Mechanism

Tirzepatide is engineered from a GIP backbone and modified at multiple residues to produce balanced agonism at both the GIP receptor and the GLP-1 receptor. The two arms cooperate:

• GLP-1 receptor activation drives glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and central appetite reduction — the same mechanism as semaglutide.
• GIP receptor activation potentiates insulin secretion in the presence of hyperglycaemia and, importantly, modulates adipose-tissue handling of fatty acids in ways that appear to offset some of the lipid-sparing effects of pure GLP-1 signalling.

A C20 fatty-diacid chain on Lys20 binds plasma albumin, extending the half-life to approximately 5 days and enabling once-weekly dosing.

Clinical evidence

SURPASS-2 (Frías et al., NEJM 2021) was the landmark head-to-head trial against semaglutide 1 mg in adults with type 2 diabetes. Tirzepatide produced significantly greater HbA1c reductions and greater body-weight reductions at every dose tested (5, 10, 15 mg).

SURMOUNT-1 (Jastreboff et al., NEJM 2022) was the phase-3 obesity trial in adults without diabetes. Mean weight reduction at 72 weeks was −15.0% at 5 mg, −19.5% at 10 mg, and −20.9% at 15 mg — the largest reduction reported for an approved weight-management drug to date.

Subsequent SURMOUNT trials extended the evidence base to obesity with comorbid type 2 diabetes, obstructive sleep apnoea, and cardiovascular disease.

Comparisons

• Retatrutide vs tirzepatide — dual- versus triple-agonist trade-offs.
• Tirzepatide vs semaglutide — SURPASS-2 head-to-head.

Storage

Store lyophilised tirzepatide at −20°C. Reconstituted material is stable refrigerated at 2–8°C for approximately 4 weeks. Follow the reconstitution guide for handling steps.