GLP 1 Receptor Agonists

GLP 1 receptor agonists are injectable (and one oral) peptide agents that lower glucose, reduce weight and, for selected members, reduce cardiovascular and kidney events. HbA1c falls by 1 to 1.8% and weight by 2 to 6 kg, with more in the higher dose semaglutide formulations.

Mechanism. Activation of the GLP-1 receptor increases glucose dependent insulin secretion, suppresses glucagon, slows gastric emptying and reduces appetite through hypothalamic and brainstem receptors. Hypoglycaemia is uncommon without insulin or a sulphonylurea.

Pharmacokinetics. Short acting agents (exenatide twice daily, lixisenatide) mainly lower postprandial glucose. Long acting agents (liraglutide, dulaglutide, semaglutide, exenatide extended release) lower fasting glucose and are dosed daily or weekly. They are given subcutaneously, apart from oral semaglutide.

Differences. Liraglutide, dulaglutide and semaglutide reduce major cardiovascular events in established atherosclerotic disease. Semaglutide also slows kidney disease progression and improves steatohepatitis. Exenatide is less potent and lacks a cardiovascular benefit.

• Type 2 diabetes with atherosclerotic disease, obesity, or kidney disease: a preferred add-on to metformin, independent of HbA1c.
• Type 2 diabetes on basal insulin: adding a GLP-1 receptor agonist reduces the insulin dose, weight gain and hypoglycaemia.
• Weight management: liraglutide 3 mg and semaglutide 2.4 mg weekly, with or without diabetes.
• Titration: hold at each step until nausea settles; do not escalate faster than every 4 weeks.
• Peri-procedural: delayed gastric emptying raises aspiration risk; practice varies, with weekly agents often held 1 week before elective anaesthesia or the patient placed on a liquid diet for 24 hours before. Follow local anaesthetic practice.

Special groups. Pregnancy: stop before conception (semaglutide at least 2 months before). Breastfeeding: avoid. Children: liraglutide and exenatide extended release are licensed from 10 years for type 2 diabetes. Older adults: titrate slowly, watch weight and sarcopenia. Kidney impairment: avoid exenatide at eGFR under 30 mL/min; others are used with attention to dehydration. Liver impairment: use with caution. Regional: unopened pens need refrigeration at 2 to 8 degrees C, which limits use where cold storage is unreliable.

Adverse effects. Nausea, vomiting and diarrhoea in 20 to 40%, usually settling in weeks. Acute pancreatitis (stop for severe abdominal pain), gallstones and cholecystitis, acute kidney injury from dehydration, injection site nodules, and worsening of established diabetic retinopathy with rapid HbA1c reduction.

Contraindications. Personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, previous pancreatitis attributed to the drug, and pregnancy.

Interactions. Delayed gastric emptying alters absorption of oral drugs, and warfarin INR needs closer checking. When added to a sulphonylurea or insulin, reduce those doses by 10 to 25% to avoid hypoglycaemia. Not combined with a DPP 4 inhibitor.

Monitoring. Weight, HbA1c every 3 months, eGFR with vomiting or diarrhoea, retinal screening before intensification in existing retinopathy, and abdominal symptoms.

Referral and escalation. Suspected pancreatitis, severe persistent vomiting with kidney injury, or new visual symptoms.