A Journey Through SURPASS Clinical Trial Program
[Healthcare Professional]
My name is Dr. Barbara Hirsch, and I am an endocrinologist partner at North Shore Diabetes and Endocrine Associates/PRINE Health in New Hyde Park, New York.
In today’s journey, we will learn about the SURPASS phase 3 clinical program, which studied the efficacy and safety of Mounjaro (tirzepatide) across a range of background therapies and comparators.
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 the 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 the 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.
In this journey, 5 hot air balloons and our animated characters will guide us through the efficacy and safety results of the 5 registration trials in the SURPASS clinical program, which studied Mounjaro as a monotherapy and as an add-on to various standard-of-care medications for the treatment of adults with type 2 diabetes.
Mounjaro was studied versus placebo as monotherapy in SURPASS-1 and as an add-on to insulin glargine with or without metformin in SURPASS-5.
Mounjaro was studied as an add-on to oral antihyperglycemic medications head-to-head versus Ozempic® (semaglutide) 1 milligram in SURPASS-2, versus Tresiba® (insulin degludec) in SURPASS-3, and versus insulin glargine in SURPASS-4.
Each SURPASS trial employed a similar study design, in which patients were treated over a course of 40 weeks in SURPASS-1, -2, and -5, 52 weeks in SURPASS-3, and 104 weeks in SURPASS-4.
Patients were randomized to receive once-weekly Mounjaro 5, 10, or 15 milligrams, or a comparator.
For patients in the Mounjaro treatment groups, 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.
In all trials, the primary objective was change from baseline in glycated hemoglobin, or A1C.
Now, let’s take a closer look at the 2 studies in which placebo was used as a comparator: SURPASS-1 and SURPASS-5.
In SURPASS-1, Mounjaro was studied as monotherapy in adults with type 2 diabetes who had inadequate glycemic control with diet and exercise.
The primary objective was to demonstrate superiority of Mounjaro 10 and/or 15 milligrams to placebo in mean change from baseline in A1C at 40 weeks.
The key secondary objectives are displayed on the panel to the right. The study participants had a mean baseline A1C of 7.9%, a mean BMI of 31.9 kilogram per meter squared, and a mean duration of type 2 diabetes of 4.7 years.
In SURPASS-5, Mounjaro was studied in adults with type 2 diabetes, who had inadequate glycemic control on insulin glargine U-100, with or without at least 1500 milligrams of metformin per day.
The primary objective was to demonstrate superiority of Mounjaro 10 and/or 15 milligrams to placebo in mean change from baseline in A1C at 40 weeks.
The key secondary objectives are displayed on the panel to the right.
The study participants had a mean baseline A1C of 8.3%, a mean BMI of 33.4 kilograms per meter squared, and a mean duration of type 2 diabetes of 13.3 years.
Now, let’s focus on the clinical trials in which Mounjaro was studied as an add-on to various oral antihyperglycemic medications.
In SURPASS-2, Mounjaro was studied in adults with type 2 diabetes who had inadequate glycemic control on stable doses of metformin alone. Patients were randomized to receive Mounjaro 5, 10, or 15 milligrams or Ozempic 1 milligram, all in combination with at least 1500 milligrams of metformin per day.
Here, the primary objective was to demonstrate noninferiority of Mounjaro 10 and/or 15 milligrams to Ozempic in mean change from baseline in A1C at 40 weeks. Upon meeting noninferiority, Mounjaro was then tested for superiority as a gated key secondary objective.
Additional key secondary objectives are displayed on the panel to the right.
The study participants had a mean baseline A1C of 8.3%, a mean BMI of 34.2 kilograms per meter squared, and a mean duration of type 2 diabetes of 8.6 years.
In SURPASS-3, Mounjaro was studied as an add-on to metformin, with or without an SGLT2 inhibitor, in adults with type 2 diabetes who had inadequate glycemic control on this regimen.
Patients were randomized to receive once-weekly subcutaneous Mounjaro 5, 10, or 15 milligrams or titrated Tresiba U-100. The primary objective was to demonstrate noninferiority of Mounjaro 10 and/or 15 milligrams to Tresiba in mean change from baseline in A1C at 52 weeks. Upon meeting noninferiority, Mounjaro was then tested for superiority as a gated key secondary objective.
Additional key secondary objectives are displayed on the panel to the right.
The study participants had a mean baseline A1C of 8.2%, a mean baseline BMI of 33.5 kilograms per meter squared, and a mean duration of type 2 diabetes of 8.4 years.
Lastly, in SURPASS-4, Mounjaro was studied as an add-on to 1-3 oral antihyperglycemic medications—metformin, sulfonylurea, and/or SGLT2 inhibitor—in adults with type 2 diabetes who had increased cardiovascular risk. Patients were randomized to receive Mounjaro 5, 10, or 15 milligrams or titrated insulin glargine 100 units per milliliter.
The primary objective was to demonstrate noninferiority of Mounjaro 10 and/or 15 milligrams to insulin glargine in mean change from baseline in A1C at 52 weeks. Upon meeting noninferiority, Mounjaro was then tested for superiority as a gated key secondary objective.
Additional key secondary objectives are displayed on the panel to the right.
Study participants had a mean baseline A1C of 8.5% and a mean duration of type 2 diabetes of 11.8 years.
Now, let’s review the primary endpoint results of the SURPASS studies.
As we follow our characters in their hot air balloons we see that all 3 doses of Mounjaro delivered superior A1C reductions when studied across a variety of background therapies and comparators. Mean A1C reductions from baseline ranged from 1.7% to 2.4% with Mounjaro, and 0.1% to 1.9% with comparators.
Next, we’ll turn our attention to one of the key secondary endpoints of the studies: mean weight change from baseline at 40 or 52 weeks. As a reminder, Mounjaro is not indicated for weight loss.
As we can see, all 3 doses of Mounjaro consistently demonstrated greater weight reductions versus comparators across studies. Mean weight changes from baseline ranged from a reduction of 11.9 pounds to 24.9 pounds with Mounjaro, and a reduction of 12.6 pounds to a gain of 4.2 pounds with comparators.
Now that we’ve reviewed some of the primary and secondary efficacy measures, let’s focus on the safety profile of Mounjaro.
Starting with the placebo-controlled trials, SURPASS-1 and SURPASS-5, we see that common adverse reactions associated with the use of Mounjaro were nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. Discontinuation rates due to gastrointestinal-related adverse events ranged from 3% to 6.6% in the Mounjaro groups versus 0.4% in the placebo group.
Before moving on, I would like also to highlight Select Important Safety Information related to acute kidney injury. Gastrointestinal adverse events associated with Mounjaro may lead to dehydration, which if severe could cause acute kidney injury. To learn more, please read the Important Safety Information.
Earlier, we saw that Mounjaro demonstrates superior A1C reductions across trials, but how does that impact hypoglycemic events?
When Mounjaro was used as monotherapy in SURPASS-1, the incidence of hypoglycemia and severe hypoglycemia was 0% across all Mounjaro treatment groups. Note that severe hypoglycemia is defined as episodes with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrates, glucagon, or other resuscitative actions.
Hypoglycemic events were more frequent when Mounjaro was used as an add-on to basal insulin with or without metformin. In SURPASS-5, the incidence of hypoglycemia was 14% to 19% in the Mounjaro treatment groups and 13% in the placebo group. The incidence of severe hypoglycemia ranged from 0% to 2% for all treatment groups.
As noted in the Select Important Safety Information, the risk of hypoglycemia—including severe hypoglycemia—may increase when Mounjaro is used alongside insulin or an insulin secretagogue. Patients who are using these concomitant medications should be informed of the potential increased risk and educated on the signs and symptoms of hypoglycemia. To learn more, please read the Important Safety Information.
Moving on to SURPASS-2, let’s review the adverse events occurring in at least 5% of patients in the Mounjaro treatment groups.
As shown here, the most common adverse events were primarily gastrointestinal-related. Nausea, diarrhea, and vomiting were most frequently reported during the dose-escalation period and tended to decrease over time.
Of note, discontinuation rates due to gastrointestinal-related adverse events were 2.8 to 4.3% in the Mounjaro groups and 3.2% in the Ozempic 1-milligram group.
Looking at the incidence of hypoglycemia in the SURPASS-2 study, we can see that it ranged from 0.2% to 1.7% in the Mounjaro treatment groups and was 0.4% in the Ozempic group.
As shown here, the incidence of severe hypoglycemia was 0.2% or less across all treatment groups.
Now, let’s look at SURPASS-3. Similar to SURPASS-2, the most common treatment-emergent adverse events reported across the treatment groups in SURPASS-3 were gastrointestinal-related. Nausea, diarrhea, and vomiting were most frequent during the dose-escalation period and tended to decrease over time.
Treatment discontinuation due to GI-related adverse events occurred in 4 to 6% of patients in the Mounjaro groups and in less than 1% of the patients in the Tresiba group.
In terms of hypoglycemic events, we can see that the incidence of hypoglycemia in SURPASS-3 was 1 to 2% in the Mounjaro treatment groups and 7% in the Tresiba group.
There was also 1 episode of severe hypoglycemia in the Mounjaro 15-milligram treatment group that occurred on day 28 of the escalation period, while the patient was receiving Mounjaro 2.5 milligrams.
Lastly, let’s review common adverse events in the SURPASS-4 study.
Consistent with what was seen in SURPASS-1, -2, -3, and -5, the most common treatment-emergent adverse events reported in SURPASS-4 were primarily gastrointestinal-related. Nausea, diarrhea, and vomiting were most frequent during the dose-escalation period in all groups. As a reminder, Mounjaro doses were escalated every 4 weeks until the final randomized dose was reached.
Please keep in mind that SURPASS-1 through -5 studies were not designed to evaluate the relative safety between Mounjaro and the comparator arms of placebo, Ozempic 1 milligram, Tresiba, and insulin glargine. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In SURPASS-4, the incidence of hypoglycemia—defined as a blood glucose value less than 54 milligrams per deciliter, is shown here. In participants also on a sulfonylurea, hypoglycemic events were more frequent compared with those not on a sulfonylurea.
The incidence of severe hypoglycemia across all groups in SURPASS-4, is shown here.
We have arrived at the end of our journey through 5 studies of the SURPASS phase 3 clinical program.
I hope you enjoyed learning about the superior A1C reductions, the weight results as a secondary endpoint, and safety data with Mounjaro.
Thank you for joining us!
For more information, please visit mounjaro.com/hcp.
[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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