The most frequent side-effects of tirzepatide include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain.[9][13][15] Developed by Eli Lilly and Company, 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,[16] and in Australia in December 2022.[2] The U.S. Food and Drug Administration (FDA) considers it a first-in-class medication.[17][18] The FDA approved it for weight loss in November 2023.[19] Also in November 2023, the U.K. Medicines and Healthcare products Regulatory Agency revised the indication for tirzepatide (as Mounjaro) to include the treatment for weight management and weight loss.[8][20] In December 2024, the FDA revised the indication for tirzepatide (as Zepbound) to include the treatment of moderate to severe obstructive sleep apnea.[10] In 2023, tirzepatide was the 110th-most commonly prescribed medication in the U.S., with more than six million prescriptions.[21][22]
Tirzepatide (as Mounjaro) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.[9][13]
Tirzepatide (as Zepbound) 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.[10][23] Zepbound is also approved for the treatment of moderate-to-severe obstructive sleep apnea in adults with obesity.[10] Within a year after stopping treatment with tirzepatide for obesity, people on average regain more than half the weight they lost during treatment,[24][25] and return to their previous weight within a year and a half.[26]
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.[13]
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 (sold as Trulicity) and semaglutide (sold as Wegovy, Ozempic, and Rybelsus). 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] To a slightly lesser extent, patients also reported reduced appetite.[27] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness, and hypoglycemia.[29][30]
A systematic review published in 2024 found that tirzepatide is well tolerated and not associated with pancreatitis.[31]
In 2026, the UK Medicines and Healthcare products Regulatory Agency (MHRA) 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.[32]
In January 2026, the US Food and Drug Administration requested removal of a suicidal behavior and ideation warning from glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications.[33]
Tirzepatide is an analog 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.[34] It completed phase III trials globally in 2021.[35][36]
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.[37]
Signaling studies reported that tirzepatide mimics the actions of natural GIP at the GIP receptor.[38] At the GLP-1 receptor, though, tirzepatide shows bias toward cAMP (a messenger associated with regulation of glycogen, sugar, and lipid metabolism) 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.[38]
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.[37]
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.[34] 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.[39]
The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company in 2016.[40] 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.[41]
Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in 2016.[40] After passing phase III clinical trials, Eli Lilly applied to the U.S. Food and Drug Administration (FDA) for approval in 2021, with a priority review voucher.[42]
After completing the SURPASS-2 trial (NCT03987919), the company announced in April 2022 that tirzepatide had successfully met its clinical endpoints in obese and overweight participants without diabetes.[43]
In industry-funded preliminary trials, tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to the injected GLP-1 analog semaglutide (1.86%).[44] 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).[37] Fasting levels of insulin-like growth factor (IGF) binding proteins such as IGFBP1 and IGFBP2 increased after tirzepatide treatment, increasing insulin sensitivity.[37]
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.[45]
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, 10, 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).[46][47][48]
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.[49] 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).[49] All nine trials were used to assess its safety, and five were used to evaluate its efficacy.[49] The five used in efficacy evaluation included 6,263 adult participants with type 2 diabetes.[49] 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.[49] Tirzepatide's benefits for the treatment of adult participants with type 2 diabetes were primarily evaluated in five clinical trials.[49] In two of these (NCT03954834 and NCT04039503), participants were randomly assigned to receive either tirzepatide or placebo injection weekly.
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.[23] 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.[23] 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.[23]
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 and obesity or overweight.[50]
The U.S. Food and Drug Administration (FDA) granted the application for tirzepatide priority review designation.[13] The FDA approved Mounjaro for use in the U.S. in 2022.[13]
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.[51] Tirzepatide was approved for medical use in the European Union in September 2022.[11][52]
In December 2024, the FDA approved tirzepatide (Zepbound) as the first medication to be used in the treatment of moderate to severe obstructive sleep apnea.[53][54][55] The FDA granted the application for tirzepatide (Zepbound) fast track, priority review, and breakthrough therapy designations for the treatment of moderate to severe obstructive sleep apnea.[53] The FDA granted the approval of Zepbound to Eli Lilly.[53]
In the U.S., some compounding 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.[56][57][58] The FDA declared a shortage of tirzepatide in December 2022.[59] 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.[60][61]
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.
On April 4, 2025, the Trump Administration declined to finalize a Biden Administration proposal that would have required Medicare, Medicaid, and CHIP to broadly cover GLP-1s for weight loss. Nevertheless, CMS has said it might cover obesity medication in the future.
In November 2025, the Trump Administration announced TrumpRx, an initiative similar to GoodRx to lower the price of GLP-1s to $245 per month for patients covered by Medicaid and CHIP and $50 month for Medicare patients if states opted in. Coverage for patients with obesity and at least one comorbidity (elevated LDL-cholesterol, high blood pressure and/or MASLD) may be implemented as early as April 1, 2026. The cost will be significantly higher because most insurance companies do not cover it in their formulary. Before this change, most Medicaid and CHIP patients paid $3 a month, the same as for brand-name medication.[64]
In a phase III trial, tirzepatide demonstrated clinically significant benefits among participants with obesity and heart failure with preserved ejection fraction.[65][66] Over two years of follow-up, tirzepatide decreased participants' risk of major cardiovascular (CV) complications—a combined endpoint including urgent heart failure visits, hospitalizations, more frequent diuretic treatment, and CV mortality—by 38% compared to a placebo.[67] An observational study on patients with obesity and type 2 diabetes and heart failure with preserved ejection fraction reported that tirzepatide had a lower risk of hospitalization for heart failure and all-cause death combined than sitagliptin.[68][69] In a 72-week, phase IIIb open-label head-to-head trial of adults with obesity without diabetes, tirzepatide at the maximum tolerated dose produced greater mean weight loss than semaglutide and larger reductions in waist circumference, while gastrointestinal adverse events were the most common with both drugs.[70]
A 2024 systematic review found that tirzepatide demonstrates benefits in the management of metabolic dysfunction–associated steatotic liver disease.[71]
