Biology:Tirzepatide

From HandWiki
Short description: Anti-diabetic medication
Tirzepatide
Tirzepatide.svg
Clinical data
Pronunciation/tɜːrˈzɛpətaɪd/
tur-ZEP-ə-tyde
Trade namesMounjaro, Zepbound
Other namesLY3298176, GIP/GLP-1 RA
AHFS/Drugs.comMonograph
MedlinePlusa622044
License data
Pregnancy
category
Routes of
administration		Subcutaneous
Drug classAntidiabetic, GLP-1 receptor agonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80%
Protein bindingAlbumin
MetabolismProteolytic cleavage, β-oxidation of fatty diacid section and amide hydrolysis
Elimination half-life5 days
ExcretionUrine and faeces
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC225H348N48O68
Molar mass4813.527 g·mol−1
3D model (JSmol)

Tirzepatide, sold under the brand names Mounjaro and Zepbound, is an antidiabetic medication used for the treatment of type 2 diabetes[8][11][12][13] and for weight loss.[9][14] Tirzepatide is administered through subcutaneous injection (under the skin).[8][11]

The most common side effects include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain.[8][11][15]

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood-sugar control.[11] After a person has eaten, these hormones are secreted by cells of the intestines, and in turn cause the secretion of insulin. Tirzepatide is a GIP-analogue that activates both the GLP-1 and GIP receptors, leading to improved blood-sugar control.[11] Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist.[9]

Tirzepatide was approved for medical use in the United States in May 2022,[8][11] in the European Union in September 2022,[10] in Canada in November 2022,[16] and in Australia in December 2022.[2] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[17][18] It was approved by the FDA for weight loss in November 2023, under the brand name Zepbound.[14][19] In November 2023, the UK Medicines and Healthcare products Regulatory Agency revised the indication for tirzepatide to include treatment for weight loss.[6][20]

Medical uses

Tirzepatide is indicated to improve blood-sugar control in adults with type 2 diabetes, as an addition to diet and exercise.[8][11]

Tirzepatide is also indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management.[9][14]

Contraindications

Tirzepatide should not be used in people with a personal or family history of medullary thyroid cancer or in people with multiple endocrine neoplasia syndrome type 2.[11]

Adverse effects

Preclinical, phase I, and phase II clinical trials indicated that tirzepatide exhibits adverse effects similar to those of other established GLP-1 receptor agonists, such as dulaglutide. These effects occur largely within the gastrointestinal tract.[21] The most frequently observed are nausea, diarrhea, and vomiting, which increased in incidence with the dosage amount (i.e. higher likelihood the higher the dose). The number 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.[22] To a slightly lesser extent, patients also reported reduced appetite.[21] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness, and hypoglycaemia.[23][24]

Pharmacology

Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a human hormone that stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids that has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism.[25] It completed phase III trials globally in 2021.[26][27]

Mechanism of action

Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behavior has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist.[12] Signaling studies reported that tirzepatide mimics the actions of natural GIP at the GIP receptor.[28] At the GLP-1 receptor, though, 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 and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.[28] Tirzepatide has been reported to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.[12]

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.[25] 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.[29]

Synthesis

The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company.[30] 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 for this compound.[31]

History

Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.[30] The patent was published late that year. After passing phase III clinical trials, Lilly applied for FDA approval in October 2021, with a priority review voucher.[32]

Following the completion of the SURPASS-2 trial (NCT03987919), the company announced in April 2022 that tirzepatide had successfully met their endpoints in obese and overweight patients without diabetes.[33]

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%).[34] 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).[12] Fasting levels of IGF binding proteins such as IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[12]

The FDA approved tirzepatide based on evidence from nine clinical trials of 7,769 participants with type 2 diabetes, of which 5,415 of these participants received tirzepatide.[35] The trials were conducted at 673 sites in 24 countries, including Argentina, Australia, Brazil, Canada, India, Israel, Japan, Mexico, Russian Federation, South Korea, Taiwan, multiple European countries, and the United States (including Puerto Rico).[35] All nine trials were used to assess safety and five of these trials were used to assess the efficacy of tirzepatide.[35] The five trials used in the efficacy evaluation included 6,263 adult participants with type 2 diabetes.[35] Four additional trials (NCT #03131687, NCT #03311724 NCT #03861052, NCT #03861039) were included in the safety evaluation, for a total of 7,769 adult participants with type 2 diabetes; therefore, the number of participants representing efficacy findings may differ from the number of participants representing safety findings due to different pools of study participants analyzed for efficacy and safety.[35] The benefits of tirzepatide for the treatment of adult participants with type 2 diabetes were primarily evaluated in five clinical trials.[35] In two of these trials (NCT #03954834 and NCT #04039503), participants were randomly assigned to receive either tirzepatide or placebo injection weekly.[35] Neither the patient nor the healthcare provider knew which treatment was being given until after the trials were completed.[35] Treatment was given for 40 weeks.[35] In the other three trials (NCT #3987919, 03882970, and 03730662), participants were randomly assigned to receive either tirzepatide or another antidiabetic medication, and the patient and provider knew which medication was being given.[35] Treatment was given for 40 weeks to 104 weeks.[35] In each trial, HbA1c was measured from the start of the trial to the end of the trial and compared between the tirzepatide group and the other groups.[35]

The efficacy of tirzepatide for chronic weight management (weight reduction and maintenance) in combination with a reduced-calorie diet and increased physical activity was established in two randomized, double-blind, placebo-controlled trials of adults with obesity or overweight with at least one weight-related condition.[14] These studies measured weight reduction after 72 weeks in a total of 2,519 participants who received either 5 mg, 10 mg or 15 mg of tirzepatide once weekly and a total of 958 participants who received once-weekly placebo injections.[14] In both trials, after 72 weeks of treatment, participants who received tirzepatide at all three dose levels experienced a statistically significant reduction in body weight compared to those who received placebo, and greater proportions of participants who received tirzepatide achieved at least 5% weight reduction compared to placebo.[14]

Meta-analysis

A 2021 meta-analysis showed that over one year of clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction.[36]

In a phase III double-blind, randomized, controlled trial supported by Eli Lilly, nondiabetic adults with a body mass index of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, were randomized to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo. The mean percentage change in weight at week 72 was −15.0% (95% confidence interval [CI], −15.9 to −14.2) with 5-mg weekly doses of tirzepatide, −19.5% (95% CI, −20.4 to −18.5) with 10-mg doses, and −20.9% (95% CI, −21.8 to −19.9) with 15-mg doses. Weight change in the placebo group was −3.1% (95% CI, −4.3 to −1.9).[37][38][39]

Society and culture

Legal status

The FDA granted the application for tirzepatide priority review designation.[11] The FDA approved Mounjaro in 2022.[11]

On 21 July 2022, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Mounjaro, intended for the treatment of type 2 diabetes.[40] Tirzepatide was approved for medical use in the European Union in September 2022.[10][41]

Brand names

Tirzepatide is the international nonproprietary name (INN).[42]

Tirzepatide is sold under the brand names Mounjaro[1][8][10] and Zepbound.[9]

References

  1. ↑ 1.0 1.1 1.2 "Australian prescription medicine decision summaries: Mounjaro". Therapeutic Goods Administration. https://www.tga.gov.au/resources/auspmd/mounjaro. 
  2. ↑ 2.0 2.1 "Mounjaro tirzepatide 15 mg/0.5 mL solution for injection pre-filled pen (379334)". Therapeutic Goods Administration. https://www.tga.gov.au/resources/artg/379334. 
  3. ↑ "Public Summary: Mounjaro tirzepatide 15 mg/0.5 mL solution for injection pre-filled pen". Therapeutic Goods Administration. http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=379334&agid=%28PrintDetailsPublic%29&actionid=1. 
  4. ↑ "Notice: Multiple Additions to the Prescription Drug List (PDL) [2023-03-08"]. 8 March 2023. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/mutliple-additions-2023-03-08.html. 
  5. ↑ "Summary Basis of Decision - Mounjaro". 17 March 2023. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00629&lang=en. 
  6. ↑ 6.0 6.1 "Mounjaro 5mg solution for injection in pre-filled pen". 16 November 2023. https://www.medicines.org.uk/emc/product/14205/smpc. 
  7. ↑ "Mounjaro 2.5mg solution for injection in pre-filled pen". 16 November 2023. https://www.medicines.org.uk/emc/product/14206/smpc. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 "Mounjaro- tirzepatide injection, solution". 13 May 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "Zepbound- tirzepatide injection, solution". 9 November 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b. 
  10. ↑ 10.0 10.1 10.2 10.3 "Mounjaro EPAR". 18 July 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/mounjaro.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 "FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes". U.S. Food and Drug Administration (FDA) (Press release). 13 May 2022. Archived from the original on 13 May 2022. Retrieved 13 May 2022. This article incorporates text from this source, which is in the public domain.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "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. January 2021. doi:10.1210/clinem/dgaa863. PMID 33236115. 
  13. ↑ "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. December 2018. doi:10.1016/j.molmet.2018.09.009. PMID 30473097. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 "FDA Approves New Medication for Chronic Weight Management". U.S. Food and Drug Administration (FDA) (Press release). 8 November 2023. Archived from the original on 8 November 2023. Retrieved 9 November 2023. This article incorporates text from this source, which is in the public domain.
  15. ↑ "Tirzepatide: A Systematic Update". Int J Mol Sci 23 (23): 14631. November 2022. doi:10.3390/ijms232314631. PMID 36498958. 
  16. ↑ "Drug and Health Product Submissions Under Review (SUR): New drug submissions completed". 10 March 2021. https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/submissions-under-review/new-drug-submissions-completed.html. 
  17. ↑ "Advancing Health Through Innovation: New Drug Therapy Approvals 2022". 10 January 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022.  This article incorporates text from this source, which is in the public domain.
  18. ↑ (PDF) New Drug Therapy Approvals 2022 (Report). January 2024. https://www.fda.gov/media/164429/download. Retrieved 14 January 2024.  This article incorporates text from this source, which is in the public domain.
  19. ↑ Kolata, Gina (8 November 2023). "F.D.A. Approves New Obesity Drug Tirzepatide That Will Compete With Wegovy". https://www.nytimes.com/2023/11/08/health/fda-tirzepatide-obesity-zepbound-wegovy.html. 
  20. ↑ "MHRA authorises diabetes drug Mounjaro (tirzepatide) for weight management and weight loss". GOV.UK (Press release). 8 November 2023. Archived from the original on 16 November 2023. Retrieved 17 November 2023.
  21. ↑ 21.0 21.1 "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. January 2021. doi:10.1007/s13300-020-00981-0. PMID 33325008. 
  22. ↑ "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. November 2018. doi:10.1016/S0140-6736(18)32260-8. PMID 30293770. 
  23. ↑ "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. June 2020. doi:10.1111/dom.13979. PMID 31984598. 
  24. ↑ "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. February 2022. doi:10.1001/jama.2022.0078. PMID 35133415. 
  25. ↑ 25.0 25.1 "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. January 2021. doi:10.1039/d0cs00354a. PMID 33404559. 
  26. ↑ "Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly's SURPASS program" (Press release). Eli Lilly and Company. 17 February 2021. Archived from the original on 28 October 2021. Retrieved 28 October 2021 – via PR Newswire.
  27. ↑ "Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes". 19 October 2021. https://markets.businessinsider.com/news/stocks/lilly-phase-3-tirzepatide-results-show-superior-a1c-and-body-weight-reductions-in-type-2-diabetes-1030876853. 
  28. ↑ 28.0 28.1 "Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist". JCI Insight 5 (17). September 2020. doi:10.1172/jci.insight.140532. PMID 32730231. 
  29. ↑ "The effect of fatty diacid acylation of human PYY3-36 on Y2 receptor potency and half-life in minipigs". Scientific Reports 11 (1): 21179. October 2021. doi:10.1038/s41598-021-00654-3. PMID 34707178. Bibcode: 2021NatSR..1121179O. 
  30. ↑ 30.0 30.1 Bokvist BK, Coskun T, Cummins RC, Alsina-Fernandez J, "GIP and GLP-1 co-agonist compounds", US patent 9474780, issued 2016-10-25, assigned to Eli Lilly and Co
  31. ↑ "Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing". Organic Process Research & Development 25 (7): 1628–1636. 2021. doi:10.1021/acs.oprd.1c00108. 
  32. ↑ Sagonowsky, Eric (26 October 2021). "As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth". https://www.fiercepharma.com/pharma/as-lilly-gears-up-for-key-2022-launches-its-existing-meds-post-solid-growth. 
  33. ↑ Kellaher, Colin (28 April 2022). "Eli Lilly's Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study". MarketWatch. https://www.marketwatch.com/story/eli-lilly-s-tirzepatide-meets-main-endpoints-in-phase-3-obesity-study-lly-271651143389. 
  34. ↑ "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes". The New England Journal of Medicine 385 (6): 503–515. August 2021. doi:10.1056/NEJMoa2107519. PMID 34170647. 
  35. ↑ 35.00 35.01 35.02 35.03 35.04 35.05 35.06 35.07 35.08 35.09 35.10 35.11 "Drug Trials Snapshots: Mounjaro". 13 June 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-mounjaro.  This article incorporates text from this source, which is in the public domain.
  36. ↑ "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. Nov–Dec 2021. doi:10.4103/ijem.ijem_423_21. PMID 35355921. 
  37. ↑ "Tirzepatide Once Weekly for the Treatment of Obesity". NEJM 387 (3): 205–216. 4 June 2022. doi:10.1056/NEJMoa2206038. PMID 35658024. 
  38. ↑ Dee, Jane E. (6 June 2022). "More Than 20% Weight Reduction in Individuals With Obesity". Yale Department of Internal Medicine. https://medicine.yale.edu/intmed/news-article/new-medication-results-in-more-than-20-weight-reduction-in-individuals-with-obesity/. 
  39. ↑ Davis, Nicola (5 June 2022). "Diabetes drug leads to notable weight loss in people with obesity – study". The Guardian. https://www.theguardian.com/science/2022/jun/05/diabetes-drug-tirzepatide-leads-to-notable-weight-loss-in-people-with-obesity-study. 
  40. ↑ "Mounjaro: Pending EC decision". 22 July 2022. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/mounjaro.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  41. ↑ "Mounjaro Product information". https://ec.europa.eu/health/documents/community-register/html/h1685.htm. 
  42. ↑ "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81". WHO Drug Information 33 (1). 2019. 

Further reading



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Tirzepatide&oldid=3659281"