Tirzepatide Outperformed Semaglutide on Weight Loss in Adults With Obesity

CATEGORY: DIET & WEIGHT

In the first randomized trial to directly compare the two most widely used weight-loss injections, adults with obesity taking tirzepatide lost an average of 20.2% of their body weight over 72 weeks, compared with 13.7% for those taking semaglutide—about 50 pounds versus 33 pounds.¹

751 Adults With Obesity Followed 72 Weeks

The trial, called SURMOUNT-5 and published in the New England Journal of Medicine, enrolled 751 adults with obesity but without diabetes at 32 sites in the United States and Puerto Rico. Participants were randomly assigned to a once-weekly injection of either tirzepatide (sold as Zepbound) or semaglutide (sold as Wegovy), each at the highest dose the person could tolerate, and were followed for 72 weeks—about a year and a half. The main outcome was the percentage of body weight lost. The trial was open-label, meaning participants and their doctors knew which drug they were taking—a design that can subtly influence behavior, though weight itself is an objective measure.¹

7.2 Inches Off the Waist Versus 5.1 Inches

Both medications produced substantial weight loss, but tirzepatide came out ahead on every measure reported: average weight loss of 20.2% versus 13.7%, and about 7.2 inches off the waist versus 5.1 inches. Participants on tirzepatide were also more likely to reach every weight-loss milestone the trial tracked, from 10% to 25% of body weight. One likely reason is mechanism: semaglutide mimics one gut hormone (GLP-1) that curbs appetite and slows digestion, while tirzepatide mimics two (GLP-1 and GIP), which appears to amplify the effect.¹

2.7% Versus 5.6% Stopped for Stomach Side Effects

The most common side effects with both drugs were digestive—nausea, constipation, and diarrhea—mostly mild to moderate and concentrated in the dose-increase phase. Stomach-related side effects led 2.7% of tirzepatide participants and 5.6% of semaglutide participants to stop treatment. The trial was funded by Eli Lilly, the maker of tirzepatide, which is worth knowing when weighing the result—though the finding was published in a top peer-reviewed journal and the comparison used semaglutide at its full approved dose. The trial also measured weight, not long-term outcomes like heart attacks, and semaglutide’s 13.7% average loss is itself a clinically meaningful result.¹

Real-World Records of 18,386 Matched Adults

The head-to-head result matches what doctors had already observed in practice. A 2024 study of electronic health records compared 18,386 matched adults with overweight or obesity taking the two drugs in everyday care and found those on tirzepatide were significantly more likely to reach 5%, 10%, and 15% weight loss, with similar rates of digestive side effects.² Consistent results from a randomized trial and real-world records make the difference between the drugs unlikely to be a statistical fluke.

Key Takeaways

• In a 72-week head-to-head randomized trial of 751 adults with obesity, tirzepatide led to an average 20.2% body-weight loss versus 13.7% with semaglutide.
• Both drugs produced meaningful weight loss; digestive side effects were the most common with each and led fewer than 6% of participants to stop either drug.
• A large real-world study of health records points the same way, strengthening confidence in the difference.
• The trial was open-label, funded by tirzepatide’s maker, and measured weight rather than long-term health outcomes such as heart disease.

References

1. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine. 2025;393(1):26–36. link
2. Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, et al. Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity. JAMA Internal Medicine. 2024;184(9):1056–1064. link