GLP-1 (glucagon-like peptide-1) receptor agonists are injectable medicines used for the treatment of type 2 diabetes and, more recently, for weight management. They are named with the suffix -tide, and include exenatide, liraglutide, dulaglutide, semaglutide and tirzepatide. In type 2 diabetes, postprandial GLP-1 secretion may be reduced, leading to an impaired insulin response. In addition, glucagon levels are often inappropriately elevated. GLP-1 agonists reduce appetite, which contributes to their role in weight management. The exact mechanism is not fully understood, but it may involve slowed gastric emptying and increased satiety through effects on central appetite centres in the brain. Mechanism of Action Incretins hormones like GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are released throughout the day, increasing at mealtimes. Synthetic GLP-1 and GIP agonists bind to their respective receptors and elicit the same response as the endogenous hormones would. Synthetic GLP-1 agonists activate GLP-1 receptors in the pancreas, increasing cyclic adenosine monophosphate (cAMP). Tirzepatide is unique as a dual GIP and GLP-1 receptor agonist. Effects of GLP-1 and GIP receptor agonists include: Stimulating insulin secretion in response to food (glucose-dependent) Reducing inappropriate glucagon release, lowering hepatic glucose output (GLP-1 enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion) When blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. During hypoglycaemia, insulin secretion is reduced and glucagon secretion is not inhibited. Slowing gastric emptying and reducing appetite Decreasing postprandial and fasting glucose, as well as serum triglycerides By TeachMeSeries Ltd (2026) Fig 1: Effects of GLP-1 agonists Pharmacokinetics Synthetic GLP-1 agonists are resistant to degradation by DPP-4, giving them a longer half-life than endogenous GLP-1. Some GLP-1 agonists only require once-weekly dosing. The following table describes GLP-1 receptor agonists, their dosing frequency and key pharmacokinetic parameters: Drug name Route, frequency Key PK parameters Exenatide (Bydureon prolonged release) SC Once weekly Minimal effective concentrations reached in 2 weeks; steady state at 8 weeks; renally excreted Dulaglutide (Trulicity) SC Once weekly Tmax 48 h; steady state 2–4 weeks; T½ 5 days Liraglutide (Victoza) SC Once daily Tmax 8–12 h; T½ 13 h; elimination route not organ-specific Semaglutide (ozempic) SC Once weekly Tmax 1–3 days; T½ 7 days; steady state 4–5 weeks; two-thirds excreted via urine, one-third via faeces; >99% protein-bound Tirzepatide (mounjaro) SC Once weekly Tmax 8–72 h; steady state 4 weeks; T½ 5 days; metabolites excreted via urine and faeces Cautions and Contraindications Cautions Contraindications History of pancreatitis Semaglutide: hepatic impairment and severe heart failure Liraglutide: thyroid disease (thyroid adverse events have been reported) Semaglutide and tirzepatide: retinopathy Tirzepatide: severe gastrointestinal disease Elderly: risk of weight loss Rapid weight loss (>1.5 kg/week): risk of cholelithiasis Risk of residual gastric content before anaesthesia (delayed gastric emptying) due to risk of pulmonary aspiration Ketoacidosis Pancreatitis Exenatide prolonged release: eGFR <50ml/min Semaglutide and dulaglutide: ESRD Liraglutide: severe hepatic impairment, eGFR <30ml/min and severe heart failure Exenatide, liraglutide, dulaglutide: severe gastrointestinal disease i.e. gastroparesis, IBD (due to common association with gastrointestinal adverse reactions) All: Not for IV or IM injection Adverse Effects Acute pancreatitis (rare) Injection site reactions Gastrointestinal disturbances (nausea, vomiting, diarrhoea → dehydration and possible renal impairment) Increase in pancreatic enzymes: lipase and amylase (dulaglutide, tirzepatide and semaglutide) Cholecystitis and cholelithiasis Delayed gastric emptying (semaglutide, exenatide, dulaglutide, tirzepatide (diminishes over time)) Increased heart rate Diabetic retinopathy complications (semaglutide, particularly in insulin-treated patients with known diabetic retinopathy) Interactions GLP-1 receptor agonists do not interact via cytochrome P450, but delayed gastric emptying may alter drug absorption. Dulaglutide, semaglutide, tirzepatide: potential for altered medicinal product exposure (↑Tmax, ↓Cmax) when administered with oral medicinal products with rapid gastrointestinal absorption or prolonged release, due to delayed gastric emptying. Drugs given concomitantly with narrow therapeutic windows should ensure monitoring is undertaken, especially at initiation of GLP-1 agonists when the effect is most pronounced. Warfarin: exenatide may increase the anticoagulant effect of warfarin. Monitor INR when warfarin is co-administered with GLP-1 analogues. Tirzepatide and oral contraceptives in obesity: switch to a non-oral contraceptive or barrier method for 4 weeks after initiation or dose escalation. Other interactions: Enhanced glucose-lowering effect: alcohol, anabolic steroids, MAOIs, testosterone. Reduced glucose-lowering effect: corticosteroids, diuretics, oestrogens, progestogens. Beta-blockers may mask symptoms of hypoglycaemia (e.g., tremor). References Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus – UpToDate accessed 5/11/24 GLP-1 receptor agonists | Prescribing information | Diabetes – type 2 | CKS | NICE Bydureon 2 mg prolonged release suspension for injection in pre-filled pen (BCise) – Summary of Product Characteristics (SmPC) – (emc) Victoza 6 mg/ml solution for injection in pre-filled pen – Summary of Product Characteristics (SmPC) – (emc) TRULICITY 1.5 mg solution for injection in pre-filled pen – Summary of Product Characteristics (SmPC) – (emc) Ozempic 0.25 mg solution for injection in pre-filled pen – Summary of Product Characteristics (SmPC) – (emc) Mounjaro KwikPen 10mg solution for injection in pre-filled pen – Summary of Product Characteristics (SmPC) – (emc) Do you think you’re ready? Take the quiz below Pro Feature - Quiz GLP-1 Receptor Agonists Question 1 of 3 Submitting... 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