Mounjaro vs. Ozempic®: a journey through SURPASS-2
[Healthcare Professional]
Hello and welcome!
My name is Chris Shadid. I'm a primary care physician at the Shadid Medical Group in Edmond, Oklahoma. In today’s journey, we will learn about the SURPASS-2 study, which compared the efficacy and safety of Mounjaro (tirzepatide) versus Ozempic (semaglutide) in people with type 2 diabetes inadequately controlled with metformin alone.
Mounjaro is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
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, 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. 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.
Before diving into our journey, let’s meet our animated characters, each of whom represents a different arm of the study.
Four study arms were Mounjaro 5 milligrams, Mounjaro 10 milligrams, Mounjaro 15 milligrams, and Ozempic 1 milligram.
Like our animated characters, participants in the SURPASS-2 trial had a mean baseline A1C of 8.3%, a mean duration of type 2 diabetes of 8.6 years, and a mean baseline BMI of 34.2 kilograms per meter squared.
As we follow our characters through the study design, we can see that SURPASS-2 was a 40-week, active-controlled, phase 3 trial that randomized 1879 adult patients with type 2 diabetes who had inadequate glycemic control on stable doses of metformin alone to receive once-weekly, subcutaneous Mounjaro 5, 10, or 15 milligrams or once-weekly subcutaneous Ozempic 1 milligram, all in combination with metformin greater than or equal to 1500 milligrams per day.
All doses of Mounjaro were initiated at 2.5 milligrams once weekly and increased by 2.5 milligrams every 4 weeks until the final randomized dose was reached. Ozempic was initiated at .25 milligrams once weekly and the dose was doubled every 4 weeks until the 1 milligram dose was reached.
Let’s keep following our characters to find out the primary objective of SURPASS-2, which was to demonstrate noninferiority of Mounjaro 10 milligrams and/or 15 milligrams to Ozempic in mean change from baseline in A1C at 40 weeks.
Key secondary objectives also included noninferiority of Mounjaro 5 milligrams to Ozempic and superiority of Mounjaro to Ozempic, both in mean change from baseline in A1C.
As shown here, every dose of Mounjaro was found to be superior to Ozempic 1 milligram in reducing A1C.
A1C reductions at 40 weeks ranged from 2% with the Mounjaro 5-milligram dose to 2.3% with the Mounjaro 15-milligram dose, compared with 1.9% for Ozempic 1 milligram.
Looking at the mean A1C over time, we can see that Mounjaro delivered sustained A1C reductions at every dose through week 40. The mean baseline A1C for all treatment groups was 8.3%, which decreased to 6.3% with the Mounjaro 5-milligram dose and to 6% with the Mounjaro 10- and 15-milligram doses, compared to 6.4% with Ozempic 1 milligram at 40 weeks.
Now, let’s review the percentage of patients who achieved an A1C less than 7%, a key secondary objective. Significantly more patients, 86%, receiving Mounjaro 10- and 15-milligram doses achieved the ADA’s recommended A1C target of less than 7%, compared to 79% of patients receiving Ozempic 1 milligram.
Additionally, 69 to 80% of patients in the Mounjaro treatment groups, and 64% of patients in the Ozempic 1-milligram group had an A1C less than or equal to 6.5% at week 40. Also, 27 to 46% of patients in the Mounjaro treatment groups and 19% of patients in the Ozempic 1-milligram group had an A1C less than 5.7% at week 40. I also want to point out Select Important Safety Information related to hypoglycemia with concomitant use of insulin secretagogues or insulin itself. Concomitant use of Mounjaro with an insulin secretagogue, such as a sulfonylurea, or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. To learn more about how to lower the risk of hypoglycemia in patients receiving Mounjaro, please read the Important Safety Information.
Let’s keep following our characters and find out another key secondary objective of SURPASS-2: superiority in mean change from baseline in weight.
As a reminder, Mounjaro is not indicated for weight loss. In clinical studies, weight change from baseline was a secondary endpoint. At 40 weeks, Mounjaro demonstrated significant weight reduction across all 3 doses compared to Ozempic 1 milligram. Weight reductions ranged from 8.2% with Mounjaro 5-milligram dose to 11.8% with the Mounjaro 15-milligram dose, compared to 6.2% with Ozempic 1 milligram.
Looking at mean weight change over time, we can see that patients taking Mounjaro had weight reductions that continued through 40 weeks. Weight reductions at 40 weeks ranged from approximately 16.8 pounds for the Mounjaro 5-milligram dose to 24.7 pounds with the Mounjaro 15-milligram dose compared to 12.6 pounds with Ozempic 1 milligram.
Now that we’ve reviewed primary and secondary efficacy measures, let’s turn our attention to the safety profile of Mounjaro.
In phase 3 placebo-controlled trials, common adverse reactions associated with the use of Mounjaro were nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain.
Similarly, in SURPASS-2, adverse events occurring in at least 5% of patients in the Mounjaro treatment groups were mostly gastrointestinal-related.
Nausea, diarrhea, and vomiting were most frequently reported during the dose-escalation period, and tended to decrease over time.
Of note, discontinuations 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. Before moving on, I would also like 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 an acute kidney injury. To learn more, please read the Important Safety Information.
Earlier we saw that Mounjaro demonstrated superior A1C reductions versus Ozempic 1 milligram, but how does that impact hypoglycemic events?
In SURPASS-2, hypoglycemia occurred in .6% of patients in the Mounjaro 5-milligram group, .2% in the Mounjaro 10-milligram group, 1.7% in the Mounjaro 15-milligram group, and .4% of patients in the Ozempic 1-milligram group. Severe hypoglycemia was reported in .2% of patients in the Mounjaro 5- and 15-milligram groups, and zero patients in the 10-milligram group as well as Ozempic 1-milligram group.
Next, let’s review the incidence of hypoglycemia across placebo-controlled studies. When used as monotherapy, 0% of patients in the Mounjaro treatment groups reported hypoglycemia or severe hypoglycemia, and 1% of patients in the placebo group reported hypoglycemia.
When used as an add-on to basal insulin, with or without metformin, hypoglycemia was reported in 16%, 19%, and 14% of patients in the Mounjaro 5-, 10-, and 15-milligram treatment groups, respectively, and in 13% of patients in the placebo group. Severe hypoglycemia occurred in 0% of patients on Mounjaro 5 milligrams, 2% of patients on Mounjaro 10 milligrams, 1% of patients on Mounjaro 15 milligrams, and 0% of patients in the placebo group.
So far, our characters have guided us through the result for A1C, weight, and hypoglycemia, but what about a composite endpoint that comprises an A1C of less than or equal to 6.5%, a weight reduction of at least 10% of their body weight, and no clinically significant or severe hypoglycemia?
Clinically significant hypoglycemia was defined as a plasma glucose level less than 54 milligrams per deciliter, and severe hypoglycemia was defined as an episode requiring assistance from another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Now, let’s review the composite endpoint results for SURPASS-2 to discover the proportion of patients with all 3 of these criteria.
At 40 weeks, 32% of patients in the Mounjaro 5-milligram group, 51% in the Mounjaro 10-milligram group, 60% in the Mounjaro 15-milligram group, and 22% in the Ozempic 1-milligram group had the composite endpoint result. While weight reduction was included as part of the composite endpoint, Mounjaro is not indicated for weight loss. In SURPASS-2, this composite endpoint analysis was a prespecified secondary endpoint not controlled for type 1 error and was based on efficacy estimand data, which is treatment without the influence of rescue therapy and may not represent a real-world setting.
As we arrive at the end of our journey through SURPASS-2, I hope you enjoyed learning about the clinical efficacy and safety of Mounjaro, including superior A1C and weight reductions, with weight as a key secondary endpoint, versus Ozempic 1 milligram.
Thank you for joining us! For more information, please visit mounjaro.com/hcp.
To learn more about the efficacy and safety of Mounjaro across five studies of the SURPASS phase 3 clinical program, watch the next video.
[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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