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| pregnancy_AU_comment =
| pregnancy_AU_comment =
| pregnancy_category=
| pregnancy_category=
| routes_of_administration = [[Subcutaneous injection|subcutaneous]]
| routes_of_administration = [[Subcutaneous injection|Subcutaneous]]
| class = [[Antidiabetic]], [[Glucagon-like peptide-1 receptor agonist|GLP-1 receptor agonist]]
| class = [[Antidiabetic]], [[Glucagon-like peptide-1 receptor agonist|GLP-1 receptor agonist]]
| ATCvet =
| ATCvet =
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<!-- Legal status -->
<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_UK_comment =
| legal_US = Rx-only
| legal_US = Rx-only
| legal_US_comment = <ref name="Mounjaro label">{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf |title=Highlights of prescribing information |website=accessdata.fda.gov |publisher=FDA |date=May 2022 |access-date=14 May 2022}}</ref><ref name="FDA PR 20220513" />
| legal_US_comment = <ref name="Mounjaro FDA label">{{cite web | title=Mounjaro- tirzepatide injection, solution | website=DailyMed | date=13 May 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0 | access-date=27 May 2022}}</ref><ref name="FDA PR 20220513" />
| legal_EU =
| legal_EU =
| legal_EU_comment =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->
| legal_status = <!-- For countries not listed above -->


<!-- Pharmacokinetic data -->
<!-- Pharmacokinetic data -->
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}}
}}


'''Tirzepatide''', sold under the brand name '''Mounjaro''',<ref name="Mounjaro label"/> is a [[medication]] used for the treatment [[type 2 diabetes]].<ref name="FDA PR 20220513">{{cite press release | title=FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes | website=U.S. [[Food and Drug Administration]] (FDA) | date=13 May 2022 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes | access-date=13 May 2022}} {{PD-notice}}</ref><ref name="moa" /><ref>{{cite journal|display-authors=6|vauthors=Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A|date=December 2018|title=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|journal=[[Molecular Metabolism]]|volume=18|pages=3–14|doi=10.1016/j.molmet.2018.09.009|pmc=6308032|pmid=30473097|doi-access=free}}</ref> Tirzepatide is given by injection under the skin.<ref name="FDA PR 20220513" /> Common side effects may include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain.<ref name="FDA PR 20220513" />
'''Tirzepatide''', sold under the brand name '''Mounjaro''', is a [[medication]] used for the treatment [[type 2 diabetes]].<ref name="Mounjaro FDA label"/><ref name="FDA PR 20220513">{{cite press release | title=FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes | website=U.S. [[Food and Drug Administration]] (FDA) | date=13 May 2022 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes | access-date=13 May 2022}} {{PD-notice}}</ref><ref name="moa" /><ref>{{cite journal | display-authors = 6 | vauthors = Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A | date = December 2018 | title = 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 | journal = [[Molecular Metabolism]] | volume = 18 | pages = 3–14 | doi = 10.1016/j.molmet.2018.09.009 | pmc = 6308032 | pmid = 30473097 | doi-access = free | title-link = doi}}</ref> Tirzepatide is given by subcutaneous injection under the skin.<ref name="Mounjaro FDA label"/><ref name="FDA PR 20220513" /> Common side effects may include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain.<ref name="Mounjaro FDA label"/><ref name="FDA PR 20220513" />


[[Glucagon-like peptide-1]] (GLP-1) and [[glucose-dependent insulinotropic polypeptide]] (GIP) are hormones involved in blood sugar control.<ref name="FDA PR 20220513" /> Tirzepatide is a [[first-in-class medication]] that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.<ref name="FDA PR 20220513" /> Tirzepatide was approved for medical use in the United States in May 2022.<ref name="FDA PR 20220513" />
[[Glucagon-like peptide-1]] (GLP-1) and [[glucose-dependent insulinotropic polypeptide]] (GIP) are hormones involved in blood sugar control.<ref name="FDA PR 20220513" /> Tirzepatide is a [[first-in-class medication]] that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.<ref name="FDA PR 20220513" /> Tirzepatide was approved for medical use in the United States in May 2022.<ref name="Mounjaro FDA label"/><ref name="FDA PR 20220513" />


== Medical uses ==
== Medical uses ==
Tirzepatide in [[indicated]] to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.<ref name="FDA PR 20220513" />
Tirzepatide in [[indicated]] to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.<ref name="Mounjaro FDA label"/><ref name="FDA PR 20220513" />


== Contraindications ==
== Contraindications ==
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== Adverse effects ==
== Adverse effects ==
Preclinical, phase I, and phase II 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.<ref name="ae">{{cite journal | vauthors = Min T, Bain SC | title = The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials | journal = Diabetes Therapy | volume = 12 | issue = 1 | pages = 143–157 | date = January 2021 | pmid = 33325008 | pmc = 7843845 | doi = 10.1007/s13300-020-00981-0 | doi-access = free | title-link = doi }}</ref> The most frequently observed adverse effects are nausea, diarrhoea 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&nbsp;mg having a 25% discontinuation rate vs 5.1% for 5&nbsp;mg patients and 11.1% for dulaglutide.<ref>{{cite journal | vauthors = Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, Haupt A | display-authors = 6 | title = 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 | journal = [[The Lancet]] | volume = 392 | issue = 10160 | pages = 2180–2193 | date = November 2018 | pmid = 30293770 | doi = 10.1016/S0140-6736(18)32260-8 | doi-access = free | title-link = doi }}</ref> To a slightly lesser extent, patients also reported reduced appetite.<ref name="ae" /> Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.<ref>{{cite journal | vauthors = Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, Milicevic Z, Urva S, Haupt A, Robins DA | display-authors = 6 | title = 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 | journal = [[Diabetes, Obesity & Metabolism]] | volume = 22 | issue = 6 | pages = 938–946 | date = June 2020 | pmid = 31984598 | pmc = 7318331 | doi = 10.1111/dom.13979 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal |vauthors=Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á |title=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 |journal=[[JAMA]] |volume=327 |issue=6 |pages=534–545 |date=February 2022 |pmid=35133415 |doi=10.1001/jama.2022.0078 |pmc=8826179 |pmc-embargo-date=August 8, 2022 }}</ref>
Preclinical, phase I, and phase II 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.<ref name="ae">{{cite journal | vauthors = Min T, Bain SC | title = The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials | journal = Diabetes Therapy | volume = 12 | issue = 1 | pages = 143–157 | date = January 2021 | pmid = 33325008 | pmc = 7843845 | doi = 10.1007/s13300-020-00981-0 | doi-access = free | title-link = doi }}</ref> The most frequently observed adverse effects are nausea, diarrhoea 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&nbsp;mg having a 25% discontinuation rate vs 5.1% for 5&nbsp;mg patients and 11.1% for dulaglutide.<ref>{{cite journal | vauthors = Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, Haupt A | display-authors = 6 | title = 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 | journal = [[The Lancet]] | volume = 392 | issue = 10160 | pages = 2180–2193 | date = November 2018 | pmid = 30293770 | doi = 10.1016/S0140-6736(18)32260-8 | doi-access = free | title-link = doi }}</ref> To a slightly lesser extent, patients also reported reduced appetite.<ref name="ae" /> Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.<ref>{{cite journal | vauthors = Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, Milicevic Z, Urva S, Haupt A, Robins DA | display-authors = 6 | title = 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 | journal = [[Diabetes, Obesity & Metabolism]] | volume = 22 | issue = 6 | pages = 938–946 | date = June 2020 | pmid = 31984598 | pmc = 7318331 | doi = 10.1111/dom.13979 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á | title = 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 | journal = [[JAMA]] | volume = 327 | issue = 6 | pages = 534–545 | date = February 2022 | pmid = 35133415 | doi = 10.1001/jama.2022.0078 | pmc = 8826179 | pmc-embargo-date = August 8, 2022 }}</ref>


== Pharmacology ==
== Pharmacology ==
Tirzepatide 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 [[Lipid-anchored protein#Fatty acylated proteins|modified by lipidation]] to improve its uptake into cells and its stability to [[metabolism]].<ref name=CSR>{{cite journal | vauthors = Ahangarpour M, Kavianinia I, Harris PW, Brimble MA | title = Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design | journal = [[Chemical Society Reviews]] | volume = 50 | issue = 2 | pages = 898–944 | date = January 2021 | pmid = 33404559 | doi = 10.1039/d0cs00354a | publisher = Royal Society of Chemistry | s2cid = 230783854 }}</ref> The compound is administered as a weekly [[Subcutaneous injection|subcutaneous]] injection.<ref>{{cite journal|vauthors=Bastin M, Andreelli F|year=2019|title=Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential|journal=[[Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy]]|volume=12|pages=1973–1985|doi=10.2147/DMSO.S191438|pmc=6777434|pmid=31686879}}</ref> It completed [[Phases of clinical research#Phase III|phase III]] trials globally in 2021.<ref>{{cite press release |url=https://www.prnewswire.com/news-releases/tirzepatide-significantly-reduced-a1c-and-body-weight-in-people-with-type-2-diabetes-in-two-phase-3-trials-from-lillys-surpass-program-301229506.html|title=Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly's SURPASS program|publisher=Eli Lilly and Company|via=PR Newswire|date=17 February 2021|access-date=28 October 2021}}</ref><ref>{{cite web|url=https://markets.businessinsider.com/news/stocks/lilly-phase-3-tirzepatide-results-show-superior-a1c-and-body-weight-reductions-in-type-2-diabetes-1030876853|website=Business Insider|agency=RTTNews|date=October 19, 2021|access-date=28 October 2021|title=Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes}}</ref>
Tirzepatide 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 [[Lipid-anchored protein#Fatty acylated proteins|modified by lipidation]] to improve its uptake into cells and its stability to [[metabolism]].<ref name=CSR>{{cite journal | vauthors = Ahangarpour M, Kavianinia I, Harris PW, Brimble MA | title = Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design | journal = [[Chemical Society Reviews]] | volume = 50 | issue = 2 | pages = 898–944 | date = January 2021 | pmid = 33404559 | doi = 10.1039/d0cs00354a | publisher = Royal Society of Chemistry | s2cid = 230783854 }}</ref> It completed [[Phases of clinical research#Phase III|phase III]] trials globally in 2021.<ref>{{cite press release |url=https://www.prnewswire.com/news-releases/tirzepatide-significantly-reduced-a1c-and-body-weight-in-people-with-type-2-diabetes-in-two-phase-3-trials-from-lillys-surpass-program-301229506.html|title=Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly's SURPASS program|publisher=Eli Lilly and Company|via=PR Newswire|date=17 February 2021|access-date=28 October 2021}}</ref><ref>{{cite web|url=https://markets.businessinsider.com/news/stocks/lilly-phase-3-tirzepatide-results-show-superior-a1c-and-body-weight-reductions-in-type-2-diabetes-1030876853|website=Business Insider|agency=RTTNews|date=October 19, 2021|access-date=28 October 2021|title=Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes}}</ref>


=== Mechanism of action ===
=== Mechanism of action ===
Tirzepatide has a greater affinity to [[Gastric inhibitory polypeptide receptor|GIP receptors]] than to [[GLP-1 receptor]]s, and this dual agonist behaviour has been shown to produce greater reductions of [[hyperglycemia]] compared to a selective GLP-1 receptor agonist.<ref name="moa">{{cite journal | vauthors = Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, Milicevic Z, Haupt A, Robins DA | display-authors = 6 | title = Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes | journal = [[The Journal of Clinical Endocrinology and Metabolism]] | volume = 106 | issue = 2 | pages = 388–396 | date = January 2021 | pmid = 33236115 | pmc = 7823251 | doi = 10.1210/clinem/dgaa863 | doi-access = free | title-link = doi }}</ref> [[Cell signaling |Signaling]] studies have shown that this is due to tirzepatide mimicking the actions of natural [[Gastric inhibitory polypeptide|GIP]] at the GIP receptor.<ref name="moa2">{{cite journal | vauthors = Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, Capozzi ME, van der Velden WJ, Stutsman C, Cardona GR, Urva S, Emmerson PJ, Holst JJ, D'Alessio DA, Coghlan MP, Rosenkilde MM, Campbell JE, Sloop KW | display-authors = 6 | title = Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist | journal = [[JCI Insight]] | volume = 5 | issue = 17 | date = September 2020 | pmid = 32730231 | pmc = 7526454 | doi = 10.1172/jci.insight.140532 | doi-access = free | title-link = doi }}</ref> However, at the [[GLP-1]] receptor, tirzepatide shows bias towards [[Cyclic adenosine monophosphate|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.<ref name="moa2" /> 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% from baseline after 26 weeks, at the 10&nbsp;mg dosage.<ref name="moa" />
Tirzepatide has a greater affinity to [[Gastric inhibitory polypeptide receptor|GIP receptors]] than to [[GLP-1 receptor]]s, and this dual agonist behavior has been shown to produce greater reductions of [[hyperglycemia]] compared to a selective GLP-1 receptor agonist.<ref name="moa">{{cite journal | vauthors = Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, Milicevic Z, Haupt A, Robins DA | display-authors = 6 | title = Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes | journal = [[The Journal of Clinical Endocrinology and Metabolism]] | volume = 106 | issue = 2 | pages = 388–396 | date = January 2021 | pmid = 33236115 | pmc = 7823251 | doi = 10.1210/clinem/dgaa863 | doi-access = free | title-link = doi }}</ref> [[Cell signaling |Signaling]] studies have shown that this is due to tirzepatide mimicking the actions of natural [[Gastric inhibitory polypeptide|GIP]] at the GIP receptor.<ref name="moa2">{{cite journal | vauthors = Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, Capozzi ME, van der Velden WJ, Stutsman C, Cardona GR, Urva S, Emmerson PJ, Holst JJ, D'Alessio DA, Coghlan MP, Rosenkilde MM, Campbell JE, Sloop KW | display-authors = 6 | title = Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist | journal = [[JCI Insight]] | volume = 5 | issue = 17 | date = September 2020 | pmid = 32730231 | pmc = 7526454 | doi = 10.1172/jci.insight.140532 | doi-access = free | title-link = doi }}</ref> However, at the [[GLP-1]] receptor, tirzepatide shows bias towards [[Cyclic adenosine monophosphate|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.<ref name="moa2" /> 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% from baseline after 26 weeks, at the 10&nbsp;mg dosage.<ref name="moa" />


== Chemistry ==
== Chemistry ==


=== Structure ===
=== Structure ===
Tirzepatide is an [[analog (chemistry)|analog]] of the human GIP hormone with a C<sub>20</sub> fatty-diacid portion attached, used to optimise the [[ADME|uptake and metabolism]] of the compound.<ref name="CSR" /> 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]].<ref>{{cite journal|display-authors=6|vauthors=Østergaard S, Paulsson JF, Kofoed J, Zosel F, Olsen J, Jeppesen CB, Spetzler J, Ynddal L, Schleiss LG, Christoffersen BØ, Raun K, Sensfuss U, Nielsen FS, Jørgensen R, Wulff BS|date=October 2021|title=The effect of fatty diacid acylation of human PYY<sub>3-36</sub> on Y<sub>2</sub> receptor potency and half-life in minipigs|journal=[[Scientific Reports]]|volume=11|issue=1|pages=21179|bibcode=2021NatSR..1121179O|doi=10.1038/s41598-021-00654-3|pmc=8551270|pmid=34707178|doi-access=free}}</ref>
Tirzepatide is an [[analog (chemistry)|analog]] of the human GIP hormone with a C<sub>20</sub> fatty-diacid portion attached, used to optimise the [[ADME|uptake and metabolism]] of the compound.<ref name="CSR" /> 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]].<ref>{{cite journal | display-authors = 6 | vauthors = Østergaard S, Paulsson JF, Kofoed J, Zosel F, Olsen J, Jeppesen CB, Spetzler J, Ynddal L, Schleiss LG, Christoffersen BØ, Raun K, Sensfuss U, Nielsen FS, Jørgensen R, Wulff BS | date = October 2021 | title = The effect of fatty diacid acylation of human PYY<sub>3-36</sub> on Y<sub>2</sub> receptor potency and half-life in minipigs | journal = [[Scientific Reports]] | volume = 11 | issue = 1 | pages = 21179 | bibcode = 2021NatSR..1121179O | doi = 10.1038/s41598-021-00654-3 | pmc = 8551270 | pmid = 34707178 | doi-access = free | title-link = doi }}</ref>


=== Synthesis ===
=== Synthesis ===
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== History ==
== History ==
Indiana-based pharmaceutical company [[Eli Lilly and Company]] first applied for a patent for a method of glycemic control using tirzepatide in early 2016.<ref name="patent" /> The patent was published late that year. After passing [[phase 3 clinical trial]]s, Lilly applied for FDA approval in October 2021 with a [[priority review]] voucher.<ref>{{Cite web |last=Sagonowsky |first=Eric |date=2021-10-26 |title=As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth |url=https://www.fiercepharma.com/pharma/as-lilly-gears-up-for-key-2022-launches-its-existing-meds-post-solid-growth |access-date=2022-04-09 |website=Fierce Pharma }}</ref>
[[Eli Lilly and Company]] first applied for a patent for a method of glycemic control using tirzepatide in early 2016.<ref name="patent" /> The patent was published late that year. After passing [[phase III clinical trial]]s, Lilly applied for FDA approval in October 2021, with a [[priority review]] voucher.<ref>{{Cite web |last=Sagonowsky |first=Eric |date=2021-10-26 |title=As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth |url=https://www.fiercepharma.com/pharma/as-lilly-gears-up-for-key-2022-launches-its-existing-meds-post-solid-growth |access-date=2022-04-09 |website=Fierce Pharma }}</ref>


Following the completion of the [[Pivotal trial|pivotal]] SURPASS-2 trial no. NCT03987919, the company announced on 28 April that tirzepatide had successfully met their [[clinical endpoint|endpoint]]s in obese and overweight patients without diabetes.<ref>{{cite web |last=Kellaher |first=Colin |date=April 28, 2022 |title=Eli Lilly's Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study >LLY |url=https://www.marketwatch.com/story/eli-lilly-s-tirzepatide-meets-main-endpoints-in-phase-3-obesity-study-lly-271651143389 |access-date=April 29, 2022 |work=[[Dow Jones & Company|Dow Jones Newswires]] |via=[[MarketWatch]]}}</ref> Alongside results from the SURMOUNT-1 trial no. NCT04184622, they suggest that tirzepatide may potentially be a competitor for existing diabetic medication [[semaglutide]], manufactured by [[Novo Nordisk]].<ref>{{cite web |last1=Kahan |first1=Scott |last2=Garvey |first2=W. Timothy |date=April 28, 2022 |title=SURMOUNT-1: Adults achieve weight loss of 16% or more at 72 weeks with tirzepatide |url=https://www.healio.com/news/endocrinology/20220428/surmount1-adults-achieve-weight-loss-of-16-or-more-at-72-weeks-with-tirzepatide |access-date=April 29, 2022 |work=healio.com}}</ref><ref>{{cite web |last=Taylor |first=Nick Paul |date=April 28, 2022 |title=SURMOUNT-able: Lilly's tirzepatide clears high bar set by Novo's Wegovy in obesity |url=https://www.fiercebiotech.com/biotech/surmount-able-lillys-tirzepatide-clears-high-bar-set-novos-wegovy-obesity |access-date=April 29, 2022 |work=[[FierceBiotech]]}}</ref>
Following the completion of the SURPASS-2 trial (NCT03987919), the company announced on 28 April that tirzepatide had successfully met their [[clinical endpoint|endpoint]]s in obese and overweight patients without diabetes.<ref>{{cite web |last=Kellaher |first=Colin |date=April 28, 2022 |title=Eli Lilly's Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study |url=https://www.marketwatch.com/story/eli-lilly-s-tirzepatide-meets-main-endpoints-in-phase-3-obesity-study-lly-271651143389 |access-date=April 29, 2022 |agency=[[Dow Jones Newswires]] |work=[[MarketWatch]]}}</ref> Alongside results from the SURMOUNT-1 trial (NCT04184622), they suggest that tirzepatide may potentially be a competitor for existing diabetic medication [[semaglutide]], manufactured by [[Novo Nordisk]].<ref>{{cite web |last1=Kahan |first1=Scott |last2=Garvey |first2=W. Timothy |date=April 28, 2022 |title=SURMOUNT-1: Adults achieve weight loss of 16% or more at 72 weeks with tirzepatide |url=https://www.healio.com/news/endocrinology/20220428/surmount1-adults-achieve-weight-loss-of-16-or-more-at-72-weeks-with-tirzepatide |access-date=April 29, 2022 |work=healio.com}}</ref><ref>{{cite web |last=Taylor |first=Nick Paul |date=April 28, 2022 |title=SURMOUNT-able: Lilly's tirzepatide clears high bar set by Novo's Wegovy in obesity |url=https://www.fiercebiotech.com/biotech/surmount-able-lillys-tirzepatide-clears-high-bar-set-novos-wegovy-obesity |access-date=April 29, 2022 |work=[[FierceBiotech]]}}</ref>


In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication [[semaglutide]] (an injected analogue of the hormone [[Glucagon-like peptide-1|GLP-1]]), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in [[glycated hemoglobin]] tests relative to semaglutide (1.86%).<ref>{{cite journal | vauthors = Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, Liu B, Cui X, Brown K | display-authors = 6 | title = Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes | journal = [[The New England Journal of Medicine]] | volume = 385 | issue = 6 | pages = 503–515 | date = August 2021 | pmid = 34170647 | doi = 10.1056/NEJMoa2107519 | s2cid = 235635529 }}</ref> A 10&nbsp;mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using [[Homeostatic model assessment|HOMA2-IR]] (computed with fasting insulin).<ref name="moa" /> Fasting levels of [[Insulin-like growth factor|IGF]] binding proteins like [[IGFBP1]] and [[IGFBP2]] increased following tirzepatide treatment, increasing insulin sensitivity.<ref name="moa" />
In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication [[semaglutide]] (an injected analogue of the hormone [[Glucagon-like peptide-1|GLP-1]]), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in [[glycated hemoglobin]] tests relative to semaglutide (1.86%).<ref>{{cite journal | vauthors = Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, Liu B, Cui X, Brown K | display-authors = 6 | title = Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes | journal = [[The New England Journal of Medicine]] | volume = 385 | issue = 6 | pages = 503–515 | date = August 2021 | pmid = 34170647 | doi = 10.1056/NEJMoa2107519 | s2cid = 235635529 }}</ref> A 10&nbsp;mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using [[Homeostatic model assessment|HOMA2-IR]] (computed with fasting insulin).<ref name="moa" /> Fasting levels of [[Insulin-like growth factor|IGF]] binding proteins like [[IGFBP1]] and [[IGFBP2]] increased following tirzepatide treatment, increasing insulin sensitivity.<ref name="moa" />

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 to date to tackle the global problem of "[[diabesity]]".<ref>{{cite journal | vauthors = Dutta D, Surana V, Singla R, Aggarwal S, Sharma M | title = 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. |journal = [[Indian Journal of Endocrinology and Metabolism]] | volume = 25 | issue = 6 | pages = 475–489 | date = Nov–Dec 2021 | doi= 10.4103/ijem.ijem_423_21 | pmid = 35355921 | pmc = 8959203 }}</ref>
A meta-analysis showed that over one-year clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction.<ref>{{cite journal | vauthors = Dutta D, Surana V, Singla R, Aggarwal S, Sharma M | title = 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. |journal = [[Indian Journal of Endocrinology and Metabolism]] | volume = 25 | issue = 6 | pages = 475–489 | date = Nov–Dec 2021 | doi= 10.4103/ijem.ijem_423_21 | pmid = 35355921 | pmc = 8959203 }}</ref>


== Society and culture ==
== Society and culture ==
=== Names ===
=== Names ===
Tirzepatide is the international nonproprietary name (INN).<ref>{{cite journal | vauthors = ((World Health Organization)) | year = 2019 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81 | journal = WHO Drug Information | volume = 33 | issue = 1 | page = | hdl = 10665/330896 | hdl-access = free | author-link = World Health Organization }}</ref>
Tirzepatide is the [[international nonproprietary name]] (INN).<ref>{{cite journal | vauthors = ((World Health Organization)) | year = 2019 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81 | journal = WHO Drug Information | volume = 33 | issue = 1 | page = | hdl = 10665/330896 | hdl-access = free | author-link = World Health Organization }}</ref>


==References==
==References==

Revision as of 05:05, 28 May 2022

Tirzepatide
Clinical data
Trade namesMounjaro
Other namesLY3298176, GIP/GLP-1 RA
License data
Routes of
administration		Subcutaneous
Drug classAntidiabetic, GLP-1 receptor agonist
ATC code
  • None
Legal status
Legal status
Identifiers
  • (2S)-2-[[20-[[(5S)-6-[[(2S,3S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-2-methylpropanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-2-methylpropanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-6-oxohexyl]amino]-20-oxoicosanoyl]amino]-5-[2-[2-[2-[2-[2-(carboxymethoxy)ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-5-oxopentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC225H348N48O68
Molar mass4813.527 g·mol−1
3D model (JSmol)
  • C[C@@H](O)[C@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)C(C)(C)NC(=O)[C@@H](N)CC1C=CC(O)=CC=1)C(=O)N[C@@H](CC1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NC(C)(C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CC[C@@H](NC(=O)CCCCCCCCCCCCCCCCCCC(O)=O)C(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2C=CC=CC1=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(N)=O
  • InChI=1S/C225H348N48O68/c1-23-126(10)183(264-198(311)146(64-50-52-88-226)246-202(315)157(109-180(297)298)252-199(312)152(103-124(6)7)261-223(337)225(21,22)269-217(330)185(128(12)25-3)266-209(322)163(120-278)257-200(313)153(107-138-74-78-141(282)79-75-138)250-203(316)158(110-181(299)300)253-207(320)162(119-277)259-216(329)187(134(18)280)267-206(319)155(106-136-60-44-41-45-61-136)254-215(328)186(133(17)279)262-174(289)114-237-193(306)147(83-87-179(295)296)260-222(336)224(19,20)268-192(305)143(227)104-137-72-76-140(281)77-73-137)214(327)242-131(15)190(303)244-148(80-84-168(228)283)196(309)245-145(65-51-53-89-231-175(290)121-340-100-99-339-97-91-233-176(291)122-341-101-98-338-96-90-232-170(285)86-82-150(221(334)335)243-171(286)70-46-38-36-34-32-30-28-26-27-29-31-33-35-37-39-47-71-178(293)294)195(308)240-130(14)191(304)248-154(105-135-58-42-40-43-59-135)205(318)263-182(125(8)9)212(325)247-149(81-85-169(229)284)197(310)251-156(108-139-111-234-144-63-49-48-62-142(139)144)201(314)249-151(102-123(4)5)204(317)265-184(127(11)24-2)213(326)241-129(13)189(302)236-112-172(287)235-115-177(292)270-92-54-66-164(270)210(323)258-161(118-276)208(321)256-160(117-275)194(307)238-113-173(288)239-132(16)218(331)272-94-56-68-166(272)220(333)273-95-57-69-167(273)219(332)271-93-55-67-165(271)211(324)255-159(116-274)188(230)301/h40-45,48-49,58-63,72-79,111,123-134,143,145-167,182-187,234,274-282H,23-39,46-47,50-57,64-71,80-110,112-122,226-227H2,1-22H3,(H2,228,283)(H2,229,284)(H2,230,301)(H,231,290)(H,232,285)(H,233,291)(H,235,287)(H,236,302)(H,237,306)(H,238,307)(H,239,288)(H,240,308)(H,241,326)(H,242,327)(H,243,286)(H,244,303)(H,245,309)(H,246,315)(H,247,325)(H,248,304)(H,249,314)(H,250,316)(H,251,310)(H,252,312)(H,253,320)(H,254,328)(H,255,324)(H,256,321)(H,257,313)(H,258,323)(H,259,329)(H,260,336)(H,261,337)(H,262,289)(H,263,318)(H,264,311)(H,265,317)(H,266,322)(H,267,319)(H,268,305)(H,269,330)(H,293,294)(H,295,296)(H,297,298)(H,299,300)(H,334,335)/t126-,127-,128-,129-,130-,131-,132-,133+,134+,143-,145-,146-,147-,148-,149-,150+,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,167-,182-,183-,184-,185-,186-,187-/m0/s1
  • Key:BTSOGEDATSQOAF-SMAAHMJQSA-N

Tirzepatide, sold under the brand name Mounjaro, is a medication used for the treatment type 2 diabetes.[1][2][3][4] Tirzepatide is given by subcutaneous injection under the skin.[1][2] Common side effects may include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain.[1][2]

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood sugar control.[2] Tirzepatide is a first-in-class medication that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.[2] Tirzepatide was approved for medical use in the United States in May 2022.[1][2]

Medical uses

Tirzepatide in indicated to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.[1][2]

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.[2]

Adverse effects

Preclinical, phase I, and phase II 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.[5] The most frequently observed adverse effects are nausea, diarrhoea 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.[6] To a slightly lesser extent, patients also reported reduced appetite.[5] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.[7][8]

Pharmacology

Tirzepatide 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.[9] It completed phase III trials globally in 2021.[10][11]

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.[3] Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor.[12] 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 and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.[12] 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% from baseline after 26 weeks, at the 10 mg dosage.[3]

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.[9] 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.[13]

Synthesis

The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company.[14] 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.[15]

History

Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.[14] 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.[16]

Following the completion of the SURPASS-2 trial (NCT03987919), the company announced on 28 April that tirzepatide had successfully met their endpoints in obese and overweight patients without diabetes.[17] Alongside results from the SURMOUNT-1 trial (NCT04184622), they suggest that tirzepatide may potentially be a competitor for existing diabetic medication semaglutide, manufactured by Novo Nordisk.[18][19]

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%).[20] 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).[3] Fasting levels of IGF binding proteins like IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[3]

A meta-analysis showed that over one-year clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction.[21]

Society and culture

Names

Tirzepatide is the international nonproprietary name (INN).[22]

References

  1. ^ a b c d e f "Mounjaro- tirzepatide injection, solution". DailyMed. 13 May 2022. Retrieved 27 May 2022.
  2. ^ a b c d e f g h i "FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes". U.S. Food and Drug Administration (FDA) (Press release). 13 May 2022. Retrieved 13 May 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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. PMC 8826179. PMID 35133415.{{cite journal}}: CS1 maint: PMC embargo expired (link)
  9. ^ 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. 50 (2). Royal Society of Chemistry: 898–944. doi:10.1039/d0cs00354a. PMID 33404559. S2CID 230783854.
  10. ^ "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. Retrieved 28 October 2021 – via PR Newswire.
  11. ^ "Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes". Business Insider. RTTNews. 19 October 2021. Retrieved 28 October 2021.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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 
  15. ^ 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.
  16. ^ Sagonowsky, Eric (26 October 2021). "As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth". Fierce Pharma. Retrieved 9 April 2022.
  17. ^ Kellaher, Colin (28 April 2022). "Eli Lilly's Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study". MarketWatch. Dow Jones Newswires. Retrieved 29 April 2022.
  18. ^ Kahan, Scott; Garvey, W. Timothy (28 April 2022). "SURMOUNT-1: Adults achieve weight loss of 16% or more at 72 weeks with tirzepatide". healio.com. Retrieved 29 April 2022.
  19. ^ Taylor, Nick Paul (28 April 2022). "SURMOUNT-able: Lilly's tirzepatide clears high bar set by Novo's Wegovy in obesity". FierceBiotech. Retrieved 29 April 2022.
  20. ^ 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.
  21. ^ Dutta D, Surana V, Singla R, Aggarwal S, Sharma M (November–December 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. PMC 8959203. PMID 35355921.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ World Health Organization (2019). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81". WHO Drug Information. 33 (1). hdl:10665/330896.

Further reading

External links

  • "Tirzepatide". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03954834 for "A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1)" at ClinicalTrials.gov
  • Clinical trial number NCT03987919 for "A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2)" at ClinicalTrials.gov
  • Clinical trial number NCT03882970 for "A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes (SURPASS-3)" at ClinicalTrials.gov
  • Clinical trial number NCT03730662 for "A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)" at ClinicalTrials.gov
  • Clinical trial number NCT04039503 for "A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5)" at ClinicalTrials.gov
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