Tirzepatide, sold under the brand name Mounjaro, is an
antidiabetic medication
Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), and pramlintide, all are administered orally and are th ...
used for the treatment of
type 2 diabetes
Type 2 diabetes, 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 urinatio ...
.
[ ] Tirzepatide is given by weekly
subcutaneous injection (under the skin).
The most common side effects include
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, 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, gastroenteri ...
,
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
,
decreased appetite
Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others ...
,
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
, 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.
Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
.
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and cert ...
(GLP-1) and
glucose-dependent insulinotropic polypeptide
Glucose-dependent insulinotropic polypeptide (GIP), also known as Gastric inhibitory polypeptide or gastric inhibitory peptide (also abbreviated as GIP), is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor ...
(GIP) are hormones involved in blood sugar control.
Tirzepatide is a
first-in-class medication A first-in-class medication is a pharmaceutical 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 medicat ...
that activates both the GLP-1 and GIP receptors.
It is a GIP-analogue that activates both the GLP-1 and GIP receptors, leading to improved
blood sugar
Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
control.
Tirzepatide was approved for medical use in the United States 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 respon ...
(FDA) considers it to be a first-in-class medication.
[ ]
Medical uses
Tirzepatide 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 ...
to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.
Contraindications
Tirzepatide should not be used in people with a personal or family history of
medullary thyroid cancer
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...
or in people with
multiple endocrine neoplasia syndrome type 2.
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
Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiov ...
. These effects occur largely within the gastrointestinal tract.
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. 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, also 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 triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...
.
Pharmacology
Tirzepatide is an analogue of
gastric inhibitory polypeptide
Glucose-dependent insulinotropic polypeptide (GIP), also known as Gastric inhibitory polypeptide or gastric inhibitory peptide (also abbreviated as GIP), is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor ...
(GIP), a human hormone that stimulates the release of
insulin from the
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
. 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
Metabolism (, from el, μεταβολή ''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 c ...
.
It completed
phase III trials globally in 2021.
Mechanism of action
Tirzepatide has a greater affinity to
GIP receptors than to
GLP-1 receptor
The glucagon-like peptide-1 receptor (GLP1R) is a receptor protein found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised b ...
s, 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.
However, at the
GLP-1
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certa ...
receptor, tirzepatide shows bias towards
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
(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
Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a refere ...
increases insulin secretion.
Tirzepatide has been reported to increase levels of
adiponectin
Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ''ADIPOQ'' gene and it is produ ...
, an
adipokine
The adipokines, or adipocytokines (Greek ', fat; ', cell; and ', movement) are cytokines (cell signaling proteins) secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metabolic ...
involved in the regulation of both glucose and
lipid metabolism
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.
Chemistry
Structure
Tirzepatide is an
analog
Analog or analogue may refer to:
Computing and electronics
* Analog signal, in which information is encoded in a continuous variable
** Analog device, an apparatus that operates on analog signals
*** Analog electronics, circuits which use analog ...
of the human GIP hormone with a C
20 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 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 the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
.
Synthesis
The synthesis of tirzepatide was first disclosed in patents filed by
Eli Lilly and Company.
This uses standard
solid phase peptide synthesis
In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxy ...
, 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
Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.
The patent was published late that year. 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 phases ...
s, Lilly applied for FDA approval in October 2021, with a
priority review
Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
voucher.
Following the completion of the SURPASS-2 trial (NCT03987919), the company announced on 28 April 2022 that tirzepatide had successfully met their
endpoint
An endpoint, end-point or end point may refer to:
* Endpoint (band), a hardcore punk band from Louisville, Kentucky
* Endpoint (chemistry), the conclusion of a chemical reaction, particularly for titration
* Outcome measure, a measure used as an e ...
s in obese and overweight patients without diabetes.
In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication
semaglutide
Semaglutide, sold under the brand names Ozempic, Wegovy and Rybelsus, is an antidiabetic medication used for the treatment of type 2 diabetes and as anti-obesity medication for long-term weight management, developed by Novo Nordisk in 2012.
...
(an injected analogue of the hormone
GLP-1
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certa ...
), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in
glycated hemoglobin
Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously (i.e. non-enzymat ...
tests relative to semaglutide (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
IGF binding proteins like
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 (IGFB ...
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 (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." mean ...
increased following tirzepatide treatment, increasing insulin sensitivity.
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.
In a phase III double-blind, randomized, controlled trial supported by Eli Lilly, non-diabetic 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
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
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 respon ...
(FDA) granted the application for tirzepatide
priority review
Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
designation.
The FDA granted the approval of Mounjaro to
Eli Lilly and Company
On 21 July 2022, the
Committee for Medicinal Products for Human Use
The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regardin ...
(CHMP) of the
European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Mounjaro, intended for the treatment of type 2 diabetes.
[ Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] Mounjaro was approved for medical use in the European Union in September 2022.
Names
Tirzepatide is the
international nonproprietary name (INN).
References
Further reading
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External links
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