Tirzepatide is an antidiabetic medication used to treat type2 diabetes and for

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

. Tirzepatide is administered via subcutaneous injections (under the skin). 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 Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial airway obstruction, obstruction of the respiratory tract#Upper respiratory tract, upper airway lea ...

. Tirzepatide is a gastric inhibitory polypeptide (GIP) analog and a GLP-1 receptor agonist. The most common side effects include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

decreased appetite Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while o ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

, upper abdominal discomfort, and

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

. Developed by

Eli Lilly and Company Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...

, tirzepatide was approved for treatment of diabetes in the US in May 2022, in the European Union in September 2022, in Canada in November 2022, and in Australia in December 2022. The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) considers it a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

. The FDA approved it for weight loss in November 2023. Also in November 2023, the UK

Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are accepta ...

revised the indication for tirzepatide (as Mounjaro) to include the treatment for weight management and weight loss. In December 2024, the FDA revised the indication for tirzepatide (as Zepbound) to include the treatment of moderate to severe obstructive sleep apnea.

Medical uses

Tirzepatide (as Mounjaro) is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

as an adjunct to diet and exercise to improve glycemic control in adults with

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

. 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. Zepbound is also approved for the treatment of moderate-to-severe

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 Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

indicated that tirzepatide exhibits adverse effects similar to those of other established GLP-1 receptor agonists, such as dulaglutide (sold as Trulicity) and

semaglutide Semaglutide is an anti-diabetic medication used for the treatment of type2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a ...

(sold as Wegovy, Ozempic, and Rybelsus). 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 (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. To a slightly lesser extent, patients also reported reduced appetite. Other side effects reported were

dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

, constipation, abdominal pain, dizziness, and

hypoglycaemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

. A systematic review published in 2024 found that tirzepatide is well tolerated and not associated with

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

Pharmacology

Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a human hormone that stimulates the release of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

from the

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

. Tirzepatide is a linear

polypeptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...

of 39

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

that has been chemically modified by lipidation to improve its uptake into cells and its stability to

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. 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 Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluc ...

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 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certai ...

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. Tirzepatide has been reported to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...

, 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 (eicosanedioic acid) is linked via a

glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α- amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can ...

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 Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

Synthesis

The synthesis of tirzepatide was first disclosed in patents filed by

in 2016. This uses standard solid phase peptide synthesis, with an allyloxycarbonyl

protecting group A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. In man ...

on the

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

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 trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phase ...

s, Eli Lilly applied to the US

(FDA) for approval in 2021, with a priority review voucher. 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. 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

(1.86%). 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). Fasting levels of

insulin-like growth factor The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF ...

(IGF) binding proteins such as

IGFBP1 Insulin-like growth factor-binding protein 1 (IBP-1) also known as placental protein 12 (PP12) is a protein that in humans is encoded by the ''IGFBP1'' gene. Function This gene is a member of the Insulin-like growth factor-binding protein (IGF ...

and

IGFBP2 Insulin-like growth factor-binding protein 2 is a protein that in humans is encoded by the ''IGFBP2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucl ...

increased after tirzepatide treatment, increasing insulin sensitivity. 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 (including Puerto Rico). 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 (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. Tirzepatide's benefits for the treatment of adult participants with type 2 diabetes were primarily evaluated in five clinical trials. In two of these (NCT03954834 and NCT04039503), 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 were completed. Treatment was given for 40 weeks. 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. 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 (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. 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. 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 (176-week treatment period) found that tirzepatide reduced the risk of developing type 2 diabetes by 94% in adults with pre-diabetes and

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

overweight Being overweight is having more body fat than is optimally healthy. Being overweight is especially common where food supplies are plentiful and lifestyles are sedentary. , excess weight reached epidemic proportions globally, with more than ...

Meta-analysis

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 Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...

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 I −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).

Society and culture

Legal status

The US

(FDA) granted the application for tirzepatide priority review designation. The FDA approved Mounjaro for use in the US in 2022. In July 2022, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

adopted a positive opinion, recommending granting a marketing authorization for the medicinal product Mounjaro, intended for the treatment of type2 diabetes. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Tirzepatide was approved for medical use in the European Union in September 2022. In December 2024, the FDA approved tirzepatide (Zepbound) as the first medication to be used in the treatment of moderate to severe

. 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. The FDA granted the approval of Zepbound to Eli Lilly.

Shortage

In the US, 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. The FDA declared a shortage of tirzepatide in December 2022. 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. The US 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. 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.

Research

In a phase III trial, tirzepatide demonstrated clinically significant benefits among participants with obesity and heart failure with preserved ejection fraction. 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 A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics ...

treatment, and CV mortality—by 38% compared to a placebo. A systematic review and meta-analysis published in 2024 found that tirzepatide demonstrates benefits in the management of metabolic dysfunction–associated steatotic liver disease.

References

External links

* * * * * {{Authority control Drugs developed by Eli Lilly and Company GLP-1 receptor agonists GIP receptor agonists Hormones of the digestive system Neuropeptides Peptide hormones Peptide therapeutics