Dual Incretin Receptor Agonists

Dual incretin receptor agonists act on both the GIP and GLP-1 receptors. Tirzepatide is the licensed member. It gives larger falls in HbA1c (2 to 2.4%) and body weight (about 5 to 12 kg in type 2 diabetes, up to about 20% of body weight at the highest dose in obesity) than single GLP-1 receptor agonists.

Mechanism. GLP-1 receptor activation raises glucose dependent insulin secretion, suppresses glucagon, slows gastric emptying and reduces appetite. GIP receptor activation adds insulin secretion, improves adipose tissue handling and may reduce nausea.

Pharmacokinetics. Given subcutaneously once weekly, half-life about 5 days, steady state after 4 weeks. Not dependent on kidney or liver function for clearance.

Tirzepatide. Start 2.5 mg weekly for 4 weeks (initiation only), then 5 mg weekly. Increase by 2.5 mg no sooner than every 4 weeks, to a maximum of 15 mg weekly. Doses of 5, 10 and 15 mg are the maintenance range.

Versus GLP-1 receptor agonists. Greater weight and glucose lowering at higher doses. Cardiovascular outcome evidence is accumulating but less established than for semaglutide and liraglutide.

Other agents. Further dual and triple agonist peptides are under development; none is established for routine use.

• Type 2 diabetes with obesity: when more weight and glucose lowering is needed than with a GLP-1 receptor agonist.
• Obesity without diabetes: licensed for weight management, with a diet and activity programme.
• Obstructive sleep apnoea with obesity: licensed in some regions.
• Sulphonylurea or insulin background: reduce the sulphonylurea by 25 to 50% and insulin by 10 to 20% on starting.
• Missed dose: may be taken within 4 days of the scheduled day; otherwise skip.

Special groups. Pregnancy: stop before conception. Oral contraceptives: efficacy is reduced during titration, so use a non-oral or barrier method for 4 weeks after starting and after each dose increase. Breastfeeding: avoid. Children: not licensed. Older adults: titrate cautiously. Kidney impairment: no adjustment, but dehydration can cause injury. Liver impairment: caution. Regional: cost and supply limit use in East Africa, and the pens need refrigeration.

Adverse effects. Nausea, vomiting, diarrhoea, constipation, reduced appetite, dyspepsia, injection site reactions, acute pancreatitis, gallbladder disease, and worsening diabetic retinopathy with rapid control.

Contraindications. Personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, and pregnancy.

Interactions. Delayed gastric emptying changes absorption of oral drugs and reduces oral contraceptive exposure. Hypoglycaemia risk rises with insulin and sulphonylureas. Not combined with another GLP-1 receptor agonist or a DPP 4 inhibitor.

Monitoring. Weight, HbA1c every 3 months, glucose diary on insulin, hydration and eGFR with gastrointestinal symptoms, and abdominal pain.

Referral and escalation. Suspected pancreatitis, gallbladder pain, severe vomiting with acute kidney injury, or visual change.