Source of Tirzepatide

{{Infobox compound | name = Tirzepatide | subtitle = Clinical data | image = peptide-chain.svg | caption = A 39-residue GIP-based backbone with Aib at positions 2 and 13 and a C-20 diacid on Lys20. | INN = tirzepatide | Class = [[Dual incretin agonist]] (GIP/GLP-1) | Route = Subcutaneous, weekly | First approval = 2022 (type 2 diabetes) <!-- Identifiers --> | CAS Number = 2023788-19-2 | Molecular formula = {{math|C_{225}H_{348}N_{48}O_{68}}} | Molar mass = 4,813.45 g·mol⁻¹ | Residues = 39 <!-- Pharmacokinetics --> | Half-life = ≈5 days | Bioavailability, SC = ≈80% | Time to steady state = 4 weeks <!-- Doses --> | Starting = 2.5 mg weekly for 4 weeks | Maintenance = 5, 10 or 15 mg weekly }} {{hatnote|Not to be confused with [[Retatrutide]], which adds glucagon-receptor agonism. For the class, see [[Dual incretin agonist]].}} {{medical|talk=Unapproved-compound notice}} '''Tirzepatide''' is a 39-residue synthetic peptide that activates both the receptor for [[Glucose-dependent insulinotropic polypeptide]] and the [[GLP-1 receptor]], making it the first [[Dual incretin agonist|dual incretin agonist]] to reach the market. Its backbone is derived from GIP rather than from GLP-1, and it is described in the literature as GIP-biased, with greater potency at the GIP receptor than at the GLP-1 receptor.{{r|coskun2018}} Half-life extension follows the same logic as [[Semaglutide|semaglutide]]: α-aminoisobutyric acid at positions 2 and 13 confers protease resistance, and a C-20 fatty diacid at Lys20 confers [[Albumin binding half-life extension|albumin binding]]. The resulting half-life of about five days supports weekly administration.{{r|coskun2018}} In [[SURMOUNT trial programme|SURMOUNT-1]], 15 mg weekly produced a mean weight change of −20.9% against −3.1% for placebo at 72 weeks in participants with obesity and without diabetes.{{r|jastreboff2022}} As with every compound covered here, tirzepatide sold as a research chemical is not the approved medicine and carries none of its assurances; see [[Research use only]]. == Design and receptor pharmacology == Tirzepatide was built from the GIP sequence rather than from GLP-1, which is the reverse of the intuitive approach and reflects the finding that a GIP backbone tolerates the substitutions needed for GLP-1 activity better than the converse.{{r|coskun2018}} Reported potency at the GIP receptor approaches that of native GIP, while potency at the GLP-1 receptor is roughly an order of magnitude below that of native GLP-1. The molecule is therefore not a balanced dual agonist, and the term "GIP-biased" is used in that sense. It also shows signalling bias at the GLP-1 receptor, favouring cAMP accumulation over β-arrestin recruitment; whether this contributes to the clinical effect is unresolved. See [[Receptor bias]]. Why dual agonism outperforms GLP-1 monotherapy is not settled. Proposed contributions include GIP action on adipose tissue, central GIP-receptor effects on nausea that permit higher effective exposure, and restored beta-cell GIP responsiveness under ambient GLP-1 signalling. The trials were not designed to separate these, and cross-trial comparison of tirzepatide with semaglutide is confounded by differences in population and escalation.{{r|frias2021}} == Clinical evidence == | Trial | Population | Dose | Primary result | |---|---|---|---| | SURPASS-2 | T2D, on metformin | 5/10/15 mg | HbA1c −2.01 to −2.30% vs semaglutide −1.86% | | SURMOUNT-1 | Obesity, no T2D | 5/10/15 mg | −15.0% to −20.9% weight vs −3.1% at 72 wk | | SURMOUNT-2 | Obesity with T2D | 10/15 mg | −12.8% to −14.7% weight vs −3.2% | | SURPASS-CVOT | T2D, high CV risk | 5–15 mg | Non-inferior to dulaglutide for MACE | The [[SURPASS trial programme|SURPASS]] programme covers the glycaemic indication and the [[SURMOUNT trial programme|SURMOUNT]] programme the obesity indication. SURPASS-2 is one of the few head-to-head trials in this field, comparing tirzepatide directly with semaglutide 1 mg — not the 2.4 mg obesity dose, a distinction routinely lost when the trial is cited.{{r|frias2021}} Discontinuation for adverse events across the programme ran at roughly 4–7% on active treatment, comparable with other agents in the field despite the larger effect size.{{r|jastreboff2022}} == Adverse effects and tolerability == The adverse-effect profile is qualitatively that of the [[GLP-1 receptor agonist|GLP-1 class]]: nausea, vomiting, diarrhoea and constipation, concentrated in escalation and dose-related. Reported frequencies at 15 mg are broadly similar to those for semaglutide 2.4 mg despite the greater weight effect, which is one of the more interesting observations in the programme and is not fully explained.{{r|jastreboff2022}} Gallbladder events, injection-site reactions and a small resting heart-rate increase are all reported. The label carries the class contraindication in personal or family history of medullary thyroid carcinoma. Hypoglycaemia is uncommon in monotherapy and becomes relevant when the drug is combined with insulin or a sulfonylurea, in which case the background agent is usually reduced. The five-step escalation from 2.5 mg with four weeks at each step exists for tolerability rather than efficacy, and compressing it predictably increases gastrointestinal events. See [[Dose escalation schedule]]. == Material outside licensed supply == Tirzepatide is widely offered by research-chemical suppliers. The same documentary cautions apply as for any peptide of this class, with one addition specific to it: at 4,813 g·mol⁻¹ and with two Aib residues and a C-20 diacid, it is a demanding synthesis, and crude purity before [[Preparative HPLC purification|preparative purification]] is lower than for shorter peptides.{{r|usp1503}} Identity is therefore worth as much attention as purity. A purity figure by [[Area percent purity|area percent]] establishes only that one peak dominates a chromatogram; it does not establish that the peak is tirzepatide. Confirmation by [[Mass spectrometry|mass spectrometry]] with a reported observed mass is the minimum that distinguishes the intended molecule from a deletion sequence differing by one residue, and deletion sequences co-elute readily on a short gradient.{{r|reports}} This wiki records what documents say and does not represent research-chemical material as suitable for human use. == References == {{reflist}} <ref name="coskun2018">Coskun T, Sloop KW, Loghin C, et al. "LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus." ''Molecular Metabolism'' 18:3–14 (2018). DOI:10.1016/j.molmet.2018.09.009. PMID 30473097.</ref> <ref name="frias2021">Frías JP, Davies MJ, Rosenstock J, et al. "Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes." ''New England Journal of Medicine'' 385(6):503–515 (2021). DOI:10.1056/NEJMoa2107519. PMID 34170647.</ref> <ref name="jastreboff2022">Jastreboff AM, Aronne LJ, Ahmad NN, et al. "Tirzepatide once weekly for the treatment of obesity." ''New England Journal of Medicine'' 387(3):205–216 (2022). DOI:10.1056/NEJMoa2206038. PMID 35658024.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> <ref name="reports">PeptidePedia Wiki community test-report tally, 2024–2026 (self-reported; see [[Project:Sourcing_guidelines]]).</ref> == External links == * [https://clinicaltrials.gov/study/NCT04184622 SURMOUNT-1 — NCT04184622] — Registry record for the pivotal obesity trial. == See also == * [[Dual incretin agonist]] * [[Semaglutide]] * [[Retatrutide]] * [[Glucose-dependent insulinotropic polypeptide]] * [[SURMOUNT trial programme]] * [[SURPASS trial programme]] {{DEFAULTSORT:Tirzepatide}} [[Category:Dual and triple agonists]] [[Category:Peptide drugs]] [[Category:Pharmacokinetics]] [[Category:Articles describing unapproved compounds]]