- Zepbound outperformed Wegovy for weight loss in a clinical trial sponsored by Eli Lilly.
- Participants who received tirzepatide, the active ingredient in Zepbound, also had greater reductions in waist size and more significant improvements in metabolic risk factors.
- Tirzepatide’s dual effects on GLP-1 and GIP may explain its superior performance over semaglutide, the active ingredient in Wegovy.
- Lack of insurance coverage and high costs remain a barrier to obtaining tirzepatide.
Eli Lilly’s weight loss drug Zepbound outperformed competitor Novo Nordisk’s Wegovy, according to a clinical trial funded by Lilly.
The SURMOUNT-5 trial, a Phase 3b open-label clinical trial, examined the safety and efficacy of tirzepatide, the active ingredient in Zepbound.
When compared with semaglutide (Wegovy), which is selective for one type of receptor versus the two targeted by tirzepatide, Zepbound was found to be more effective.
Study participants using tirzepatide lost more weight after 72 weeks (average loss of 20.2% compared to 13.7% for semaglutide). This translates to an average of 50.3 pounds for those using tirzepatide and 33.1 pounds for those using semaglutide.
It was additionally noted that significantly more tirzepatide users achieved at least 15.0% weight loss and a greater reduction in their waist circumference.
Lilly’s study compared the drugs tirzepatide and semaglutide in adults with obesity but without diabetes.
Altogether, 751 individuals were randomly assigned to receive the maximum tolerated dose of one of the two medications on a weekly basis. Of these, 750 received at least one dose.
However, tirzepatide was more likely to help participants achieve major weight-loss milestones.
Nearly one-third (32%) of participants experienced a 25% or more body weight reduction due to tirzepatide. By comparison, those who received semaglutide experienced a 16% reduction in body weight.
Side effects were mostly mild to moderate gastrointestinal issues such as nausea and diarrhea, occurring mainly during dose increases.
Although both medications had similar overall safety profiles, semaglutide users experienced slightly more treatment discontinuations due to gastrointestinal side effects.
Tirzepatide users reported more injection-site reactions, like redness or irritation, but these were generally not severe.
Still, some experts, like Austin Shuxiao, MD, a board certified internal medicine physician and founder of Peach IV, who was not involved in the study, advised caution in interpreting the results.
“It is important to point out that Eli Lilly is both the maker of Zepbound and the sponsor for this study,” he told Healthline.
“This represents a clear conflict of interest, which is common in these head-to-head studies, and is always good to keep in mind before we take the study at face value,” Shuxiao noted.
Experts suggest that tirzepatide’s dual mechanism of action, targeting two metabolic receptors, may explain its superior weight-loss results compared to semaglutide’s single-receptor approach.
Raj Dasgupta, MD, chief medical advisor for Sleepopolis, who was also not a part of the study, explained that it is believed that tirzepatide acts on both GLP-1 (glucagon-like peptide-1) receptors and GIP (glucose-dependent insulinotropic polypeptide) receptors.
Semaglutide, however, only acts on GLP-1 receptors.
“That second pathway seems to give Zepbound an extra edge when it comes to appetite control and how the body handles energy and fat,” Dasgupta told Healthline.
“In real-world terms, that means many patients on Zepbound are losing more weight than those on Wegovy,” he noted.
Dasgupta described the results of the trial as a “big deal’ for people with obesity.
“We now have more than one highly effective option, and Zepbound seems to be leading the pack,” he said.
An important implication, for instance, is that if a person doesn’t respond well or experiences intolerable side effects with one weight loss medication, they have another option to try.
“That kind of flexibility is important because weight loss isn’t the same journey for everyone,” Dasgupta said.
“If you’ve plateaued or had a tough time with side effects, it’s worth asking your doctor whether Zepbound might be a better fit,” he advised.
However, if you’re doing well on Wegovy, there’s no need to switch, he noted.
Of course, it’s important to keep in mind that no single medication is a magic bullet for weight loss.
“The best results still come when people combine these treatments with changes in diet, sleep, movement, and stress — things we work on together over time,” Dasgupta said.
Shuxiao said that while tirzepatide could become a first-line choice for obesity treatment, it’s more expensive and tends to be less covered by insurance.
“Insurance will dictate patients’ access to medication, not clinical preference,” he said, noting that he has greater difficulty getting tirzepatide approved for his patients, especially if they have suboptimal insurance plans.
Still, Shuxiao said he feels that anyone who is in the overweight-obesity BMI range should consider GLP-1 medications, provided there are no contraindications.
“GLP-1 agonists are the most effective weight loss medication in human history, and if they are proven free of long-term side effects, they will remain a staple in modern medicine,” he said.
The SURMOUNT-5 trial reinforces tirzepatide’s role as a leading treatment option for obesity, offering greater weight loss and metabolic benefits than semaglutide in adults without diabetes.
With its dual-targeting mechanism acting on both GLP-1 and GIP receptors, tirzepatide appears to provide more robust appetite regulation and fat metabolism.
While both medications were generally well tolerated, differences in side effect profiles and insurance coverage may guide individual treatment decisions.
Experts agree that the findings are encouraging, but also stress the importance of a holistic approach to weight management. Medication alone isn’t a cure — sustainable success still hinges on long-term lifestyle changes.
As more options become available, patients and providers can better tailor treatment to individual needs and preferences.
However, the financial accessibility of these medications remains a concern. As research continues and coverage improves, tirzepatide may become a cornerstone of obesity care — but only if patients can afford to access it.
