DRPSHP

Scientific Reference

Tirzepatide

Evidence profile: Human Phase 3 evidence

Two incretin receptors, one for GIP and one for GLP-1, are both switched on by tirzepatide, a synthetic 39-residue peptide. Its sequence is built mainly on GIP, carries aminoisobutyric acid at positions 2 and 13, and finishes with a tail that resembles exendin-4. Circulation time is extended by a 20-carbon fatty diacid joined to a lysine through a linker, which lets the molecule bind albumin. The compound has been examined in receptor pharmacology, rodent work and an extensive set of human clinical studies in metabolic disease. A continuing debate concerns the GIP half of the design, partly because rodent experiments have produced overlapping outcomes from both stimulating and blocking the GIP receptor.

Mechanism of Action

Both receptors involved are class B G-protein-coupled receptors working mostly through Gs and cyclic AMP, and tirzepatide has been reported to activate each. Test-tube measurements put its grip on the GIP receptor close to that of native GIP but its grip on the GLP-1 receptor below that of native GLP-1, hence the label imbalanced agonist. At the GLP-1 receptor it is also reported to prefer producing cyclic AMP over recruiting beta-arrestin, so the receptor is internalised less. Receptors for GIP occur in pancreatic islets, adipose tissue and brain, and those for GLP-1 in islets, the gut and brain areas connected with feeding.

Molecular Information

  • Type: Dual GIP/GLP-1 receptor agonist
  • Molecular weight: 4813 g/mol
  • Molecular formula: C225H348N48O68
  • CAS: 2023788-19-2

Pharmacokinetics

The apparent population mean clearance of tirzepatide is 0.061 L/h with an elimination half-life of approximately 5 days, enabling once-weekly dosing. Table 2, normal hepatic function group: "t max , h: 24.00 (8.00-72.00)" reported as median (range) following a single 5-mg subcutaneous dose (n=13).

Published Research

  • SURMOUNT-5

    Tirzepatide as Compared with Semaglutide for the Treatment of Obesity

    Aronne LJ et al. · The New England journal of medicine · 2025 · Clinical

    PMID 40353578 — View on PubMed

  • SURMOUNT-1

    Tirzepatide Once Weekly for the Treatment of Obesity

    Jastreboff AM et al. · The New England journal of medicine · 2022 · Clinical

    PMID 35658024 — View on PubMed

  • SURPASS-2

    Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes

    Frías JP et al. · The New England journal of medicine · 2021 · Clinical

    PMID 34170647 — View on PubMed

  • Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

    Willard FS et al. · JCI insight · 2020 · Preclinical

    PMID 32730231 — View on PubMed

  • Tirzepatide for maintenance of bodyweight reduction in people with obesity in the USA (SURMOUNT-MAINTAIN): a multicentre, double-blind, randomised, placebo-controlled trial

    Horn DB et al. · Lancet (London, England) · 2026 · Clinical

    PMID 42119587 — View on PubMed

  • Efficacy and safety of tirzepatide in children and adolescents with type 2 diabetes (SURPASS-PEDS): a randomised, double-blind, placebo-controlled, phase 3 trial

    Hannon TS et al. · Lancet (London, England) · 2025 · Clinical

    PMID 40975112 — View on PubMed