Reset your expectations with Mounjaro¹

David Kayne, MD, FACP, CDCES:
Hi, I’m David Kayne. I’m board certified in internal medicine and am a certified diabetes care and education specialist. Thank you for joining me today. I’m excited to share some Mounjaro clinical data with you. But 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 and pediatric patients 10 years of age and older with type 2 diabetes mellitus.

Mounjaro also 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 (or MTC), in humans as the 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 (or 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, or 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.

As we consider treatment decisions for our adult patients with type 2 diabetes, it’s helpful to refer to guideline recommendations from the American Diabetes Association and American Association of Clinical Endocrinology. When a patient is diagnosed with type 2 diabetes, we as healthcare professionals have a decision to make: what are you going to treat them with?

Metformin is a commonly used medication that historically has been the first-line treatment for type 2 diabetes in individuals without additional considerations beyond glucose lowering.

Today, guidelines recommend metformin as well as other agents, including combination therapy, that provide adequate efficacy to achieve and maintain individualized glycemic goals. Treatment approaches should also take into consideration additional individualized goals, such as addressing excess weight.

Given the progressive nature of type 2 diabetes, many individuals may require more than one medication in addition to lifestyle modification to achieve and maintain their individualized treatment goals over the course of the disease. When selecting additional therapy, understanding the efficacy and safety profiles of available treatment options is important for making informed treatment decisions.

With that guideline foundation in mind, here’s what we’ll cover in this video: First, I’ll start by reviewing efficacy and safety data from the Mounjaro registrational clinical trials, SURPASS-1 through SURPASS-5, in adults with type 2 diabetes. Then I’ll walk you through the phase 4 SURPASS-EARLY trial, which evaluated Mounjaro and intensified conventional care in adults recently diagnosed with type 2 diabetes.

Let’s start by taking a look at the SURPASS-1 through SURPASS-5 trials, which established the effectiveness of Mounjaro as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Mounjaro was studied as monotherapy and as an add-on to various standard-of-care medications for type 2 diabetes. As you can see here in trials that allowed background glucose-lowering therapy, various combinations of metformin, sodium-glucose co-transporter 2, or SGLT2, inhibitors, sulfonylureas, and basal insulin were permitted. Comparator treatments including placebo, Ozempic^® 1 milligram, Tresiba^®, and insulin glargine. Mean type 2 diabetes duration for the patients in these SURPASS trials ranged from 4.7 years to 13.3 years.

Each of these SURPASS trials used a similar study design. A detailed study description for SURPASS-1 through SURPASS-5 can be viewed at the end of this presentation. Across these studies, patients were randomized to receive Mounjaro 5 milligrams, 10 milligrams, or 15 milligrams once weekly, or a comparator treatment, with or without background antihyperglycemic therapy, depending on the trial.

For patients in the Mounjaro treatment arms, all patients started on a dose of 2.5 milligrams once weekly. The dose was escalated by 2.5 milligrams every 4 weeks until the target dose was reached.

The primary endpoint was evaluated at 40 weeks in SURPASS-1, SURPASS-2, and SURPASS-5 and at 52 weeks in SURPASS-3 and SURPASS-4.

Now let's take a look at the primary endpoint, mean change in glycated hemoglobin, or A1C, from baseline.

Across 5 trials in adults with type 2 diabetes, Mounjaro delivered superior A1C reductions, compared with placebo or active comparator. All 3 doses of Mounjaro demonstrated superior A1C reductions versus comparators, with mean A1C reductions ranging from 1.7% to 2.4% with Mounjaro and 0.1% to 1.9% with comparators.

As a key secondary endpoint in adults with type 2 diabetes, Mounjaro consistently demonstrated greater weight reductions than comparators across the SURPASS-1 through SURPASS-5 studies.

Reductions in body weight ranged from 12 to 25 pounds with Mounjaro, while with comparators, changes in weight ranged from 13-pound reduction to a 4-pound increase.

Please note that Mounjaro is not indicated for weight loss.

Now let’s take a look at safety data from the pool of placebo-controlled trials in adults with type 2 diabetes.

In the pool of placebo-controlled trials, adverse reactions reported in at least 5% of patients taking Mounjaro included nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. Treatment discontinuation due to gastrointestinal-related adverse events ranged from 3% to 7% for the Mounjaro 5-, 10-, and 15-milligram arms and was 0% for the placebo arm.

Before moving on, I’d like to highlight Select Important Safety Information related to acute kidney injury due to volume depletion and severe gastrointestinal adverse reactions. Use of Mounjaro has been associated with gastrointestinal reactions, sometimes severe. The majority of acute kidney injury events occurred in patients who experienced gastrointestinal adverse reactions that led to dehydration. In addition, Mounjaro is not recommended in patients with severe gastroparesis. To learn more, please take a closer look at the Important Safety Information by clicking the accompanying link.

In placebo-controlled trials in adults, when Mounjaro was used as monotherapy, the incidence of hypoglycemia and severe hypoglycemia was 0% across all Mounjaro treatment arms. In the placebo arm, the incidence of hypoglycemia was 1% and the incidence of severe hypoglycemia was 0% after 40 weeks.

In placebo-controlled trials in adults, when Mounjaro was used as an add-on to insulin glargine with or without metformin, the incidence of hypoglycemia ranged from 14 to 19% for patients receiving Mounjaro 5, 10, or 15 milligrams, and was 13% for patients receiving placebo. The incidence of severe hypoglycemia ranged from 0 to 2% in the Mounjaro arms, with no reported incidence for placebo.

Please note the Select Important Safety Information related to hypoglycemia with concomitant use of insulin secretagogues or insulin, as using Mounjaro with these medications may increase the risk of hypoglycemia. For more information, please take a closer look at the Important Safety Information by clicking the accompanying link.

The adult studies we just reviewed evaluated Mounjaro in patients with a mean type 2 diabetes duration ranging from 4.7 years to 13.3 years. But what about patients earlier in their type 2 diabetes disease course? Let's turn our attention to SURPASS-EARLY, which enrolled adults who were recently diagnosed with type 2 diabetes within 4 years before trial screening and had inadequate glycemic control when treated with metformin alone.

SURPASS-EARLY was an open-label, parallel-group, phase 4 trial that randomized 794 adult patients with type 2 diabetes to receive Mounjaro 15 milligrams or maximum tolerated dose, or intensified conventional care, in a 1-to-1 ratio. All patients were recently diagnosed with type 2 diabetes within 4 years before screening and had inadequate glycemic control with diet and exercise and a stable dose of at least 1500 milligrams of metformin for at least 90 days before screening. Metformin was continued as background therapy in both treatment arms.

This is a 208-week study, but today we’re going to focus on the primary endpoint at 104 weeks. The primary endpoint was change in A1C from baseline to week 104. Key secondary and additional secondary endpoints are also shown in the study description on the right, including change in weight from baseline to week 104.

Looking at the treatment arms, you can see that patients in the Mounjaro treatment arm started on 2.5 milligrams once weekly for 4 weeks, and the dose was escalated by 2.5 milligrams every 4 weeks until 15 milligrams or the maximum tolerated dose, or MTD, was reached. Patients in the intensified conventional care, or ICC, arm received any approved glucose-lowering medication, alone or in combination, except for tirzepatide.

Let's take a closer look at the ICC treatment arm. Patients in the ICC arm could receive any medications approved for type 2 diabetes, alone or in combination, except for tirzepatide. This included glucagon-like peptide-1, or GLP-1, receptor agonists, SGLT2 inhibitors, sulfonylureas, dipeptidyl peptidase-4, or DPP-4, inhibitors, and insulin. Medications were administered per standard clinical practice, supported by local treatment guidelines, and used in accordance with local product labels. It’s also important to note that study investigators faced no cost or insurance restrictions when selecting type 2 diabetes medications to prescribe.

Both treatment arms had the same follow-up schedule: patients had monthly follow-up visits for the first 6 months, followed by visits every 3 months starting at month 8 to evaluate progress. In the ICC arm, treatment was intensified at each follow-up if patients were not reaching glycemic control safely per local type 2 diabetes treatment guidelines. Guideline-recommended adjustments to therapy included escalation of doses and adding or switching type 2 diabetes medications. This approach was intended to represent what care looks like when guidelines are strictly followed and treatment intensifications occur without delay.

So, what did the ICC arm look like at the primary endpoint at 104 weeks?

At week 104, medications prescribed to patients in the ICC treatment arm in addition to metformin consisted of about 85% GLP-1 receptor agonists, including injectable and oral formulations. Almost 17% of patients were taking SGLT2 inhibitors, around 3% sulfonylureas, almost 3% insulin, and 2% DPP-4 inhibitors.

With that understanding of the study design, let’s turn our attention to the results at 104 weeks.

Mean A1C over time from baseline to 104 weeks is shown here. The final A1C value at 104 weeks was 5.6% for Mounjaro 15 milligrams or MTD and 6.4% for ICC. These correspond to mean changes of A1C of minus 2% for Mounjaro and minus 1.3% for ICC using treatment-regimen estimand, which was the primary outcome of the study.

Now, let’s look at the mean weight change over time from baseline to 104 weeks. At 104 weeks weight changes were minus 34.8 pounds for Mounjaro 15 milligrams or MTD and minus 14.3 pounds for ICC. These correspond to mean changes in weight of minus 30.5 pounds for Mounjaro and minus 13 pounds for ICC using treatment-regimen estimand, which was a key secondary outcome of the study.
As a reminder, Mounjaro is not indicated for weight loss. Change in weight was a secondary endpoint in this study.


The study also looked at insulin resistance as an exploratory endpoint, assessed by homeostasis model assessment 2 of insulin resistance, or HOMA2-IR. HOMA2-IR is a validated method used to estimate insulin resistance from fasting blood glucose and insulin levels or C-peptide.

In SURPASS-EARLY, mean baseline HOMA2-IR was 2.3. From baseline to 104 weeks, changes in HOMA2-IR were minus 38.9% with Mounjaro 15 milligrams or MTD and minus 20.5% with ICC.

So far, we’ve looked at several efficacy measures; now let’s turn our attention to safety data for SURPASS-EARLY. The most common adverse events reported in at least 5% of patients included nausea, diarrhea, dyspepsia, constipation, vomiting, eructation, decreased appetite, headache, influenza, and nasopharyngitis.

The incidence of severe hypoglycemia was 0% for both treatment arms. The incidence of hypoglycemia was 4.3% for Mounjaro 15 milligrams or MTD and 3.3% for ICC.

Now that we’ve looked at the change in A1C, change in weight, and hypoglycemia results for SURPASS-EARLY, let’s review a composite endpoint comprising an A1C of less than or equal to 6.5%, weight reduction of at least 10%, and no clinically significant or severe hypoglycemia.

The proportion of patients who had this composite endpoint at 104 weeks was 54.2% for the Mounjaro arm and 21.1% for the ICC arm.

As a reminder, Mounjaro is not indicated for weight loss.

I hope you’ve found this discussion on Mounjaro clinical data helpful.

First, we reviewed SURPASS-1 through SURPASS-5 in which Mounjaro demonstrated superior A1C reductions and significant weight reductions in adults with type 2 diabetes across 5 trials.

Then we turned our attention to SURPASS-EARLY, a phase 4 clinical trial that provides complementary data to the SURPASS registrational trials. We examined A1C and weight outcomes, insulin resistance data, and a composite endpoint for Mounjaro and intensified conventional care in adults recently diagnosed with type 2 diabetes.

As a clinician who sees many adults with type 2 diabetes, I find these studies relevant to my practice. For a comprehensive understanding of Mounjaro, let’s review 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 or severe abdominal pain sometimes radiating to the back, which may or may not be accompanied by nausea or 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 in adults, 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%). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. 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 placebo-controlled clinical trials in adults, 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 in Adults
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
In a single-dose clinical lactation study, the concentration of tirzepatide in breast milk was found to be either undetectable or low compared to the maternal administered dose. There are no available data on the effects of tirzepatide on the breastfed infant or 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
Adverse reactions reported in pediatric patients 10 years of age and older treated with Mounjaro were similar to those reported in adults with the exception of a higher incidence of vomiting, abdominal pain, and hypoglycemia. The safety and effectiveness of Mounjaro have not been established and use is not recommended in patients less than 10 years of age.

Please see the full Prescribing Information, including Boxed Warning about possible thyroid tumors, including thyroid cancer, and Medication Guide by clicking the accompanying links.

Please see Instructions for Use included with the pen.

TR HCP ISI 19DEC2025

The Mounjaro logo, Mounjaro^®, and its delivery device base are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Dr. Kayne: Thank you for tuning in.

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