limiting their therapeutic potential in their native form. This understanding prompted two parallel development strategies: creating DPP-4-resistant GLP-1 analogues and developing DPP-4 inhibitors. It is important to note that in UK clinical practice, GLP-1 receptor agonists should not be used in combination with DPP-4 inhibitors, as this is ineffective and duplicative.

A pivotal moment occurred in the 1990s when scientists studying the Gila monster (Heloderma suspectum), a venomous lizard native to the southwestern United States, isolated a peptide called exendin-4 from its saliva. This compound shared approximately 53% amino acid sequence homology with human GLP-1 but demonstrated resistance to DPP-4 degradation and a longer half-life.

Exenatide, a synthetic version of exendin-4, became the first GLP-1 receptor agonist to enter clinical development in the late 1990s. Early phase trials demonstrated promising glucose-lowering effects alongside unexpected weight loss, generating considerable interest in this novel therapeutic approach. The pharmaceutical industry recognised the potential of incretin-based therapies, leading to substantial investment in developing both short-acting and long-acting formulations, as well as exploring modifications to native human GLP-1 sequences.

Evolution of GLP-1 Receptor Agonists in Clinical Practice

The clinical landscape of GLP-1 receptor agonists has evolved dramatically since the first agent reached the market. Exenatide (Byetta) was approved in the United States in 2005 and subsequently in Europe, requiring twice-daily subcutaneous injection. Whilst effective, the frequent dosing schedule and gastrointestinal adverse effects—particularly nausea and vomiting—presented challenges for patient adherence.

The development of longer-acting formulations marked a significant advancement. Exenatide prolonged-release (Bydureon), utilising microsphere technology for once-weekly administration, received approval in 2011. Concurrently, liraglutide (Victoza), a once-daily GLP-1 analogue with 97% homology to human GLP-1, entered clinical practice in 2009, offering improved tolerability for many patients.

Subsequent years witnessed an expansion of the therapeutic class with agents offering progressively longer durations of action. Dulaglutide (Trulicity), approved in 2014, provided once-weekly dosing in a pre-filled pen device. Semaglutide (Ozempic), licensed in 2018, demonstrated superior glycaemic control and weight reduction compared with earlier agents, administered once weekly. The approval of oral semaglutide (Rybelsus) in 2020 represented a paradigm shift, offering the first oral GLP-1 receptor agonist. Oral semaglutide must be taken on an empty stomach with a small volume of water (up to half a glass, approximately 120 mL), and patients must wait at least 30 minutes before eating, drinking, or taking other oral medicines, as per the SmPC.

Clinical experience has refined understanding of optimal patient selection and management strategies. Common adverse effects include:

• Gastrointestinal symptoms: nausea, vomiting, diarrhoea (typically transient, improving with gradual dose titration). Severe gastrointestinal symptoms may lead to dehydration and acute kidney injury; patients should be advised to maintain adequate fluid intake and seek medical advice if symptoms are persistent or severe.

• Injection site reactions: erythema, pruritus (generally mild)

• Pancreatitis: patients should be counselled to report severe, persistent abdominal pain immediately; treatment should be discontinued if acute pancreatitis is suspected

• Gallbladder disease: increased risk reported; patients should be advised to seek medical attention if they develop symptoms such as sustained pain in the upper right abdomen

• Diabetic retinopathy: with semaglutide, early worsening of diabetic retinopathy has been observed, particularly in patients with pre-existing retinopathy or rapid improvement in glycaemic control; appropriate monitoring is advised

Hypoglycaemia risk is low when GLP-1 receptor agonists are used alone, but increases when combined with insulin or sulfonylureas. Dose reduction of insulin or sulfonylureas should be considered when initiating a GLP-1 receptor agonist, in accordance with the SmPC and NICE guidance.

Pregnancy and breastfeeding: GLP-1 receptor agonists are generally not recommended during pregnancy or breastfeeding. Women of childbearing potential should discontinue treatment if planning pregnancy, as per the SmPC.

Rodent studies have shown thyroid C-cell tumours with GLP-1 receptor agonists; the relevance to humans is unknown. Patients should be advised to report symptoms of a thyroid mass, such as a persistent lump in the neck, difficulty swallowing, or persistent hoarseness.

The evolution continues with ultra-long-acting agents and combination therapies currently in development, promising further improvements in efficacy and convenience.

Regulatory Milestones and UK Approval Timeline

The regulatory journey of incretin mimetics in the United Kingdom has been shaped by evaluations from both the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA), alongside health technology assessments by the National Institute for Health and Care Excellence (NICE).

Exenatide received European marketing authorisation in 2006, with NICE issuing guidance recommending its use as an option in specific patient populations with type 2 diabetes. Liraglutide gained EMA approval in 2009, with NICE guidance following in 2010, initially recommending it as an option for dual or triple therapy in patients meeting specific BMI and HbA1c criteria.

The once-weekly formulations represented important regulatory milestones. Exenatide prolonged-release received approval in 2011, whilst dulaglutide was licensed in 2015. NICE technology appraisals evolved to reflect accumulating evidence, providing recommendations for dulaglutide and liraglutide in dual and triple therapy regimens.

Semaglutide subcutaneous formulation received EMA approval in 2018, with NICE guidance (TA664, 2021) recommending it as an option for adults with type 2 diabetes. The oral formulation gained approval in 2020, with NICE guidance (TA693, 2021) following, representing the first oral GLP-1 receptor agonist available in the UK.

Regulatory scrutiny has extended beyond efficacy to safety monitoring. The MHRA has issued communications regarding potential risks, including pancreatitis, thyroid tumours, and gallbladder disease, requiring ongoing pharmacovigilance. Post-marketing surveillance continues to monitor long-term safety profiles. Healthcare professionals and patients are encouraged to report suspected adverse drug reactions via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or via the Yellow Card app).

Cardiovascular outcome trials have influenced regulatory perspectives significantly. Liraglutide (LEADER trial), semaglutide (SUSTAIN-6), and dulaglutide (REWIND) demonstrated cardiovascular benefits, leading to label updates reflecting these findings. This evidence has positioned certain GLP-1 receptor agonists with proven cardiovascular benefit as important treatment options in patients with type 2 diabetes and established cardiovascular disease, as reflected in NICE guidance.

Impact on Diabetes Management and Current Guidelines

The introduction of incretin mimetics has fundamentally transformed type 2 diabetes management in the UK, shifting therapeutic paradigms beyond glycaemic control alone. Current NICE guidelines (NG28, Type 2 diabetes in adults: management, updated 2022) reflect this evolution, recommending GLP-1 receptor agonists as important treatment options across various clinical scenarios.

Guideline recommendations position GLP-1 receptor agonists as options for:

• Dual therapy: combined with metformin when HbA1c targets are not achieved with metformin monotherapy, particularly in patients where weight loss would be beneficial

• Triple therapy: added to metformin plus another oral agent when glycaemic control remains inadequate

• Established cardiovascular disease: NICE NG28 prioritises SGLT2 inhibitors for people with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic heart failure, or chronic kidney disease. GLP-1 receptor agonists with proven cardiovascular benefit (liraglutide, semaglutide subcutaneous, or dulaglutide) should be considered when SGLT2 inhibitors are contraindicated or not tolerated, or when additional glucose-lowering or weight loss is a priority.

• Chronic kidney disease: SGLT2 inhibitors are prioritised for renoprotection in people with CKD. GLP-1 receptor agonists have shown secondary kidney benefits in cardiovascular outcome trials, and evidence continues to evolve, but they are not first-line for CKD alone.

The impact on clinical outcomes extends beyond glucose lowering. Meta-analyses demonstrate HbA1c reductions of 1.0–1.5% (11–16 mmol/mol), accompanied by weight loss averaging 2–5 kg, depending on the specific agent and dose. Cardiovascular outcome trials have shown 12–26% relative risk reductions in major adverse cardiovascular events with liraglutide, semaglutide subcutaneous, and dulaglutide, influencing treatment algorithms significantly.

Patient selection and continuation criteria require consideration of multiple factors. Healthcare professionals should discuss:

• Administration preferences: daily versus weekly injections, or oral formulation

• Tolerability: gradual dose titration to minimise gastrointestinal adverse effects

• NICE continuation criteria: NICE technology appraisals specify criteria for initiation and continuation, typically including review at 6 months with HbA1c and weight-loss thresholds; refer to NG28 and relevant technology appraisals for agent-specific guidance

• Safety monitoring: patients should report severe abdominal pain, symptoms of gallbladder disease, or signs of dehydration promptly; discontinuation is advised if pancreatitis is suspected. Patients with pre-existing diabetic retinopathy or rapid HbA1c reduction on semaglutide should be monitored appropriately.

• Combination therapy: GLP-1 receptor agonists should not be combined with DPP-4 inhibitors. When used with insulin or sulfonylureas, dose reduction of these agents should be considered to reduce hypoglycaemia risk.

Future directions include ongoing research into dual GLP-1/GIP receptor agonists, expanded indications for obesity management, and potential applications in non-alcoholic fatty liver disease. The incretin mimetic story continues to evolve, with these agents now firmly established as important therapies in contemporary diabetes management, offering benefits that extend well beyond their original glucose-lowering indication.

Reporting adverse reactions: Suspected adverse drug reactions should be reported via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk or via the Yellow Card app.

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