Obesity is a significant global health challenge, contributing to numerous related medical problems. In recent years, a new class of medications targeting incretin hormones like GLP-1 has revolutionized weight management. Two prominent drugs in this class are semaglutide, marketed as Wegovy for weight loss and Ozempic for type 2 diabetes, and tirzepatide, marketed as Zepbound for obesity and Mounjaro for type 2 diabetes in the U.S., and under one or both names for these indications in some countries outside the U.S.. While both have demonstrated significant weight loss in clinical trials, until recently, there had been no direct comparison between them to evaluate their relative efficacy and safety.
That changed with the publication of the detailed results from the SURMOUNT-5 trial in The New England Journal of Medicine. This Phase 3b open-label clinical trial marked the first head-to-head comparison of Zepbound (tirzepatide) and Wegovy (semaglutide) in adults living with obesity, or who were overweight with at least one weight-related medical problem and did not have diabetes. The findings from this trial, also presented at the 32nd European Congress on Obesity (ECO), offer crucial insights for healthcare providers and patients navigating the options for obesity management.
The SURMOUNT-5 Trial: Design and Participants
The SURMOUNT-5 trial (NCT05822830) was designed as a 72-week, multi-center, randomized, open-label study. It enrolled 751 participants across the U.S. and Puerto Rico who were adults living with obesity (defined as a Body Mass Index of 30 kg/m² or greater) or who were overweight (BMI of 27 kg/m² or greater) and had at least one weight-related comorbidity such as hypertension, dyslipidemia, obstructive sleep apnea (OSA), or cardiovascular disease. Notably, participants with diabetes were excluded from this particular trial. Participants had an average weight of 113 kg (nearly 18 stone) at the start of the trial.
Participants were randomly assigned in a 1:1 ratio to receive either the maximum tolerated dose of Zepbound (10 mg or 15 mg) or Wegovy (1.7 mg or 2.4 mg). For tirzepatide, 89.3% of participants received at least one dose of the 15 mg dose, and for semaglutide, 92.8% received at least one dose of the 2.4 mg dose. Both treatment groups also received counseling on a reduced-calorie diet and increased physical activity, emphasizing that these medications are intended to be used in combination with lifestyle changes. The primary objective of the study was to demonstrate Zepbound’s superiority in the percent change from baseline body weight at 72 weeks compared to Wegovy.
The trial was sponsored and funded by Eli Lilly and Company, the manufacturer of Zepbound/Mounjaro. As noted by Dr. Céline Gounder, a CBS News medical contributor, when considering results from a study funded by the manufacturer, one should “take that with a grain of salt”. However, she also stated that the research “does look legit, and we have seen hints of this in other studies”. A disclosure also noted that Dr. Louis J. Aronne, a principal investigator for SURMOUNT-5, is a paid consultant and advisory board member for both Lilly and Novo Nordisk (the manufacturer of Wegovy).
Superior Weight Loss with Zepbound
At the conclusion of the 72-week study period, Zepbound met the primary endpoint and all five key secondary endpoints, demonstrating superiority over Wegovy across the trial.
For the primary endpoint, participants treated with Zepbound achieved an average weight reduction of 20.2% from their baseline weight at 72 weeks, compared to an average reduction of 13.7% for those treated with Wegovy. Using the treatment-regimen estimand, which accounts for efficacy regardless of adherence and assumes no benefit from randomized treatment if a participant had weight loss procedures during the study, this represents a 47% greater relative weight loss with Zepbound. In terms of absolute weight loss, participants using Zepbound lost an average of 50.3 lbs (22.8 kg), while participants on Wegovy lost an average of 33.1 lbs (15.0 kg). Dr. Gounder noted that this translates to an average difference of about eight pounds between the two drugs.
Zepbound also demonstrated superiority in key secondary endpoints related to achieving specific weight loss targets. For instance, 64.6% of participants treated with Zepbound achieved at least 15.0% weight loss, compared to 40.1% on Wegovy. Furthermore, 32% of people on Mounjaro (tirzepatide) lost a quarter (25%) of their body weight compared to only 16% on Wegovy (semaglutide).
Beyond total body weight, Zepbound users also saw a superior reduction in waist circumference. Participants treated with Zepbound achieved an average waist circumference reduction of 7.2 inches (18.4 cm), while those treated with Wegovy saw an average reduction of 5.1 inches (13.0 cm). Another source reported this as 18cm on Mounjaro compared to 13cm on Wegovy.
The source material also indicates that those on Mounjaro had better blood pressure, blood sugar, and cholesterol levels. However, specific data points for these improvements were not provided in the provided excerpts.
Dr. Louis J. Aronne, the principal investigator, stated that the results “demonstrated tirzepatide led to greater weight reduction compared to semaglutide, providing further evidence to support tirzepatide as an effective option for obesity management”. Leonard Glass, MD, Senior Vice President at Lilly, echoed this, stating that “Zepbound demonstrated a significantly higher magnitude of weight reduction compared to Wegovy across all comparisons” and that the data “confirm Zepbound as a leading treatment option for people living with obesity”.
Understanding the Difference: Dual vs. Mono Agonism
The source material attributes the difference in effectiveness between the two drugs to subtle differences in how they work. Both drugs mimic natural incretin hormones that affect appetite and blood sugar regulation. Wegovy (semaglutide) is a mono GLP-1 receptor agonist. It mimics glucagon-like peptide-1 (GLP-1), a hormone released after a meal, tricking the brain into feeling full so a person eats less and burns stored fat. This flipping of “one appetite switch in the brain” is a key mechanism.
Zepbound (tirzepatide), on the other hand, is a dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptor agonist. Tirzepatide is a single molecule that activates receptors for both GIP and GLP-1. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. By activating both receptors, tirzepatide “flips two” appetite switches. The sources state that tirzepatide decreases calorie intake, likely mediated by affecting appetite. This dual action is believed to be the reason for the superior weight loss observed with tirzepatide compared to semaglutide.
Safety Profile and Important Warnings
The safety profile of Zepbound in the SURMOUNT-5 trial was consistent with previous SURMOUNT trials. Adverse events reported were primarily gastrointestinal-related and were generally mild to moderate in severity. During the trial, 6.1% of participants taking Zepbound discontinued treatment due to adverse events, compared to 8.0% of participants taking Wegovy. However, it’s important to note that the study was not powered to statistically compare the safety and tolerability of Zepbound and Wegovy.
The provided safety summaries for Zepbound and Mounjaro (tirzepatide for type 2 diabetes) detail important warnings and potential serious and common side effects associated with tirzepatide. Many of these warnings and side effects overlap between the two brand names, as they contain the same active ingredient, tirzepatide.
Serious Side Effects and Warnings include:
- Thyroid Tumors, Including Thyroid Cancer: Zepbound and Mounjaro may cause tumors in the thyroid, including thyroid cancer. Patients should watch for symptoms like a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath and tell their healthcare provider if they occur. Zepbound/Mounjaro should not be used if the patient or any family member has a history of medullary thyroid carcinoma (MTC) or if the patient has Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
- Severe Stomach Problems: Severe stomach problems have been reported. Patients should report severe or persistent stomach problems to their healthcare provider.
- Kidney Problems (Kidney Failure): Diarrhea, nausea, and vomiting can lead to dehydration, which may cause kidney problems. Drinking fluids is important to help reduce the chance of dehydration.
- Gallbladder Problems: Gallbladder problems have occurred in some users. Symptoms like pain in the upper stomach, fever, yellowing of skin or eyes (jaundice), or clay-colored stools should be reported right away.
- Inflammation of the Pancreas (Pancreatitis): Patients should stop using the medication and call their healthcare provider right away if they have severe, non-resolving stomach pain (abdomen), with or without vomiting, which may radiate to the back. It is not known if Mounjaro can be used in people who have had pancreatitis.
- Serious Allergic Reactions: Symptoms of a serious allergic reaction include swelling of the face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat. Patients should stop using the medication and get medical help immediately if these occur.
- Low Blood Sugar (Hypoglycemia): The risk of low blood sugar may be higher when used with other diabetes medicines like a sulfonylurea or insulin. Symptoms include dizziness, sweating, confusion, headache, blurred vision, shakiness, fast heartbeat, anxiety, and hunger.
- Changes in Vision in Patients with Type 2 Diabetes: Patients with type 2 diabetes should report changes in vision during treatment.
- Depression or Thoughts of Suicide: Patients should pay attention to changes in mood, behaviors, feelings, or thoughts and call their healthcare provider right away if they have new, worse, or worrying mental changes.
- Food or liquid getting into the lungs during surgery (Aspiration): Zepbound/Mounjaro may increase the chance of food getting into the lungs during surgery or other procedures requiring anesthesia or deep sedation. Patients should inform all healthcare providers they are taking the medication before scheduled procedures.
Common Side Effects:
The most common side effects listed for Zepbound are nausea, diarrhea, vomiting, constipation, stomach (abdominal) pain, indigestion, injection site reactions, feeling tired, allergic reactions, belching, hair loss, and heartburn. For Mounjaro, the most common side effects are nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not exhaustive lists, and patients should talk to their healthcare provider about any bothersome or persistent side effects.
Before Starting Treatment and Other Considerations
Before using Zepbound or Mounjaro, healthcare providers should show patients how to use the injectable pen. Patients should inform their healthcare provider about all medical conditions, including problems with the pancreas or kidneys, severe stomach problems (like gastroparesis or problems digesting food), history of diabetic retinopathy, and if scheduled for surgery or procedures with anesthesia/sedation. They should also disclose all prescription medicines, over-the-counter drugs, vitamins, or herbal supplements they take.
If taking oral birth control pills, their effectiveness may be reduced while using Zepbound or Mounjaro. Healthcare providers may recommend an alternative birth control method for 4 weeks after starting the medication and for 4 weeks after each dose increase.
Pregnancy and breastfeeding considerations are also important. Zepbound may harm an unborn baby. It is not known if tirzepatide passes into breast milk. There is a pregnancy exposure registry for women who take Zepbound during pregnancy.
Zepbound and Mounjaro are administered by subcutaneous injection (stomach, thigh, or upper arm) once weekly, at any time of day. Injection sites should be rotated each week. Zepbound and Mounjaro should not be used with other tirzepatide-containing products or any GLP-1 receptor agonist medicines. For Mounjaro, insulin and Mounjaro should not be mixed in the same injection, though they can be injected in the same body area (but not right next to each other).
Sex Differences in Treatment Response
An intriguing observation from the SURMOUNT-5 trial, consistent with findings in other studies of injectable GLP-1 medications, is that they appear to work better on average for women than they do for men. While diet and exercise traditionally benefit men more for weight loss, these medications show the opposite trend.
In the SURMOUNT-5 study, men lost about 6% less weight than women. This contributed to the observation that participants in this study lost slightly less weight overall compared to the same medications in other trials, as men made up a larger percentage of participants (about 35%) in this study than in previous trials (20-25%). Dr. Louis Aronne noted this sex difference has been seen “again and again” in trials. For example, in a long-term follow-up of a semaglutide trial, women lost an average of 11% of their starting weight after two years, while men lost 8%. Across tirzepatide trials versus placebo, women lost up to 28% of their starting weight, compared to up to 19% for men.
Researchers are keen to understand why this difference exists to optimize treatment for everyone. Several potential explanations were discussed by experts Dr. Melanie Jay and Dr. Karolina Skibicka:
- Dosing relative to body size: Women tend to weigh less than men but receive the same doses, potentially resulting in a higher relative dose for women.
- Fat storage location: Women tend to have more subcutaneous fat (under the skin) compared to visceral fat (around organs) than men. The drugs might be more effective on one type of fat.
- Societal pressure and side effect tolerance: Women may face greater societal pressure to be thin, potentially increasing their motivation to tolerate common, bothersome side effects like nausea, vomiting, and constipation and adhere to treatment. Dr. Jay has observed this in her own practice. Side effects tend to improve over time as patients learn to eat differently and exercise more.
- Role of Estrogen: This is a particularly intriguing clue. Estrogen is a hormone present in higher amounts in women. Research in rats suggests that estrogen directly interacts with GLP-1 and other gut hormones, potentially making them more potent in the brain. Studies injecting rats with GLP-1 and estrogen together show an “enhanced effect” on feeding behavior and GLP-1 actions. Conversely, blocking estrogen action can reduce GLP-1’s effect on suppressing feeding. Estrogen might amplify GLP-1 effects by increasing the number of GLP-1 receptors on cells, leading to an amplified effect inside the cell as well.
These theories are currently educated guesses, and more research is needed. Clinical studies often do not explore sex differences in detail or confirm the reasons for observed differences. Besides weight loss, some studies suggest other sex-specific differences: women may report more GI side effects, while men may get more cardiovascular benefits. Some studies also indicate women might be more likely to experience depression on these medications than men. Understanding these differences could have significant implications for treatment, such as adjusting dosing based on sex, considering hormone levels (like in menopause or with hormone-blocking therapies), and developing strategies for non-responders. As Dr. Jay noted, men and women have different biologies and shouldn’t always be treated the same way.
Conclusion
The SURMOUNT-5 trial provides compelling head-to-head evidence that tirzepatide (Zepbound/Mounjaro) is superior to semaglutide (Wegovy/Ozempic) in achieving weight reduction in adults with obesity or overweight with comorbidities, demonstrating significantly greater percentage and absolute weight loss, as well as superior waist circumference reduction. This difference is attributed to tirzepatide’s dual action on both GIP and GLP-1 receptors compared to semaglutide’s mono GLP-1 action.
While both drugs led to substantial weight loss and have a role in obesity management, Zepbound may be a better option for those aiming for greater weight loss. The safety profiles were generally consistent, with primarily mild to moderate GI side effects, though the study was not powered for a direct safety comparison. Important warnings and potential serious side effects must be carefully considered and discussed with a healthcare provider.
Furthermore, the trial highlighted the observed phenomenon of GLP-1 medications appearing to work better in women than men, sparking research into potential biological and behavioral reasons, including the intriguing possibility of estrogen’s interaction with incretin hormones. Understanding these sex differences is crucial for optimizing treatment outcomes for all patients.
This trial reinforces that these medications, used in conjunction with diet and exercise, are powerful tools in the fight against obesity. While ongoing research explores higher doses, new formulations, and novel mechanisms, the results of SURMOUNT-5 provide valuable data to help healthcare providers and patients make informed decisions in the evolving landscape of obesity treatment. As noted in the sources, despite the promising results from these medications, efforts to create a healthier society to prevent obesity in the first place remain critically important.
