Liraglutide

Liraglutide is a once-daily subcutaneous GLP-1 receptor agonist. At up to 1.8 mg it lowers HbA1c by about 1 to 1.5% and body weight by 2 to 3 kg, and it reduces major cardiovascular events in type 2 diabetes with established cardiovascular disease. At 3 mg it is used for weight management, with typical loss of about 5 to 8% of body weight. It carries a thyroid C-cell tumour warning.

Classification. GLP-1 receptor agonist, human GLP-1 analogue with a fatty acid chain that binds albumin. Pens delivering 0.6, 1.2 and 1.8 mg (diabetes presentation) or up to 3 mg (weight presentation); a fixed-dose combination with insulin degludec exists.

Mechanism. Activates the GLP-1 receptor, increasing glucose-dependent insulin release, suppressing glucagon, slowing gastric emptying and reducing appetite through central appetite circuits.

Pharmacodynamics. Lowers fasting and post-meal glucose with low hypoglycaemia risk alone. Slows gastric emptying, an effect that fades with continued use, and raises resting heart rate by 2 to 3 beats a minute.

Pharmacokinetics. Subcutaneous bioavailability about 55%; peak 8 to 12 hours; over 98% albumin bound. Degraded slowly by proteases, with no single organ of elimination. Half-life about 13 hours; steady state is reached in 2 to 3 days.

Type 2 diabetes, adults.

• Start 0.6 mg subcutaneously once daily for at least 1 week (a tolerability dose that does not lower glucose enough).
• Increase to 1.2 mg once daily; after at least 1 more week increase to 1.8 mg if needed.
• Maximum 1.8 mg daily. No loading dose.

Type 2 diabetes, children aged 10 years and over.

• Start 0.6 mg once daily; after at least 1 week increase to 1.2 mg, then to 1.8 mg if needed after at least 1 more week.

Weight management (adults with obesity, or overweight with weight-related disease; and adolescents from 12 years with obesity).

• Start 0.6 mg subcutaneously once daily in week 1, then raise by 0.6 mg weekly: 1.2 mg, 1.8 mg, 2.4 mg, then 3 mg once daily from week 5.
• If an increase is not tolerated, wait 1 more week before trying again.
• Stop if weight loss is under 4% of starting weight after 12 weeks at the 3 mg dose.

Combination use. Adds to metformin, sulphonylureas, SGLT2 inhibitors, pioglitazone and basal insulin. Reduce the sulphonylurea or insulin dose when adding liraglutide. Do not combine with a DPP-4 inhibitor or another GLP-1 receptor agonist.

Missed doses. If 3 days or more are missed, restart at 0.6 mg and re-titrate. If under 3 days, take the next dose as usual.

Adjustments.

• Kidney: no change in mild to moderate impairment; limited data in severe impairment and end-stage kidney disease; use with caution and watch fluid status.
• Liver: no change in mild impairment; limited data in moderate and none in severe impairment.
• Older adults: no change; start cautiously.
• Weight: no weight-based dosing in adults.

Boxed-warning-level risk. Thyroid C-cell tumours occurred in rodents. Contraindicated with a personal or family history of medullary thyroid carcinoma and in multiple endocrine neoplasia type 2. Advise patients to report a neck mass, dysphagia, dyspnoea or persistent hoarseness.

Contraindications. Hypersensitivity; medullary thyroid carcinoma history; multiple endocrine neoplasia type 2; pregnancy (weight management presentation).

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Gallbladder disease: cholelithiasis and cholecystitis, more with rapid weight loss.
• Acute kidney injury from dehydration with vomiting and diarrhoea.
• Hypoglycaemia with sulphonylureas or insulin.
• Heart rate rise; diabetic retinopathy review during rapid HbA1c fall; mood changes and suicidal thoughts reported with the weight presentation.
• Delayed gastric emptying: aspiration risk during sedation or anaesthesia.

Common adverse effects. Nausea (about 20%), vomiting, diarrhoea, constipation, dyspepsia, injection site reactions; mostly in the first weeks and reduced by slow titration.

Major interactions.

• Insulin and sulphonylureas: hypoglycaemia.
• Delayed gastric emptying may alter the absorption of oral medicines; monitor INR with warfarin when starting.
• Do not combine with DPP-4 inhibitors or other GLP-1 receptor agonists.

Special groups.

• Pregnancy: avoid; stop on confirmation of pregnancy and use insulin.
• Breastfeeding: avoid; no human data.
• Children: licensed from 10 years for type 2 diabetes and from 12 years for obesity in some markets.
• Older adults: dehydration and weight loss in frail adults.
• Kidney and liver impairment: no change in mild to moderate kidney impairment, caution in severe impairment; limited data in moderate liver impairment and none in severe.
• East Africa: unopened pens need a fridge (2 to 8 degrees Celsius) and must not freeze; in-use pens keep at room temperature up to 30 degrees Celsius for up to 30 days, so power cuts and heat need planning. Cost and supply restrict use; prioritise those with established cardiovascular disease or obesity with diabetes.

Administration. Inject subcutaneously into the abdomen, thigh or upper arm once daily at any time, with or without food; rotate sites. Pen needles are single-use. Do not mix with insulin in the same syringe.

Perioperative. Tell the anaesthetist; delayed gastric emptying can leave food in the stomach after fasting. Practice varies between withholding doses before the procedure and continuing with a clear-fluid diet beforehand.

Baseline. HbA1c, eGFR, weight, history of pancreatitis, gallstones and thyroid disease, retinal screening result.

Monitoring.

• HbA1c at 3 and 6 months, then every 6 months.
• Weight and gastrointestinal symptoms at each visit.
• eGFR when vomiting or diarrhoea occur.
• Retinal screening within the usual interval; earlier if vision changes.
• Capillary glucose when on sulphonylurea or insulin.

Stopping thresholds. Stop with suspected pancreatitis, thyroid mass with suspicion of medullary carcinoma, severe hypersensitivity, pregnancy, or inadequate response (HbA1c reduction under 1% or weight loss under 3% at 6 months for diabetes use).

Referral and escalation. Admit severe abdominal pain with vomiting for pancreatitis assessment; assess biliary symptoms by ultrasound. Refer a neck mass for thyroid ultrasound and calcitonin.