Tirzepatide
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Other names | LY3298176, GIP/GLP-1 RA |
Drug class | Not classified |
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Formula | C225H348N48O68 |
Molar mass | 4813.527 g·mol−1 |
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Solubility in water | Insoluble |
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Tirzepatide is an experimental drug proposed to help treat type 2 diabetes, obesity and non-alcoholic fatty liver disease.[2][3] It is an analogue of gastric inhibitory polypeptide (GIP), a human hormone which stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids which has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism.[4] The compound is administered as a weekly subcutaneous injection.[5] It completed phase 3 trials globally in 2021.[6][7]
Mechanism of action[]
Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist.[2] Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor.[8] However, at the GLP-1 receptor tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor & distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.[8] Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% (10 mg dosage) from baseline after 26 weeks.[2]
Chemistry[]
Structure[]
Tirzepatide is an analog of the human GIP hormone (with a C20 fatty-diacid portion attached, used to optimise the uptake and metabolism of the compound.[4] The fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue. This arrangement allows for a much longer half life, extending the time between doses, because of its high affinity to albumin.[9]
Synthesis[]
The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company.[10] This uses standard solid phase peptide synthesis, with an allyloxycarbonyl protecting group on the lysine at position 20 of the linear chain of amino acids, allowing a final set of chemical transformations in which the sidechain amine of that lysine is derivatized with the lipid-containing fragment.
Large-scale manufacturing processes have been reported.[11]
Efficacy[]
In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication semaglutide (an injected analogue of the hormone GLP-1), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to semaglutide (1.86%).[12] A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using HOMA2-IR (computed with fasting insulin).[2] Fasting levels of IGF binding proteins like IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[2] A meta-analysis published by Dutta et. al. showed that over 1-year clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction. Tirzepatide is perhaps the most potent agent developed till date to tackle the global problem of "diabesity".[13]
Adverse effects[]
Preclinical, phase 1 & phase 2 trials have indicated that tirzepatide exhibits similar adverse effects to other established GLP-1 receptor agonists, such as GLP-1 receptor agonist dulaglutide. These effects occur largely within the gastrointestinal tract.[14] The most frequently observed adverse effects are nausea, diarrhoea and vomiting which were linked to dosage amount (i.e. higher likelihood the higher the dose). The amount of patients who discontinued taking tirzepatide also increased as dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5 mg patients and 11.1% for dulaglutide.[15] To a slightly lesser extent, patients also reported reduced appetite.[14] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.[16][17]
History[]
Indiana-based pharmaceutical company Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide back in early 2016,[10] which was published late that year. After passing phase 3 clinical trials (the last phase before a company is able to seek FDA approval), Eli Lilly and Company expect to apply for FDA approval in late 2021 or early 2022.[18][19]
References[]
- ^ "Tirzepatide". Compound Report Card. ChEMBL. Retrieved 4 December 2021.
- ^ a b c d e Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. (January 2021). "Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes". The Journal of Clinical Endocrinology and Metabolism. 106 (2): 388–396. doi:10.1210/clinem/dgaa863. PMC 7823251. PMID 33236115.
- ^ Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. (December 2018). "LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept". Molecular Metabolism. 18: 3–14. doi:10.1016/j.molmet.2018.09.009. PMC 6308032. PMID 30473097.
- ^ a b Ahangarpour M, Kavianinia I, Harris PW, Brimble MA (January 2021). "Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design". Chemical Society Reviews. Royal Society of Chemistry. 50 (2): 898–944. doi:10.1039/d0cs00354a. PMID 33404559. S2CID 230783854.
- ^ Bastin M, Andreelli F (2019). "Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 12: 1973–1985. doi:10.2147/DMSO.S191438. PMC 6777434. PMID 31686879.
- ^ "Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly's SURPASS program". prnewswire.com. 17 February 2021. Retrieved 28 October 2021.
- ^ RTTNews (October 19, 2021). "Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes". market.businessinsider.com. Retrieved 28 October 2021.
- ^ a b Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. (September 2020). "Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist". JCI Insight. 5 (17). doi:10.1172/jci.insight.140532. PMC 7526454. PMID 32730231.
- ^ Østergaard S, Paulsson JF, Kofoed J, Zosel F, Olsen J, Jeppesen CB, et al. (October 2021). "The effect of fatty diacid acylation of human PYY3-36 on Y2 receptor potency and half-life in minipigs". Scientific Reports. 11 (1): 21179. Bibcode:2021NatSR..1121179O. doi:10.1038/s41598-021-00654-3. PMC 8551270. PMID 34707178.
- ^ a b US patent 9474780, Bokvist BK, Coskun T, Cummins RC, Alsina-Fernandez J, "GIP and GLP-1 co-agonist compounds", issued 2016-10-25, assigned to Eli Lilly and Co
- ^ Frederick MO, Boyse RA, Braden TM, Calvin JR, Campbell BM, Changi SM, et al. (2021). "Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing". Organic Process Research & Development. 25 (7): 1628–1636. doi:10.1021/acs.oprd.1c00108. S2CID 237690232.
- ^ Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes". The New England Journal of Medicine. 385 (6): 503–515. doi:10.1056/NEJMoa2107519. PMID 34170647. S2CID 235635529.
- ^ Dutta D, Surana V, Singla R, Aggarwal S, Sharma M (Nov–Dec 2021). "Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis". Indian Journal of Endocrinology and Metabolism. 25 (6): 475–489. doi:10.4103/ijem.ijem_423_21.
- ^ a b Min T, Bain SC (January 2021). "The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials". Diabetes Therapy. 12 (1): 143–157. doi:10.1007/s13300-020-00981-0. PMC 7843845. PMID 33325008.
- ^ Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. (November 2018). "Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial". The Lancet. 392 (10160): 2180–2193. doi:10.1016/S0140-6736(18)32260-8. PMID 30293770.
- ^ Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, et al. (June 2020). "Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens". Diabetes, Obesity & Metabolism. 22 (6): 938–946. doi:10.1111/dom.13979. PMC 7318331. PMID 31984598.
- ^ Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á (February 2022). "Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial". JAMA. 327 (6): 534–545. doi:10.1001/jama.2022.0078. PMID 35133415.
- ^ Vinluan F (20 May 2021). "Eli Lilly looks ahead to FDA after diabetes drug wraps up last clinical test". medcitynews.com. Retrieved 22 December 2021.
- ^ Sarwar J (29 March 2021). "Tirzepatide Clinical Trials Show Promising Results for People With Type 2 Diabetes". goodrx.com. Retrieved 22 December 2021.
- Hormones of the digestive system
- Neuropeptides