Diabetes Dialogue: Tirzepatide vs Semaglutide for Obesity, Understanding SURMOUNT-5

Welcome back to Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives!

Full results from the SURMOUNT-5 trial show tirzepatide (Zepbound) led to significantly greater weight loss than semaglutide 2.4 mg (Wegovy) in adults with obesity, according to findings published in The New England Journal of Medicine and presented at the 32nd European Congress on Obesity.

“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 and the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, in a press release.

The phase 3b trial enrolled 751 participants across 32 US and Puerto Rican sites, with 750 receiving at least one dose of study drug. Participants were randomized to their maximum tolerated dose of tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg). The primary endpoint was percent change in body weight at 72 weeks.

Results showed tirzepatide produced a 20.2% average reduction in body weight versus 13.7% with semaglutide, a 6.5-point difference (P<0.001). In absolute terms, patients lost 22.8 kg with tirzepatide versus 15.0 kg with semaglutide.

Tirzepatide also outperformed semaglutide for the proportion of patients achieving 10%, 15%, 20%, 25%, and 30% weight loss thresholds, with more than 64% of tirzepatide patients achieving a 15% or greater body weight reduction.

Both drugs had safety profiles consistent with previous trials, with gastrointestinal symptoms being the most common adverse events. Serious adverse events occurred in 4.8% of tirzepatide users and 3.5% of semaglutide users. Six patients from each group discontinued due to side effects.

In this special edition episode of Diabetes Dialogue, hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, breakdown the trial, how they interpret the findings, and how it could impact care decisions in the future.

Relevant disclosures for Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others.

References:

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

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.

"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."

References:

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

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.

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.