Dulaglutide

Dulaglutide is a once-weekly subcutaneous GLP-1 receptor agonist. It lowers HbA1c by about 1 to 1.8% and body weight by 1 to 5 kg depending on dose, and reduces major cardiovascular events (particularly stroke) in type 2 diabetes, including people without established cardiovascular disease. It needs no renal dose change and carries a thyroid C-cell tumour warning.

Classification. GLP-1 receptor agonist; two GLP-1 analogue chains linked to a modified human immunoglobulin Fc fragment. Single-dose pens of 0.75, 1.5, 3 and 4.5 mg.

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

Pharmacodynamics. Lowers fasting and post-meal glucose with low hypoglycaemia risk alone. Raises resting heart rate by 2 to 4 beats a minute and slows gastric emptying early in treatment.

Pharmacokinetics. Subcutaneous bioavailability about 47%; peak 24 to 72 hours; steady state after 2 to 4 weeks. Degraded by general protein catabolism, with no single organ of elimination. Half-life about 5 days.

Type 2 diabetes, adults.

• Start 0.75 mg subcutaneously once weekly.
• Increase to 1.5 mg weekly after at least 4 weeks if control is inadequate; then to 3 mg weekly after at least 4 more weeks, and to 4.5 mg weekly after at least 4 more weeks.
• Maximum 4.5 mg weekly. No loading dose.
• Some labels use 1.5 mg as the starting dose and stop at 1.5 mg; the higher steps are not licensed in all markets.

Type 2 diabetes, children aged 10 years and over.

• 0.75 mg weekly, increasing to 1.5 mg weekly after at least 4 weeks if needed.

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

Missed doses. Give as soon as possible if the next dose is at least 3 days (72 hours) away; otherwise skip it and keep the usual day.

Adjustments.

• Kidney: no change at any eGFR; limited data in end-stage kidney disease, so watch fluid status.
• Liver: no change.
• Older adults: no change.
• 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.

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Gallbladder disease: cholelithiasis and cholecystitis.
• Acute kidney injury from dehydration with vomiting and diarrhoea.
• Hypoglycaemia with sulphonylureas or insulin.
• Hypersensitivity including angioedema.
• Diabetic retinopathy complications with rapid HbA1c fall.
• Delayed gastric emptying: aspiration risk during sedation or anaesthesia.

Common adverse effects. Nausea, vomiting, diarrhoea, abdominal pain, reduced appetite, dyspepsia; mostly during the first weeks and after each dose step.

Major interactions.

• Insulin and sulphonylureas: hypoglycaemia.
• Delayed gastric emptying may alter 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 and use insulin.
• Breastfeeding: avoid; no human data.
• Children: licensed from 10 years for type 2 diabetes.
• Older adults: dehydration risk with gastrointestinal effects.
• Kidney and liver impairment: no dose change; watch hydration.
• East Africa: pens need a fridge (2 to 8 degrees Celsius) and must not freeze; a pen may stay at room temperature up to 30 degrees Celsius for up to 14 days. 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 weekly on the same day, at any time, with or without food; rotate sites. The pen is single-dose with a hidden needle. The day can be changed if the previous dose was at least 3 days earlier.

Perioperative. Tell the anaesthetist; delayed gastric emptying can leave food in the stomach after fasting. Practice varies between withholding the weekly dose 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% at 6 months).

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.