Mounjaro vs Tresiba®: a journey through SURPASS-3
[Healthcare Professional]
Hello and welcome!
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-3 study, which compared the efficacy and safety results of Mounjaro (tirzepatide) versus Tresiba® (insulin degludec) in adults with type 2 diabetes inadequately controlled with metformin with or without an SGLT2 inhibitor.
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.
Before diving into our journey, let’s meet our animated characters, each of whom represents a different treatment arm of the study.
The 4 study arms were Mounjaro 5, 10, and 15 milligrams, and Tresiba.
Like our animated characters, participants in the SURPASS-3 trial had a mean baseline glycated hemoglobin, or A1C, of 8.2%, a mean duration of type 2 diabetes of 8.4 years, and a mean baseline body mass index, or BMI, of 34 kilograms per meter squared.
As we begin the journey of SURPASS-3, we can see it was a 52-week, open-label, active-controlled, phase 3 trial that included 1444 adult patients with type 2 diabetes who had inadequate glycemic control on stable doses of metformin, with or without an SGLT2 inhibitor.
Patients were randomized to receive once-weekly subcutaneous Mounjaro 5, 10, or 15 milligrams or titrated Tresiba U-100.
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.
For patients randomized to Tresiba, the dose was initiated at 10 units once daily and adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values, targeting less than 90 milligrams per deciliter. At week 52, the mean daily Tresiba dose was 49 units, or 0.5 units per kilogram.
Let’s keep following our characters to find out the primary objective of SURPASS-3, which was to demonstrate noninferiority of Mounjaro 10 milligrams and/or 15 milligrams to Tresiba in mean change from baseline in A1C at 52 weeks.
Key secondary objectives, also assessed at 52 weeks, included
- Noninferiority of Mounjaro 5 milligrams to Tresiba in mean change from baseline in A1C
- Superiority of Mounjaro 5, 10, and/or 15 milligrams to Tresiba in mean change from baseline in A1C
- Mean change from baseline in weight, and
- The proportion of patients with an A1C less than 7%
As shown here, Mounjaro demonstrated superior A1C reductions versus Tresiba across all doses studied. Reductions ranged from a mean of 1.9% with the Mounjaro 5-milligram dose to 2.1% with the Mounjaro 15-milligram dose, compared to 1.3% with Tresiba.
Looking at mean A1C over time, we can see that Mounjaro delivered sustained A1C reductions across all 3 doses through week 52. Starting from a mean baseline value of 8.2%, A1C was reduced to 6.3% in the Mounjaro 5-milligram group, to 6.2% in the Mounjaro 10-milligram group, and to 6% in the Mounjaro 15-milligram group. In the Tresiba group, mean A1C was reduced to 6.9% at 52 weeks.
SURPASS-3 was also designed to assess several key secondary endpoints at the end of the 52-week treatment period, including the percentage of patients who reached specific A1C thresholds.
Here we can see that significantly more patients—79% receiving Mounjaro 5 milligrams, 82% receiving Mounjaro 10 milligrams, and 83% receiving Mounjaro 15 milligrams—reached the American Diabetes Association’s recommended A1C target of less than 7%, compared with 58% of patients receiving Tresiba.
Additionally, 67 to 74% of patients receiving Mounjaro, and 42% of patients receiving Tresiba, had an A1C of less than or equal to 6.5% at week 52; 24 to 41% of patients receiving Mounjaro and 5% receiving Tresiba had an A1C of less than 5.7%.
Remember that the risk of hypoglycemia—including severe hypoglycemia—may increase when Mounjaro is used in combination with 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.
Another key secondary endpoint in SURPASS-3 was mean change in body weight from baseline. Mounjaro demonstrated significant reductions in body weight across all doses, ranging from 7.6% at the 5-milligram dose to 12% at the 15-milligram dose. Patients in the Tresiba group experienced a mean body weight increase of 2.3%.
Remember that Mounjaro is not indicated for weight loss.
Looking at changes in body weight over time, we can see that Mounjaro demonstrated sustained weight reductions across all 3 doses at 52 weeks. The weight change at 52 weeks ranged from a reduction of 15.4 pounds for the Mounjaro 5-milligram dose to a reduction of 24.9 pounds for the Mounjaro 15-milligram dose, and an increase of 4.2 pounds with Tresiba. Again, keep in mind that Mounjaro is not indicated for weight loss and that change in weight was a secondary endpoint in SURPASS-3.
A subset of participants from SURPASS-3 were also enrolled in a substudy that evaluated glucose control with continuous glucose monitoring, or CGM.
Let’s review the results of one of the secondary endpoints of this substudy, which was the percentage of time during a 24-hour period that CGM values were 71 to 140 milligrams per deciliter.
As shown here at 52 weeks, the percentage of time spent within these glucose values ranged from 60 to 73% in the Mounjaro treatment groups and 48% in the Tresiba group.
Now that we’ve reviewed efficacy measures from SURPASS-3, let’s have our characters guide us through the safety results in the next exhibit.
Here, we see the adverse reactions in a pool of placebo-controlled trials reported in at least 5% of patients treated with Mounjaro. Percentages reflect the proportion of patients who reported at least 1 treatment-emergent occurrence of the adverse reaction. As shown, most of the adverse reactions seen with Mounjaro were gastrointestinal, or GI, related, which occurred more frequently among patients receiving Mounjaro than placebo.
In SURPASS-3, treatment-emergent adverse events occurring in at least 5% of patients in the Mounjaro treatment groups were also primarily GI-related. Reports of nausea, vomiting, and diarrhea were mostly mild to moderate in severity, occurred more frequently during the dose-escalation period, and tended to decrease over time.
Treatment discontinuation due to GI-related adverse events occurred in 4%, 6%, and 5% of people in the Mounjaro 5-, 10-, and 15-milligram groups, respectively, and in less than 1% of patients in the Tresiba group.
As noted in the Important Safety Information, GI adverse reactions associated with Mounjaro can potentially lead to dehydration, which if severe could cause acute kidney injury.
To learn more, please read the Important Safety Information.
Now let’s take a closer look at the incidence of hypoglycemia, defined as a blood glucose value less than 54 milligrams per deciliter.
In SURPASS-3, hypoglycemia was reported in 1% of patients in the Mounjaro 5- and 10-milligram groups, 2% of patients in the Mounjaro 15-milligram group, and 7% of patients 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. Severe hypoglycemia was defined as episodes with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Now, let’s review the incidence of hypoglycemia across placebo-controlled studies. When used as monotherapy, hypoglycemia occurred in 0% of patients in the Mounjaro 5-, 10-, and 15-milligram group, and in 1% of patients in the placebo group. There were no episodes of severe hypoglycemia.
In another placebo-controlled trial that evaluated Mounjaro as an add-on to basal insulin, with or without metformin, the rate of hypoglycemia ranged from 14% to 19% in the Mounjaro treatment groups versus 13% in the placebo group. Severe hypoglycemia ranged from 0 to 2% in the Mounjaro treatment groups and was 0% in the placebo group.
We have arrived at the end of our journey through the SURPASS-3 study. I hope you enjoyed learning about how Mounjaro may help adults with type 2 diabetes improve glycemic control, and as a secondary endpoint, reduce body weight.
Thank you for joining us, and I’ll see you next time!
For more information, please visit mounjaro.com/hcp.
To learn more about the efficacy and safety of Mounjaro across 5 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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