Lixisenatide

Lixisenatide is a short-acting once-daily subcutaneous GLP-1 receptor agonist taken before the first meal of the day. It mainly lowers post-meal glucose, reducing HbA1c by about 0.5 to 1%, and is neutral for cardiovascular events. It is used alone with metformin or as a partner to basal insulin. Marketing has been withdrawn in several countries, so availability is limited.

Classification. GLP-1 receptor agonist; exendin-4 analogue with a C-terminal lysine tail. Pens of 10 and 20 micrograms; a fixed-dose combination with insulin glargine exists.

Mechanism. Activates the GLP-1 receptor, increasing glucose-dependent insulin release, suppressing glucagon and slowing gastric emptying, with a marked effect on post-meal glucose.

Pharmacodynamics. Delayed gastric emptying blunts post-meal glucose rise after the injected meal and has less effect on fasting glucose. Hypoglycaemia risk is low alone.

Pharmacokinetics. Peak 1 to 3.5 hours; half-life about 3 hours. Cleared by glomerular filtration and proteolytic degradation, so exposure rises as kidney function falls.

Type 2 diabetes, adults.

• Start 10 micrograms subcutaneously once daily for 14 days, within 1 hour before the first meal of the day.
• Then 20 micrograms once daily (maintenance and maximum).
• Always give before the same meal each day. If a dose is missed, give it within 1 hour before the next meal.

Combination with basal insulin. Adds to basal insulin with or without metformin. Reduce the basal insulin dose by about 20% when starting if fasting glucose is near target or HbA1c is under 8% (64 mmol/mol). Reduce the sulphonylurea dose when adding it. Do not combine with a DPP-4 inhibitor or another GLP-1 receptor agonist.

Adjustments.

• Kidney: eGFR 60 or more, no change; 30 to 59, no change but monitor; 15 to 29, use with caution because experience is limited; under 15 or end-stage kidney disease, avoid.
• Liver: no change.
• Older adults: no change; limited data over 75 years.
• Weight: no weight-based dosing.
• Children: not licensed.

Contraindications. Hypersensitivity; eGFR under 15 or end-stage kidney disease; gastroparesis or severe gastrointestinal disease.

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Hypersensitivity including anaphylaxis and angioedema; antibody formation.
• Hypoglycaemia with sulphonylureas or insulin.
• Acute kidney injury from dehydration.
• No thyroid C-cell boxed warning in labels, though thyroid findings in rodents exist at high doses.

Common adverse effects. Nausea, vomiting, diarrhoea, headache, dizziness; mostly early in treatment.

Major interactions.

• Insulin and sulphonylureas: hypoglycaemia.
• Delayed gastric emptying may reduce absorption of oral medicines needing rapid onset; take antibiotics and oral contraceptives at least 1 hour before lixisenatide, and gastro-resistant tablets at least 1 hour before or 4 hours after it.
• Warfarin: monitor INR after starting.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid.
• Children: not licensed.
• Older adults: dehydration risk.
• Kidney and liver impairment: caution at eGFR 15 to 29; avoid under 15; no liver adjustment.
• East Africa: availability is very limited; liraglutide, dulaglutide or semaglutide are usual alternatives where GLP-1 therapy is available. Pens need a fridge (2 to 8 degrees Celsius) before first use and keep at room temperature up to 30 degrees Celsius for 14 days after.

Administration. Inject subcutaneously into the abdomen, thigh or upper arm within 1 hour before the first meal of the day; rotate sites. Do not mix with insulin in the same syringe.

Perioperative. Tell the anaesthetist; delayed gastric emptying raises aspiration risk, and the short half-life allows the dose to be omitted on the day of the procedure.

Baseline. HbA1c, eGFR, weight, history of pancreatitis and gallstones.

Monitoring.

• HbA1c at 3 and 6 months, then every 6 months.
• Post-meal capillary glucose during titration.
• eGFR when vomiting or diarrhoea occur and every 6 months when eGFR is under 60.
• Weight and gastrointestinal symptoms at each visit.

Stopping thresholds. Stop with suspected pancreatitis, severe hypersensitivity, eGFR under 15, pregnancy, or inadequate response (HbA1c reduction under 0.5% at 6 months).

Referral and escalation. Admit severe abdominal pain with vomiting for pancreatitis assessment, and anaphylaxis or acute kidney injury for urgent care.