Tirzepatide
Tirzepatide is an antidiabetic medication used to treat type2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections. In the United States, it is sold under the brand name Mounjaro for diabetes treatment and Zepbound for weight loss and treatment of obstructive sleep apnea.
Tirzepatide is a gastric inhibitory polypeptide analog and a GLP-1 receptor agonist. The most common side effects include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain.
Developed by Eli Lilly and Company, tirzepatide was approved for treatment of diabetes in the U.S. in May 2022, in the European Union in September 2022, in Canada in November 2022, and in Australia in December 2022. The U.S. Food and Drug Administration considers it a first-in-class medication. The FDA approved it for weight loss in November 2023. Also in November 2023, the U.K. Medicines and Healthcare products Regulatory Agency revised the indication for tirzepatide to include the treatment for weight management and weight loss. In December 2024, the FDA revised the indication for tirzepatide to include the treatment of moderate to severe obstructive sleep apnea. In 2023, tirzepatide was the 110th-most commonly prescribed medication in the U.S., with more than six million prescriptions.
Medical uses
Tirzepatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.Tirzepatide is indicated, alongside a reduced-calorie diet and increased physical activity, for long-term weight reduction in adults with obesity or overweight with at least one weight-related comorbidity. Zepbound is also approved for the treatment of moderate-to-severe obstructive sleep apnea in adults with obesity.
Contraindications
Tirzepatide is contraindicated for use in people with a personal or family history of medullary thyroid cancer and people with multiple endocrine neoplasia syndrome type2.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 and semaglutide. These effects occur largely in the gastrointestinal tract. The most frequently observed are nausea, diarrhea, and vomiting, which increased in incidence with the dosage amount. 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. To a slightly lesser extent, patients also reported reduced appetite. Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness, and hypoglycemia.A systematic review published in 2024 found that tirzepatide is well tolerated and not associated with pancreatitis.
In 2026 the UK Medicines and Healthcare products Regulatory Agency updated its guidance on GLP-1 medication, after an increase in reports of acute pancreatitis to the agency’s yellow card scheme, to warn of a small risk of developing severe acute pancreatitis.
Pharmacology
Tirzepatide is an analog of gastric inhibitory polypeptide, 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. It completed phase III trials globally in 2021.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.Signaling studies reported that tirzepatide mimics the actions of natural GIP at the GIP receptor. At the GLP-1 receptor, though, tirzepatide shows bias toward cAMP generation rather than β-arrestin recruitment. This combination of preference toward GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.
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.
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. The fatty-diacid section is linked via a glutamic acid and two 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.Synthesis
The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company in 2016. 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.
History
first applied for a patent for a method of glycemic control using tirzepatide in 2016. After passing phase III clinical trials, Eli Lilly applied to the U.S. Food and Drug Administration for approval in 2021, with a priority review voucher.After completing the SURPASS-2 trial, the company announced in April 2022 that tirzepatide had successfully met its clinical endpoints in obese and overweight participants without diabetes.
In industry-funded preliminary trials, tirzepatide showed minor improvement of reductions in glycated hemoglobin tests relative to the injected GLP-1 analog semaglutide. 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. Fasting levels of insulin-like growth factor binding proteins such as IGFBP1 and IGFBP2 increased after tirzepatide treatment, increasing insulin sensitivity.
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.
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 or placebo. The mean percentage change in weight at week 72 was −15.0% with 5-mg weekly doses of tirzepatide, −19.5% with 10-mg doses, and −20.9% with 15-mg doses. Weight change in the placebo group was −3.1%.
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. 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. All nine trials were used to assess its safety, and five were used to evaluate its efficacy. The five used in efficacy evaluation included 6,263 adult participants with type 2 diabetes. Four additional trials 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. Tirzepatide's benefits for the treatment of adult participants with type 2 diabetes were primarily evaluated in five clinical trials. In two of these, participants were randomly assigned to receive either tirzepatide or placebo injection weekly. Neither the patient nor the healthcare provider knew which treatment was being given until after the trials. Treatment was given for 40 weeks. In the other three trials, participants were randomly assigned to receive either tirzepatide or another antidiabetic medication, and both the patient and the provider knew which medication was being given. Treatment was given for 40 weeks to 104 weeks. 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.
Tirzepatide's efficacy for chronic weight management 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. These studies measured weight reduction after 72 weeks in 2,519 participants who received either 5, 10, or 15 mg of tirzepatide once weekly and 958 participants who received weekly placebo injections. 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.
In August 2024, the SURMOUNT-1 three-year study found that tirzepatide reduced the risk of developing type 2 diabetes by 94% in adults with pre-diabetes and obesity or overweight.
Society and culture
Legal status
The U.S. Food and Drug Administration granted the application for tirzepatide priority review designation. The FDA approved Mounjaro for use in the U.S. in 2022.In July 2022, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending granting a marketing authorization for the medicinal product Mounjaro, intended for the treatment of type2 diabetes. Tirzepatide was approved for medical use in the European Union in September 2022.
In December 2024, the FDA approved tirzepatide as the first medication to be used in the treatment of moderate to severe obstructive sleep apnea. The FDA granted the application for tirzepatide fast track, priority review, and breakthrough therapy designations for the treatment of moderate to severe obstructive sleep apnea. The FDA granted the approval of Zepbound to Eli Lilly.