May 12, 2025 – Turns out, two really is better than one – at least when it comes to weight loss drugs.
In the first head-to-head trial of its kind, people with obesity who took tirzepatide (sold under the brand names Mounjaro and Zepbound) lost more weight and inches from their waist than those who took semaglutide (Ozempic, Wegovy).
Semaglutide is a GLP-1 agonist that boosts the hunger-suppressing hormone GLP-1. Tirzepatide is a dual agonist, targeting both GLP-1 and GIP. That means it acts on two hormone pathways, while semaglutide works on one.
"We've learnt over the past 20 years or so that you can overcome the plateau effect with obesity drugs if you can add in drugs with mechanisms that are completely different," said Louis J. Aronne, MD, who led the study and is also the director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City. "This is exactly what we see here."
In the study, people taking tirzepatide lost about 20% of their body weight, while those taking semaglutide lost around 14%. They also were more likely to hit big weight loss goals – among those who lost 25% or more body weight, twice as many (32%) were on tirzepatide compared with semaglutide (16%).
The findings were presented Sunday at the European Congress on Obesity 2025 in Spain, and published in The New England Journal of Medicine on the same day. The trial was sponsored by Eli Lilly & Company, the maker of tirzepatide.
"They're both very good medications," said David Horner, MD, of the University of Copenhagen in Denmark, who was not involved in the study. "One is not in doubt that tirzepatide has a greater weight loss benefit from the data. We're comparing a very good drug with a very good drug."
First Head-to-Head Comparison Between Two Weight Loss Drugs
Both tirzepatide and semaglutide have helped people lose weight in earlier studies, but this is the first time they've been compared side by side.
Of the 751 people in the study, half took tirzepatide and half took semaglutide. Both groups received weekly shots for 72 weeks, using the highest dose they could handle without strong side effects.
Most people in the study were women in their mid-40s. Most were White. Everyone had struggled with their weight for many years – 16 years, on average – and had tried and failed to lose weight through diet alone.
Beyond the weight loss results, tirzepatide also helped people shrink their waistlines by an extra 2 inches – by 7 inches, versus 5 inches for semaglutide. That kind of difference is "clinically meaningful and has been shown to reduce blood pressure and other metabolic parameters," Aronne said.
Sure enough, people on tirzepatide saw greater improvements in key health markers like blood pressure, blood sugar, insulin, and cholesterol.
"In general, the more weight someone loses, then the better the metabolic parameters will be," Aronne said.
Side effects were common and were mostly mild stomach problems like nausea or diarrhea, but few people stopped taking the medicine because of them, he said – only about 6% on tirzepatide and 8% on semaglutide.
Of course, the right medicine for each patient depends on a lot of things – including insurance coverage and doctor recommendations – not just which one works best in studies, said Horner.
Many more weight loss drugs like these are on the way. "There are around 150 medications currently in trial," he said. "It is the golden age of these medicines."
