Tirzepatide

Tirzepatide is a once-weekly subcutaneous dual GIP and GLP-1 receptor agonist. It is the most effective glucose-lowering and weight-reducing injectable currently in common use, lowering HbA1c by about 2 to 2.4% and body weight by about 15 to 20% at higher doses. It is licensed for type 2 diabetes and for chronic weight management, and carries a thyroid C-cell tumour warning.

Classification. Dual GIP and GLP-1 receptor agonist; a linear peptide with a fatty diacid chain for albumin binding. Single-dose pens and vials of 2.5, 5, 7.5, 10, 12.5 and 15 mg.

Mechanism. Activates the GIP receptor (more potent) and the GLP-1 receptor. Glucose-dependent insulin release rises, glucagon falls, gastric emptying slows and appetite is reduced; GIP activity probably adds to insulin sensitivity and fat handling.

Pharmacodynamics. Lowers fasting and post-meal glucose with low hypoglycaemia risk alone. Reduces energy intake, weight, blood pressure and triglycerides, and raises resting heart rate by 2 to 4 beats a minute. Gastric emptying is delayed mainly after the first dose.

Pharmacokinetics. Subcutaneous bioavailability about 80%; peak 8 to 72 hours; over 99% albumin bound. Degraded by proteolytic cleavage, beta-oxidation of the fatty chain and amide hydrolysis; excreted in urine and faeces as metabolites. Half-life about 5 days; steady state after 4 weeks.

Type 2 diabetes, adults.

• Start 2.5 mg subcutaneously once weekly for 4 weeks (a tolerability dose that does not lower glucose enough).
• Increase to 5 mg weekly; then raise by 2.5 mg after at least 4 weeks at each dose if more control is needed.
• Usual maintenance 5, 10 or 15 mg weekly. Maximum 15 mg weekly. No loading dose.

Chronic weight management (adults with obesity, or overweight with weight-related disease).

• Same schedule: 2.5 mg weekly for 4 weeks, then 5 mg, then raise by 2.5 mg every 4 weeks or more to a maintenance of 5, 10 or 15 mg weekly. Maximum 15 mg weekly.
• Moderate to severe obstructive sleep apnoea with obesity (where licensed): maintenance 10 or 15 mg weekly.

Combination use. Adds to metformin, SGLT2 inhibitors, sulphonylureas, pioglitazone and basal insulin. Reduce the sulphonylurea dose and consider reducing insulin when adding tirzepatide, and check glucose more often during dose steps. Do not combine with a DPP-4 inhibitor or another GLP-1 receptor agonist.

Missed doses. Give within 4 days (96 hours) of the missed dose; otherwise skip it and give the next dose on the usual day. The day can be changed if the previous dose was at least 3 days earlier.

Adjustments.

• Kidney: no change at any eGFR; monitor kidney function when vomiting or diarrhoea occur.
• Liver: no change; limited data in severe impairment.
• Older adults: no change.
• Weight: no weight-based dosing in adults.
• Children: not licensed.

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 use).

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.
• Diabetic retinopathy complications with rapid HbA1c fall.
• Hypersensitivity including anaphylaxis and angioedema.
• Delayed gastric emptying: aspiration risk during sedation or anaesthesia.
• Mood changes and suicidal thoughts reported with weight-management use.

Common adverse effects. Nausea, vomiting, diarrhoea, constipation, abdominal pain, reduced appetite, dyspepsia; mostly during dose steps. Loss of lean mass accompanies weight loss.

Major interactions.

• Oral contraceptives: exposure falls after the first dose and after each dose step; advise a non-oral method, or a barrier method, for 4 weeks after starting and after each increase.
• Insulin and sulphonylureas: hypoglycaemia.
• Delayed gastric emptying may alter absorption of other oral medicines; monitor INR with warfarin when starting.

Special groups.

• Pregnancy: avoid; stop at least 2 months before a planned pregnancy and use insulin for diabetes in pregnancy. Women using oral contraceptives may become fertile with weight loss.
• Breastfeeding: avoid; no human data.
• Children: not licensed.
• Older adults: dehydration and loss of lean mass in frail adults.
• 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 21 days. Cost and supply restrict use; prioritise those with established cardiovascular disease or obesity with diabetes, and check that the product is registered locally.

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. Pens are single-dose.

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, contraceptive method.

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 before starting and 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 5% 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.