A new clinical trial has revealed that tirzepatide (Zepbound) surpasses semaglutide (Wegovy) in promoting weight loss among people with obesity.
A new clinical trial has found that tirzepatide, sold under the name Zepbound, led to significantly greater weight loss in people with obesity compared to semaglutide, known as Wegovy. Both are injectable medications designed to support weight management, but tirzepatide came out ahead in this direct comparison.
Over the course of 72 weeks, participants taking tirzepatide lost an average of 50 pounds, which equates to about 20.2% of their starting body weight. Those receiving semaglutide lost an average of 33 pounds, or 13.7% of their baseline weight. The study was led by researchers at Weill Cornell Medicine and NewYork-Presbyterian, in collaboration with institutions including the University of Texas McGovern Medical School, UCLA, University College Dublin, and the drug’s manufacturer, Eli Lilly.
Published in the New England Journal of Medicine, the SURMOUNT-5 phase 3b trial revealed that when both drugs were given at their highest approved doses, tirzepatide not only helped more participants reach their weight loss goals but also led to greater reductions in waist size compared to semaglutide.
In some ways, the outcome was not a surprise. “The results are consistent with—in fact, almost identical to—what we’ve seen in trials in which these drugs were evaluated independently,” said Dr. Louis Aronne, director of the Comprehensive Weight Control Center and the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine and principal investigator of SURMOUNT-5. In 2022, for example, Dr. Aronne led a study showing that a 72-week course of tirzepatide at its maximum dosage reduced body weight by 20.9%; a similar study published in 2021 reported a 14.9% loss with semaglutide after 68 weeks.
A Head-to-Head Comparison
The benefit of this study—a randomized, controlled trial of 751 people with obesity but without type 2 diabetes—is that the drugs could be compared head-to-head. “Doctors, insurance companies, and patients are always asking, ‘which drug is more effective?’” said Dr. Aronne, who is also an internist specializing in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Center. “This study allowed us to do a direct comparison.” However, the trial was not conducted as a blinded analysis—the gold standard for minimizing bias in clinical trials. Because these drugs are administered via labeled auto-injection devices, participants knew which medication they were receiving.
Eli Lilly, the company that produces tirzepatide, sponsored the study, which was conducted at 32 sites across the United States and Puerto Rico. All participants received counseling regarding diet and exercise, and the side effects associated with both drugs were very similar. For example, about 44% of individuals in each treatment arm experienced nausea and 25% reported abdominal pain.
Nearly one-third (32%) of the people who took tirzepatide achieved a body-weight reduction of at least 25%, compared with 16% of those who received semaglutide. The improved performance is likely linked to tirzepatide’s dual mechanism of action, said Dr. Aronne. Whereas semaglutide works by activating receptors for a hormone called glucagon-like peptide 1, or GLP-1, tirzepatide mimics not only GLP-1 but an additional hormone, glucose-dependent insulinotropic peptide (GIP). Together, these actions reduce hunger, lower blood-glucose levels, and affect fat cell metabolism.
“The pathways that regulate weight are incredibly complicated,” Dr. Aronne said. Targeting multiple mechanisms may pave the way to additive weight loss. Trials are underway to determine whether tirzepatide, like semaglutide, also reduces the risk of cardiovascular events, such as heart attack and stroke.
The Next Generation
Dr. Aronne and his colleagues are currently testing the next generation of weight-loss drugs, including compounds such as Eli Lilly’s retatrutide, dubbed “triple G” for the three hormones it mimics: GLP-1, GIP, and glucagon. In addition to possibly being more effective, drugs like retatrutide could also potentially benefit a broader population.
“Even though drugs like tirzepatide and semaglutide work really well, better than anything we have ever seen, we still have people who don’t respond to them,” said Dr. Aronne. “So, moving forward, we want to keep trying to do better.”
Reference: “Tirzepatide as Compared with Semaglutide for the Treatment of Obesity” by Louis J. Aronne, Deborah Bade Horn, Carel W. le Roux, Wayne Ho, Beverly L. Falcon, Elisa Gomez Valderas, Sagar Das, Clare J. Lee, Leonard C. Glass, Cagri Senyucel and Julia P. Dunn, 11 May 2025, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2416394
Dr. Louis Aronne is a paid consultant and advisory board member for Eli Lilly and Company, the study sponsor and the manufacturer of Zepbound (tirzepatide). Dr. Aronne also serves as a paid advisory board member for Novo Nordisk, the manufacturer of Wegovy (semaglutide).
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4 Comments
The most effective obesity drug is exercise+diet!
Sorry, no. It’s a species appropriate species specific diet, and the standard American diet is not fit for human consumption
Until long term trials double-blind and examining longevity can be performed, no one will know which is better. Hopefully, there will not be a huge difference in death rates, as by the time statistical significance is established for any of them there have to be quite a few deaths. For that reason, there should be 3 groups to allow the most dangerous one to be discontinued sooner if there’s a very large difference. Genetic profiles to identify whether there are correlations in that area would also be prudent. All 3 manufacturers should be required to donate for an independent trial that none of the manufacturers can choose not to publish would also be appropriate, Not just for this but for all medication trials, so it might not take decades to find out that a few trials were not published because the manufacturer chose to use the nondisclosure agreement currently routine for trials. If the manufacturer feels the lab made mistakes, they can publish an addendum explaining why they feel those particular results are invalid. Maybe they will then figure out that a specific gene makes a specific medication dangerous before thousands have been killed or made ill!
Identifying specific possible issues should not mean people with a specific genetic profile can not be included in a trial, but they should have disclosure of the issue and closer supervision. Giving everyone closer supervision, regardless of genetic profile would be even better.