Tirzepatide outperforms semaglutide in weight loss clinical trial

Tirzepatide (trade name Zepbound) promoted greater weight loss in individuals with obesity than did semaglutide (trade name Wegovy) in a clinical trial that compared the safety and efficacy of the injectable drugs. In the 72-week trial—led by an investigator at Weill Cornell Medicine and NewYork-Presbyterian and conducted with the University of Texas McGovern Medical School, the David Geffen School of Medicine at the University of California, Los Angeles, the University College Dublin and Eli Lilly—participants taking tirzepatide lost about 50 pounds—or 20.2% of their body weight—compared with those on semaglutide, who lost an average of 33 pounds or 13.7% of their baseline weight.

The results of the SURMOUNT-5 phase 3b study, published May 11 in the New England Journal of Medicine, showed that when both drugs are administered at their maximum doses, participants receiving tirzepatide were more likely to reach weight loss targets and saw a greater reduction in waist circumference than those on 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. So, moving forward, we want to keep trying to do better."

Dr. Louis Aronne, Director, Comprehensive Weight Control Center and the Sanford I. Weill Professor of Metabolic Research, Weill Cornell Medicine

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).