SURMOUNT-5: Tirzepatide (Zepbound) Proves Benefit over Semaglutide (Wegovy) for Obesity

Full data from the SURMOUNT-5 trial highlight key differences in the effects of tirzepatide (Zepbound) compared to semaglutide 2.4 mg (Wegovy) for the treatment of obesity.

Published in the New England Journal of Medicine and simultaneously presented at the 32nd European Congress on Obesity, data from the head-to-head study provide specific insight into the magnitude of benefit with tirzepatide versus semaglutide for amount of body weight lost, change in waist circumference, and proportion of patients achieving 10%, 15%, 20%, and 25% weight loss milestones.1,2

"The SURMOUNT-5 head-to-head results demonstrated tirzepatide led to greater weight reduction compared to semaglutide, providing further evidence to support tirzepatide as an effective option for obesity management,” said principal investigator Louis J. Aronne, MD, director of the Comprehensive Weight Control Center, the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, and an internist specializing in diabetes and obesity at New York-Presbyterian/Weill Cornell Medical Center.2

Published on May 11, 2025, the release of full data from the trial come less than 6 months after Eli Lilly and Company announced topline results from the trial in December 2024. In recent years, few, if any, storylines have captivated public health and the general public in the same way as the rise of the obesity epidemic in the US and the revelation of weight loss benefits of incretins, which was led by semaglutide.3

However, as the GLP-1 receptor agonist class began to earn a reputation in management of obesity, tirzepatide, a dual GLP-1 and glucagon agonist for both type 2 diabetes and obesity management-based ointment the SURMOUNT program. The first 4 SURMOUNT trials examined tirzepatide against placebo therapy in different patient populations defined by presence of obesity or type 2 diabetes.1,2,3

Now, SURMOUNT-5 offers insight into the benefits and safety profiles of tirzepatide and semaglutide in a head-to-head fashion.1

Launched in 2023, SURMOUNT-5 was a multicenter, randomized, open-label, phase 3b trial conducted across 32 sites in the United States and Puerto Rico. For inclusion, patients need to be at least 18 years of age and have a body mass index (BMI) of 30 or higher or a BMI of 27 or higher and at least 1 prespecified obesity-related complication and reported at least 1 unsuccessful dietary effort for weight reduction.1

The trial enrolled 751 people who were randomized in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg). Of these, 750 received at least 1 dose of the assigned study drug. The final analytical cohorts included 374 patients randomized to tirzepatide and 376 randomized to semaglutide.1

Investigators noted demographic and clinical characteristics of the participants were similar between study groups. Overall, the study cohort had a mean age of 44.7 years, 64.7% were women, and 76.1% were White. The overall cohort had a mean body weight of 113 kg (249.1 lb), mean BMI of 39.4 kg/m2, mean waist circumference of 118.3 cm (46.57 in.), 50.1% had at least 2 obesity-related complications, and the mean duration of obesity was 16 years.1

The primary outcome of interest for the trial was the percent change in body weight from baseline to week 72 with tirzepatide as compared with semaglutide. The trial’s secondary outcomes of interest included the proportion of patients achieving a weight reduction of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72.1

Results of the study indicated use of tirzepatide was associated with a greater magnitude of benefit for percent change in body weight, absolute weight loss, and proportion of patients achieving predefined weight loss thresholds.1

Tirzepatide vs Semaglutide: Percent Change in Body Weight

• Tirzepatide: −20.2% (95% CI: −21.4 to −19.1)
• Semaglutide: −13.7% (95% CI: −14.9 to −12.6)
• Difference: Tirzepatide led to a 6.5 percentage point greater reduction (P <.001)

Tirzepatide vs Semaglutide: Absolute Weight Loss

• Tirzepatide: −22.8 kg (95% CI; −24.1 to −21.5)
• Semaglutide: −15.0 kg (95% CI; −16.3 to −13.7)
• Difference: Tirzepatide led to 7.8 kg more weight loss on average

Tirzepatide vs Semaglutide: Proportion of Participants Achieving Key Weight Loss Thresholds:

• ≥10%: 81.6% vs 60.5%
• ≥15%: 64.6% vs 40.1%
• ≥20%: 48.4% vs 27.3%
• ≥25%: 31.6% vs 16.1%
• ≥30%: 19.7% vs 6.9%

Analysis of safety data from the trial indicated use of tirzepatide and semaglutide had safety profiles consistent with those in previous trials. The most common adverse events in both treatment groups were gastrointestinal. A total of 4.8% of the tirzepatide group experienced a series adverse event compared to 3.5% of the semaglutide group, with 6 patients discontinuing the trial because of adverse events in each group.

"In the SURMOUNT-5 trial, Zepbound demonstrated a significantly higher magnitude of weight reduction compared to Wegovy across all comparisons," said Leonard Glass, MD, FACE, senior vice president, global medical affairs at Eli Lilly and Company.2 "These data confirm Zepbound as a leading treatment option for people living with obesity and equip healthcare providers with critical insights to make well-informed treatment decisions as part of a comprehensive obesity care plan."

References:

1. Aronne L, Horn D, le Roux C. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine. Published online May 11, 2025. doi: 10.1056/NEJMoa2416394

2. Eli Lilly and Company. Zepbound (tirzepatide) showed superior weight loss over Wegovy (semaglutide) in complete SURMOUNT-5 results published in The New England Journal of Medicine | Eli Lilly and Company. Eli Lilly and Company. Published May 11, 2025. Accessed May 11, 2025. https://investor.lilly.com/news-releases/news-release-details/zepbound-tirzepatide-showed-superior-weight-loss-over-wegovy.

3. Eli Lilly and Company. Lilly’s Zepbound® (tirzepatide) superior to Wegovy® (semaglutide) in head-to-head trial showing an average weight loss of 20.2% vs. 13.7% | Eli Lilly and Company. Eli Lilly and Company. Published December 4, 2024. Accessed May 11, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-zepboundr-tirzepatide-superior-wegovyr-semaglutide-head.