How Mounjaro Works

Mounjaro MOA video

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What is Mounjaro? Mounjaro (tirzepatide), an injectable prescription medicine, is indicated as an adjunt to diet and exercise to improve glycemic control with type 2 diabetes mellitus. Limitations of Use: Mounjaro has not been studied in patients with a history of pancreatitis. Mounjaro is not indicated for use in patients with type 1 diabetes mellitus.

Mounjaro includes a boxed warning related to risk of thyroid C-cell tumors. In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether Mounjaro causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined. Mounjaro is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Mounjaro and inform them of symptoms of thyroid tumors (for example, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Mounjaro.

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How does Mounjaro bind to GIP and GLP-1 receptors?

The native incretin and GLP-1 bind to their respective receptors on beta cells in the pancreas to enhance insulin release.

Mounjaro is a single peptide designed from the structure of native GIP and modified to bind to the GIP and GLP-1 receptors.

While the activity of Mounjaro on the GLP-1 receptor is lower than the activity of the native GLP-1 hormone, the activity of Mounjaro on the GIP receptor is similar to that of the native GIP hormone.

Where does Mounjaro act in the body? In individuals with type 2 diabetes, Mounjaro improves glycemic control through several mechanisms.

It directly stimulates insulin secretion by activating GIP and GLP-1 receptors in the pancreas, improves insulin sensitivity and decreases food intake.

Mounjaro also reduces blood glucagon concentrations and slows postprandial glucose absorption by delaying gastric emptying, though the latter effect is largest after the first dose and diminishes with time.

All these actions work together to lower blood glucose concentration in both the fasting and postprandial states.

Why does Mounjaro only need to be given once weekly?

Mounjaro is given as a subcutaneous injection and typically reaches its maximum plasma concentration within 8 to 72 hours.

It was specifically engineered with a C20 fatty diacid portion that allows binding to serum albumin, extending the elimination half-life to approximately 5 days and enabling once-weekly dosing.

Following initiation of the 2.5-milligram dose, the plasma concentration of Mounjaro increases and reaches a steady state. The same pattern holds true when patients who are already receiving Mounjaro are escalated to a higher dose.

How is Mounjaro metabolized and eliminated in the body?

Mounjaro is metabolized by proteolytic cleavage of the peptide backbone, beta oxidation of the C20 fatty diacid moiety, and amide hydrolysis.

Mounjaro has low potential to inhibit or induce CYP enzymes.

Neither renal impairment nor hepatic impairment impact the overall pharmacokinetics of Mounjaro, so no dose adjustment is recommended for people with either of these conditions.

In summary, Mounjaro is a single molecule that activates the GIP and GLP-1 receptors in the body.

Its structure is based on the amino-acid backbone of native GIP, with modifications to allow binding to GIP and GLP-1 receptors. Its half-life has been extended by the addition of a fatty diacid group to allow once-weekly dosing. It has a multifaceted glucose-lowering action that functions by increasing insulin secretion, improving insulin sensitivity, decreasing food intake, lowering glucagon concentrations, and delaying gastric emptying.

Together, these actions have established Mounjaro as the first in a new class of therapy for people with type 2 diabetes.

Select Important Safety Information

Acute Gallbladder Disease: In clinical trials, acute gallbladder disease was reported by 0.6% of Mounjaro-treated patients and 0% of placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Mounjaro works differently than a GLP-1 RA¹

Tirzepatide is the first and only approved single molecule that activates GIP and GLP-1 receptors in the body.¹

Mounjaro acts in the following ways ¹

1. ENHANCES insulin secretion

2. IMPROVES insulin sensitivity.

3. DECREASES food intake.

Additional actions include delayed gastric emptying^*and reduced glucagon levels.

Resulting in lower glucose concentration in both fasting and postprandial states.

*This effect diminishes over time.

GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1; RA=receptor agonist; T2D=type 2 diabetes.

Reference:

Mounjaro. Prescribing Information. Lilly USA, LLC.

INDICATION

Mounjaro (tirzepatide), an injectable prescription medicine, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use: Mounjaro has not been studied in patients with a history of pancreatitis. Mounjaro is not indicated for use in patients with type 1 diabetes mellitus.

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF THYROID C-CELL TUMORS
In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether Mounjaro causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.
Mounjaro is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Mounjaro and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Mounjaro.

Mounjaro is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with known serious hypersensitivity to tirzepatide or any of the excipients in Mounjaro. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with Mounjaro.

Risk of Thyroid C-cell Tumors

Counsel patients regarding the potential risk for MTC with the use of Mounjaro and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Mounjaro. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

Pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists. Pancreatitis has been reported in Mounjaro clinical trials. Mounjaro has not been studied in patients with a prior history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on Mounjaro. Observe patients for signs and symptoms, including persistent severe abdominal pain sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, discontinue Mounjaro and initiate appropriate management.

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Concomitant use with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. The risk of hypoglycemia may be lowered by reducing the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with Mounjaro. If hypersensitivity reactions occur, discontinue use of Mounjaro; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous serious hypersensitivity to Mounjaro. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown if such patients will be predisposed to these reactions with Mounjaro.

Acute Kidney Injury

Mounjaro has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhea. These events may lead to dehydration, which if severe could cause acute kidney injury. In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, sometimes requiring hemodialysis. Some of these events have been reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of Mounjaro in patients with renal impairment reporting severe adverse gastrointestinal reactions.

Severe Gastrointestinal Disease

Use of Mounjaro has been associated with gastrointestinal adverse reactions, sometimes severe. Mounjaro has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Mounjaro has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

Acute Gallbladder Disease

In clinical trials, acute gallbladder disease was reported by 0.6% of Mounjaro-treated patients and 0% of placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Most Common Adverse Reactions

The most common adverse reactions reported in ≥5% of Mounjaro treated patients in placebo controlled trials were nausea diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain.

Drug Interactions

When initiating Mounjaro, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia. Mounjaro delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications, so caution should be exercised.

Pregnancy

Limited data on Mounjaro use in pregnant women are available to inform on drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide. Use only if potential benefit justifies the potential risk to the fetus.

Lactation

There are no data on the presence of tirzepatide in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Mounjaro and any potential adverse effects on the breastfed infant from Mounjaro or from the underlying maternal condition.

Females of Reproductive Potential

Advise females using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation.

Pediatric Use

Safety and effectiveness of Mounjaro have not been established and use is not recommended in patients less than 18 years of age.

Please click to access Prescribing Information, including Boxed Warning about possible thyroid tumors, including thyroid cancer, and Medication Guide.

Please see Instructions for Use included with the pen.

TR HCP ISI 23MAY2023

Mounjaro works differently than a GLP-1 RA1

Tirzepatide is the first and only approved single molecule that activates GIP and GLP-1 receptors in the body.1