Tirzepatide was approved for treatment of diabetes in the U.S. in May 2022,[9][13] in the European Union in September 2022,[11] in Canada in November 2022,[19] and in Australia in December 2022.[2] The U.S.Food and Drug Administration (FDA) considers it afirst-in-class medication.[20][21] The FDA approved it for weight loss in November 2023.[16][22] Also in November 2023, the UKMedicines and Healthcare products Regulatory Agency revised the indication for tirzepatide (as Mounjaro) to include the treatment for weight management and weight loss.[8][23] In December 2024, the FDA revised the indication for tirzepatide (as Zepbound) to include the treatment of moderate to severe obstructive sleep apnea.[10][17]
Tirzepatide (as Mounjaro) isindicated to improveblood sugar control in adults with type2 diabetes, as an addition to diet and exercise.[9][13]
Tirzepatide (as Zepbound) is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity or overweight adults in the presence of at least one weight-related comorbid condition;[10][16] and to treat moderate to severeobstructive sleep apnea in adults with obesity.[10]
In a phase III trial, tirzepatide has demonstrated significant benefits in obese patients with a common type of heart failure, preserved ejection fraction (HFpEF).[24][25] Over two years, tirzepatide reduced the risk of major complications, including urgent heart failure visits, hospitalizations, increased diuretic treatment, and cardiovascular-related deaths, by 38% compared to placebo.[26]
Preclinical, phase I, and phase IIclinical trials indicated that tirzepatide exhibits adverse effects similar to those of other established GLP-1 receptor agonists, such asdulaglutide. These effects occur largely in the gastrointestinal tract.[27] The most frequently observed are nausea, diarrhea, and vomiting, which increased in incidence with the dosage amount (that is, the higher the dose, the higher the likelihood of side effects). The number of patients who discontinued taking tirzepatide also increased as the dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5 mg patients and 11.1% for dulaglutide.[28][clarification needed] To a slightly lesser extent, patients also reported reduced appetite.[27] Other side effects reported weredyspepsia, constipation, abdominal pain, dizziness, andhypoglycaemia.[29][30]
A systematic review published in 2024 found that tirzepatide is well tolerated and not associated withpancreatitis.[31]
Tirzepatide has a greater affinity toGIP receptors than toGLP-1 receptors, and this dual agonist behavior has been shown to produce greater reductions ofhyperglycemia compared to a selective GLP-1 receptor agonist.[14]Signaling studies reported that tirzepatide mimics the actions of naturalGIP at the GIP receptor.[35] At theGLP-1 receptor, though, tirzepatide shows bias towardcAMP (a messenger associated with regulation of glycogen, sugar, and lipid metabolism) generation rather thanβ-arrestin recruitment. This combination of preference toward GIP receptor and distinct signaling properties at GLP-1 suggest thisbiased agonism increases insulin secretion.[35] Tirzepatide has been reported to increase levels ofadiponectin, anadipokine involved in the regulation of both glucose andlipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.[14]
Tirzepatide is ananalog of the human GIP hormone with a C20fatty diacid portion attached, used to optimise theuptake and metabolism of the compound.[32] The fatty-diacid section (eicosanedioic acid) is linked via aglutamic 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 toalbumin.[36]
The synthesis of tirzepatide was first disclosed in patents filed byEli Lilly and Company in 2016.[37] This uses standardsolid phase peptide synthesis, with anallyloxycarbonylprotecting group on thelysine 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.[38]
After completing the SURPASS-2 trial (NCT03987919), the company announced in April 2022 that tirzepatide had successfully met itsclinical endpoints in obese and overweight participants without diabetes.[40]
In industry-funded preliminary trials, tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) inglycated hemoglobin tests relative to the injected GLP-1 analogsemaglutide (1.86%).[41] A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured usingHOMA2-IR (computed with fasting insulin).[14] Fasting levels ofinsulin-like growth factor (IGF) binding proteins such asIGFBP1 andIGFBP2 increased after 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 whom 5,415 received tirzepatide.[42] 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 U.S. (including Puerto Rico).[42] All nine trials were used to assess its safety, and five were used to evaluate its efficacy.[42] The five used in efficacy evaluation included 6,263 adult participants with type 2 diabetes.[42] Four additional trials (NCT03131687, NCT03311724, NCT03861052, and NCT03861039) 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 representing safety findings due to different pools of study participants analyzed for efficacy and safety.[42] Tirzepatide's benefits for the treatment of adult participants with type 2 diabetes were primarily evaluated in five clinical trials.[42] In two of these (NCT03954834 and NCT04039503), participants were randomly assigned to receive either tirzepatide or placebo injection weekly.[42] Neither the patient nor the healthcare provider knew which treatment was being given until after the trials were completed.[42] Treatment was given for 40 weeks.[42] In the other three trials (NCT3987919, NCT03882970, and NCT03730662), participants were randomly assigned to receive either tirzepatide or another antidiabetic medication, and the patient and provider knew which medication was being given.[42] Treatment was given for 40 weeks to 104 weeks.[42] In each trial, HbA1c was measured from the start to the end of the trial and compared between the tirzepatide group and the other groups.[42]
Tirzepatide's efficacy 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 2,519 participants who received either 5 mg, 10 mg, or 15 mg of tirzepatide once weekly and 958 participants who received 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]
In August 2024, the SURMOUNT-1 three-year study (176-week treatment period) found that tirzepatide reduced the risk of developing type 2 diabetes by 94% in adults with pre-diabetes andobesity oroverweight.[43]
A 2021 meta-analysis found that over one year of clinical use, tirzepatide was superior to dulaglutide, semaglutide, insulin degludec, and insulin glargine in improving blood sugar and obesity.[44]
In a phase III double-blind, randomized, controlled trial supported by Eli Lilly, nondiabetic adults with abody 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).[45][46][47]
In July 2022, theCommittee for Medicinal Products for Human Use of theEuropean Medicines Agency adopted a positive opinion, recommending granting a marketing authorization for the medicinal product Mounjaro, intended for the treatment of type2 diabetes.[48] Tirzepatide was approved for medical use in the European Union in September 2022.[11][49]
In December 2024, the FDA approved tirzepatide (Zepbound) as the first medication to be used in the treatment of moderate to severeobstructive sleep apnea.[17][50][51] The FDA granted the application for tirzepatide (Zepbound)fast track,priority review, andbreakthrough therapy designations for the treatment of moderate to severe obstructive sleep apnea.[17] The FDA granted the approval of Zepbound to Eli Lilly.[17]
In the U.S., somecompounding pharmacies prepare compounded versions of a drug on the FDA's drug shortages list if the compounded drug meets certain conditions detailed in federal law.[52][53][54] The FDA declared a shortage of tirzepatide in December 2022.[55] It declared the shortage over in October 2024, but enforcement was delayed until the end of 2024, after a lawsuit by compounding pharmacies challenged the declaration.[56][57]
The U.S.National Association of Boards of Pharmacy says there are tens of thousands of online pharmacies operating out of compliance with state and federal regulations or the association's recommendations.[58] Novo Nordisk has taken action against several compounding pharmacies producing bad versions of the drug, with impurities, the wrong amount of active ingredient, or even no active ingredient.[58] Some compounded versions have been found to containsalts of semaglutide, including thesodium and theacetate, in an attempt to avoid the patent of the base semaglutide product.[59] The FDA has not evaluated these for safety and effectiveness and they are thus considered not to have been shown to be safe or effective.[60]
^abc"Mounjaro EPAR".European Medicines Agency (EMA). 18 July 2022.Archived from the original on 12 December 2022. Retrieved2 January 2023. 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.
^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. Retrieved30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^Kamrul-Hasan AB, Dutta D, Nagendra L, Kuchay MS, Islam MS, Pappachan JM (December 2024). "Hepatobiliary effects and safety of tirzepatide: A systematic review and meta-analysis".Diabetes, Obesity & Metabolism.26 (12):6074–6079.doi:10.1111/dom.15948.PMID39268951.
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.
Clinical trial numberNCT04184622 for "A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1)" atClinicalTrials.gov
Clinical trial numberNCT04657003 for "A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Who Have Obesity or Are Overweight (SURMOUNT-2)" atClinicalTrials.gov
Clinical trial numberNCT04657016 for "A Study of Tirzepatide (LY3298176) In Participants After A Lifestyle Weight Loss Program (SURMOUNT-3)" atClinicalTrials.gov
Clinical trial numberNCT04660643 for "A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight for the Maintenance of Weight Loss (SURMOUNT-4)" atClinicalTrials.gov
Clinical trial numberNCT05412004 for "Obstructive Sleep Apnea Master Protocol GPIF: A Study of Tirzepatide (LY3298176) in Participants With Obstructive Sleep Apnea (SURMOUNT-OSA)" atClinicalTrials.gov
This article incorporates text from this source, which is in thepublic domain.