Glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in
blood-sugar control.[13] 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 long-acting GIP-analogue that activates both the GLP-1 and GIP receptors, leading to improved blood-sugar control.[13][11]
In April 2024, the Food and Drug Administration’s drug shortage database indicates most doses of Zepbound and diabetes counterpart Mounjaro will be in short supply through the second quarter 2024.[23]
Medical uses
Tirzepatide is
indicated to improve blood-sugar control in adults with type2 diabetes, as an addition to diet and exercise.[10][13]
Tirzepatide is also indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management.[11][16]
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.[24] 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.[25] To a slightly lesser extent, patients also reported reduced appetite.[24] Other side effects reported were
dyspepsia, constipation, abdominal pain, dizziness, and
hypoglycaemia.[26][27]
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.[14]Signaling studies reported that tirzepatide mimics the actions of natural
GIP at the GIP receptor.[31] 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.[31] 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.[14]
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.[28] 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.[32]
Synthesis
The synthesis of tirzepatide was first disclosed in patents filed by
Eli Lilly and Company.[33] This uses standard
solid phase peptide synthesis, with an
allyloxycarbonylprotecting 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.[34]
History
Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.[33] 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.[35]
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.[36]
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%).[37] 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).[14] Fasting levels of
IGF binding proteins such as
IGFBP1 and
IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[14]
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.[38] The trials were conducted at 673 sites in 24 countries, including Argentina, Australia, Brazil, Canada, India, Israel, Japan, Mexico, Russian Federation, South Korea, Taiwan, European Union, and the United States (including Puerto Rico).[38] All nine trials were used to assess safety and five of these trials were used to assess the efficacy of tirzepatide.[38] The five trials used in the efficacy evaluation included 6,263 adult participants with type 2 diabetes.[38] 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.[38] The benefits of tirzepatide for the treatment of adult participants with type 2 diabetes were primarily evaluated in five clinical trials.[38] In two of these trials (NCT #03954834 and NCT #04039503), participants were randomly assigned to receive either tirzepatide or placebo injection weekly.[38] Neither the patient nor the healthcare provider knew which treatment was being given until after the trials were completed.[38] Treatment was given for 40 weeks.[38] 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.[38] Treatment was given for 40 weeks to 104 weeks.[38] 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.[38]
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.[16] 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.[16] 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.[16]
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.[39]
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).[40][41][42]
Society and culture
Legal status
The FDA granted the application for tirzepatide priority review designation.[13] The FDA approved Mounjaro for use in the United States in 2022.[13]
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.[43] Tirzepatide was approved for medical use in the European Union in September 2022.[12][44]
^
abcd"Mounjaro EPAR". European Medicines Agency (EMA). 18 July 2022.
Archived from the original on 12 December 2022. Retrieved 2 January 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^
abAhangarpour 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.
PMID33404559.
S2CID230783854.
^
abUS 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
^"Mounjaro: Pending EC decision". European Medicines Agency. 22 July 2022.
Archived from the original on 28 July 2022. Retrieved 30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^World Health Organization (2019). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81". WHO Drug Information. 33 (1).
hdl:10665/330896.
Frías JP (November 2020). "Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes". Expert Rev Endocrinol Metab. 15 (6): 379–394.
doi:
10.1080/17446651.2020.1830759.
PMID33030356.
S2CID222213936.