Zepbound (tirzepatide) showed superior weight loss over Wegovy (semaglutide) in complete SURMOUNT-5 results published in The New England Journal of Medicine - Eli Lilly

Eli Lilly  announced detailed results from SURMOUNT-5, a Phase IIIb open-label clinical trial, evaluating the safety and efficacy of Zepbound (tirzepatide), a dual GIP and GLP-1 receptor agonist, compared to Wegovy (semaglutide), a mono GLP-1 receptor agonist, in adults living with obesity, or overweight with at least one weight-related medical problem and without diabetes. At 72 weeks, Zepbound met the primary endpoint and all five key secondary endpoints, demonstrating superiority compared to Wegovy across the trial. The detailed results were presented at the European Congress on Obesity (ECO) 2025 and simultaneously published in The New England Journal of Medicine (see citation below).

For the primary endpoint, participants treated with Zepbound achieved an average weight reduction of 20.2% compared to 13.7% with Wegovy at 72 weeks using the treatment-regimen estimand,1 a 47% greater relative weight loss. Participants using Zepbound lost an average of 50.3 lbs (22.8 kg) and participants on Wegovy lost an average of 33.1 lbs (15.0 kg).

In key secondary endpoints, Zepbound was superior across all weight reduction targets with 64.6% of participants treated with Zepbound achieving at least 15.0% weight loss compared to 40.1% on Wegovy. Additionally, participants treated with Zepbound achieved a superior average waist circumference reduction of 7.2 in (18.4 cm), while those treated with Wegovy saw an average reduction of 5.1 in (13.0 cm).

"Thanks to the latest advancements in obesity management medications, more physicians and patients are witnessing significant weight reduction beyond what they have seen before," said Dr. Louis J. Aronne, director of the Comprehensive Weight Control Center and the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, an internist specializing in diabetes and obesity at New York-Presbyterian/Weill Cornell Medical Center, and principal investigator of SURMOUNT-5. "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."

"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, Lilly. "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."

The safety profile of Zepbound in SURMOUNT-5 was consistent with previous SURMOUNT trials. Adverse events reported during the trial 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, the study was not powered to compare the safety and tolerability of Zepbound and the safety and tolerability of Wegovy.

Tirzepatide is commercialized for adults with obesity or with overweight who also have weight-related medical problems as Zepbound in the U.S. and Mounjaro in some countries outside of the U.S. Tirzepatide is also commercialized as Mounjaro for adults with type 2 diabetes in the U.S. and in some countries outside of the U.S. Semaglutide is commercialized as Wegovy for people living with obesity or for adults with overweight who also have weight-related medical problems and Ozempic for people with type 2 diabetes.

SURMOUNT-5 (NCT05822830) was a 72-week, multi-center, randomized, open-label, Phase IIIb trial evaluating the efficacy and safety of Zepbound (tirzepatide) compared with Wegovy (semaglutide) in adults with obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea (OSA) or cardiovascular disease, who did not have diabetes. Participants in both treatment groups received counseling on a reduced-calorie diet and increased physical activity. The trial randomized 751 participants across the U.S. and Puerto Rico in a 1:1 ratio to receive maximum tolerated dose of Zepbound (10 mg or 15 mg) or Wegovy (1.7 mg or 2.4 mg). With tirzepatide, 89.3% received at least one dose of the 15 mg dose and with semaglutide 92.8% received at least one dose of the 2.4 mg dose. The primary objective of the study was to demonstrate Zepbound's superiority in percent change from baseline in body weight at 72 weeks compared to Wegovy.

Citation: Aronne LJ, Horn DB, le Roux CW et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025 May 11. doi: 10.1056/NEJMoa2416394. Online ahead of print. PMID: 40353578