CATEGORY: DIET & WEIGHT
Two weekly injections dominate obesity treatment, and until this trial nobody had run them against each other. SURMOUNT-5 did. Over 72 weeks, adults with obesity taking tirzepatide lost an average of 20.2% of their body weight. Those taking semaglutide lost 13.7%. That is roughly 50 pounds against 33.1
751 Adults, 32 Sites, and No Blindfold
The trial enrolled 751 adults who had obesity but not diabetes, at 32 sites in the United States and Puerto Rico. A random draw decided which weekly injection each person got, at the highest dose that person could tolerate. Follow-up ran 72 weeks, about a year and a half. The measure that counted was percentage of body weight lost. Patients and their doctors both knew which drug was in the syringe, since the trial was open-label. Knowing can nudge behavior. Weight itself is an objective measure.1
Two Gut Hormones Instead of One
Tirzepatide, sold as Zepbound, came out ahead of semaglutide, sold as Wegovy, on every measure reported. Waists shrank 7.2 inches on average against 5.1 inches. At every weight-loss milestone the trial tracked, from 10% of body weight up to 25%, more people on tirzepatide reached it. Mechanism is the likely explanation. Semaglutide imitates one gut hormone, GLP-1, which curbs appetite and slows digestion. Tirzepatide imitates that hormone and a second one, GIP, and the pair appears to amplify the effect.1
Nausea Ended Treatment More Often on Semaglutide
Digestive trouble was the common complaint with both drugs: nausea, constipation, diarrhea. Most of it was mild to moderate, and most of it clustered in the weeks when doses were climbing. Stomach side effects ended treatment for 2.7% of the tirzepatide group and 5.6% of the semaglutide group. Eli Lilly makes tirzepatide and funded the trial, which belongs in any reading of the result. The comparison did use semaglutide at its full approved dose, and the paper ran in a top peer-reviewed journal. What the trial measured was weight. Heart attacks and strokes were not among its outcomes, and semaglutide’s own 13.7% average is a clinically meaningful loss.1
Ordinary practice had already hinted at the same gap. A 2024 study of electronic health records matched 18,386 adults with overweight or obesity taking one drug or the other in everyday care. Those on tirzepatide reached 5%, 10% and 15% weight loss significantly more often, with digestive side effects at similar rates.2
Key Takeaways
- Over 72 weeks, tirzepatide averaged 20.2% of body weight lost against 13.7% for semaglutide, roughly 50 pounds versus 33, with 7.2 inches off the waist versus 5.1.
- Both drugs produced substantial loss. Digestive side effects were the usual complaint and ended treatment for fewer than 6% of either group.
- The trial was open-label, funded by tirzepatide’s maker, and measured weight rather than long-term outcomes such as heart disease.
References
- 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
- 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