How is Mounjaro different than a GLP-1 receptor agonist?
[Healthcare Professional]
Hi, my name is Dr. Ebon Bourne and today we’re going to learn about the mechanism of action of Mounjaro.
Mounjaro is a glucose-dependent insulinotropic polypeptide, or GIP, and glucagon-like peptide-1, or GLP-1, receptor agonist.
At times, Mounjaro has been incorrectly categorized as a GLP-1 receptor agonist within the class of incretin-based therapies.
However, Mounjaro works differently—by binding to both the GIP and GLP-1 receptors in the body. Today, we’ll discuss GIP, GLP-1, and Mounjaro—a treatment option for adults with type 2 diabetes.
First, let’s review the Indication and Boxed Warning for Mounjaro.
Mounjaro is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Mounjaro has a Boxed Warning related to the 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.
Now, let’s take a closer look at the incretin hormones. GIP and GLP-1 interact with their respective receptors in various tissues throughout the body, eliciting a range of pleiotropic effects. Notably, both GIP and GLP-1 receptors are abundantly expressed in the pancreas, where GIP and GLP-1 have a role in regulating blood glucose levels.
When blood glucose is low in people without type 2 diabetes, GIP enhances glucagon secretion to increase hepatic glucose production and normalize blood glucose levels.
On the other hand, when blood glucose levels are high, GLP-1 inhibits glucagon secretion, and both GIP and GLP-1 enhance insulin secretion to promote cellular glucose uptake and return blood glucose to a normal level.
Together, GIP and GLP-1 potentiate glucose-induced insulin secretion through the incretin effect, which is responsible for approximately 70% of insulin secretion after nutrient absorption in the gut.
Since GIP and GLP-1 are secreted in response to nutrients in the gut, there is a marked difference in insulin secretion following oral versus intravenous glucose administration in people without type 2 diabetes, a phenomenon known as the incretin effect.
In people with type 2 diabetes, the incretin effect is diminished, likely due to changes in insulinotropic activities of GIP and GLP-1.
But GIP and GLP-1 don’t contribute equally to the incretin effect.
In fact, GIP is responsible for nearly two-thirds of the incretin effect, acting as a primary mediator of insulin secretion.
In addition to the functions we’ve already discussed, preclinical studies indicate GIP can increase lipid storage and utilization, increase insulin sensitivity via direct action on adipocytes, and decrease food intake.
Now that we’ve learned about GIP and GLP-1, let’s take a look at one incretin-based treatment option for patients with type 2 diabetes.
Mounjaro is based on the native GIP sequence but modified to also bind to the GLP-1 receptor. This results in a single molecule that selectively binds to and activates both GIP and GLP-1 receptors in the body to improve glycemic control in adults with type 2 diabetes.
In this way, Mounjaro works differently than a GLP-1 receptor agonist.
In terms of mechanism of action, Mounjaro enhances insulin secretion, improves insulin sensitivity, decreases food intake, delays gastric emptying, and reduces glucagon levels, resulting in lower glucose concentrations in both fasting and postprandial states.
I hope you enjoyed learning about GIP, GLP-1, and Mounjaro’s mechanism of action.
And remember—Mounjaro works differently than a GLP-1 receptor agonist.
Thank you and see you next time!
[Select Important Safety Information]
Contraindications
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 (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. 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 greater than 50 nanograms per liter. 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.
Acute Pancreatitis
Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, or 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 (for example, 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 (for example, anaphylaxis and 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 tirzepatide or any of the excipients in 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 Due to Volume Depletion
There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, or Mounjaro. The majority of reported events occurred in patients who experienced gastrointestinal adverse reactions leading to dehydration such as nausea, vomiting, or diarrhea. Monitor renal function in patients reporting adverse reactions to Mounjaro that could lead to volume depletion, especially during dosage initiation and escalation of Mounjaro.
Severe Gastrointestinal Adverse Reactions
Use of Mounjaro has been associated with gastrointestinal adverse reactions, sometimes severe. In the pool of placebo-controlled trials, severe gastrointestinal adverse reactions occurred more frequently among patients receiving Mounjaro (5 milligrams 1.3%, 10 milligrams 0.4%, 15 milligrams 1.2%) than placebo (0.9%). Mounjaro is not recommended in patients with severe gastroparesis.
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.
Pulmonary Aspiration During General Anesthesia or Deep Sedation
Mounjaro delays gastric emptying. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking Mounjaro.
Adverse Reactions
The most common adverse reactions reported in greater than or equal to 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 pediatric patients.
Please see the Full Prescribing Information, including Boxed Warning about possible thyroid tumors, including thyroid cancer, and Medication Guide by clicking the links within www.mounjaro.lilly.com/hcp.
Please see Instructions for Use included with the pen.
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