Exenatide

Exenatide is a GLP-1 receptor agonist available as a twice-daily subcutaneous injection and as a once-weekly extended-release injection. Both lower HbA1c by about 0.8 to 1.6%, and the weekly form gives the larger effect. It is cleared by the kidney, so it is avoided in advanced kidney disease. The weekly form carries a thyroid C-cell tumour warning.

Classification. GLP-1 receptor agonist; synthetic form of exendin-4 from the Gila monster. Twice-daily pens of 5 and 10 micrograms a dose; once-weekly extended-release 2 mg pen or kit.

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

Pharmacodynamics. The twice-daily form mainly lowers post-meal glucose through slowed gastric emptying. The weekly form gives continuous receptor activation with a larger effect on fasting glucose.

Pharmacokinetics. Twice-daily form: peak about 2 hours, half-life about 2.4 hours, cleared mainly by glomerular filtration and proteolysis. Weekly form: released from polymer microspheres, steady state after about 7 weeks.

Type 2 diabetes, adults, twice-daily form.

• Start 5 micrograms subcutaneously twice daily, within 60 minutes before the morning and evening main meals (at least 6 hours apart).
• Increase to 10 micrograms twice daily after 1 month if tolerated and needed.
• Maximum 10 micrograms twice daily. Do not give after a meal. If a dose is missed, skip it and continue as scheduled.

Type 2 diabetes, adults, once-weekly extended-release form.

• 2 mg subcutaneously once weekly on the same day, at any time, with or without food.
• Maximum 2 mg weekly. No titration. If a dose is missed, give it as soon as noticed if the next dose is at least 3 days away; otherwise skip it.

Type 2 diabetes, children aged 10 years and over (weekly form, where licensed).

• 2 mg subcutaneously once weekly.

Combination use. Adds to metformin, sulphonylureas, pioglitazone, SGLT2 inhibitors and basal insulin. Reduce the sulphonylurea dose when adding it; reduce insulin if hypoglycaemia occurs. Do not combine with a DPP-4 inhibitor or another GLP-1 receptor agonist. The twice-daily form is not combined with prandial insulin.

Adjustments.

• Kidney: eGFR 60 or more, no change. eGFR 30 to 59, use with caution; for the twice-daily form do not raise from 5 to 10 micrograms without close monitoring; the weekly form is not advised when eGFR is under 45 in some labels. eGFR under 30 or end-stage kidney disease: avoid.
• Liver: no change.
• Older adults: no change; caution over 75 years for the twice-daily form.
• Weight: no weight-based dosing in adults.

Boxed-warning-level risk (weekly form). 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. The twice-daily form does not carry the boxed warning in most labels, but the same contraindications are sensible.

Contraindications. Hypersensitivity; medullary thyroid carcinoma history; multiple endocrine neoplasia type 2; severe renal impairment (eGFR under 30) or end-stage kidney disease; severe gastrointestinal disease including gastroparesis (twice-daily form).

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Acute kidney injury, including cases needing dialysis, usually with dehydration.
• Injection site nodules with the weekly form; rarely abscess or necrosis.
• Hypersensitivity including angioedema; antibody formation that can blunt effect.
• Hypoglycaemia with sulphonylureas or insulin.
• Bleeding with warfarin: raised INR reported.

Common adverse effects. Nausea (up to 40% early), vomiting, diarrhoea, headache, dizziness, injection site reactions.

Major interactions.

• Insulin and sulphonylureas: hypoglycaemia.
• Warfarin: monitor INR after starting.
• Delayed gastric emptying may reduce the absorption of oral medicines needing high peak levels; take antibiotics and oral contraceptives at least 1 hour before the twice-daily dose.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid.
• Children: weekly form licensed from 10 years in some markets.
• Older adults: dehydration risk.
• Kidney and liver impairment: no change in eGFR 60 or more; caution at 30 to 59; avoid under 30; no liver adjustment.
• East Africa: pens need a fridge (2 to 8 degrees Celsius) before first use; the twice-daily pen may be kept at room temperature up to 30 degrees Celsius for 30 days after first use. Supply is uncertain, and the weekly form is rarely stocked.

Administration. Inject subcutaneously into the abdomen, thigh or upper arm; rotate sites. Weekly form: mix the microspheres and diluent thoroughly as the device directs, and inject immediately. Do not mix with insulin in the same syringe.

Perioperative. Tell the anaesthetist; delayed gastric emptying raises aspiration risk. Practice varies between withholding the dose and continuing with a clear-fluid diet before the procedure.

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

Monitoring.

• HbA1c at 3 and 6 months, then every 6 months.
• eGFR at baseline, and whenever vomiting or diarrhoea occur.
• Weight and gastrointestinal symptoms at each visit.
• Injection sites for nodules (weekly form).
• INR if on warfarin.

Stopping thresholds. Stop with suspected pancreatitis, thyroid mass with suspicion of medullary carcinoma, severe hypersensitivity, acute kidney injury attributable to it, eGFR under 30, pregnancy, or inadequate response (HbA1c reduction under 1% at 6 months).

Referral and escalation. Admit severe abdominal pain with vomiting for pancreatitis assessment, and acute kidney injury. Refer a neck mass for thyroid ultrasound and calcitonin.