, 2025-05-12 09:15:00
MÁLAGA, Spain — In the first head-to-head trial of its kind, tirzepatide (Mounjaro for type 2 diabetes and Zepbound for obesity; Eli Lilly) produced significantly greater weight loss, and reduction in waist circumference, than semaglutide (Ozempic for type 2 diabetes and Wegovy for weight loss; Novo Nordisk) in adults with obesity but without type 2 diabetes over 72 weeks in the SURMOUNT-5 trial.
The phase 3b open-label, randomized controlled trial showed that patients treated with tirzepatide vs semaglutide lost an average of 20.2% vs 13.7% of their baseline weight over the 72 weeks. Nearly twice as many participants achieved a target of ≥ 25% weight reduction on tirzepatide vs semaglutide.
“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, often leading to additional weight loss. This is exactly what we see here,” said Louis J. Aronne, MD, principal investigator of the trial and director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City.
The findings were presented at European Congress on Obesity (ECO) 2025 and simultaneously published in The New England Journal of Medicine. The trial was sponsored by Eli Lilly & Company, the manufacturer of tirzepatide.
First Comparative Data Between Two Weight-Loss Drugs
While both drugs have demonstrated significant weight-loss effects in previous trials, this is the first study directly comparing the dual agonist glucose-dependent insulinotropic peptide (GIP)/glucagon-like peptide 1 (GLP-1) tirzepatide with GLP-1 semaglutide. The results suggest tirzepatide’s dual action on both GIP and GLP-1 receptors yields superior outcomes in weight reduction and waist circumference. Both tirzepatide and semaglutide are approved for chronic weight management, although clinicians have lacked comparative data to guide prescribing choices between them.
Study Design — SURMOUNT-5
The trial enrolled 751 adults with obesity (mean body mass index [BMI], 39.4; mean body weight, 113.0 kg; mean waist circumference, 118.3 cm) but without type 2 diabetes. Participants were randomized 1:1 to receive either the maximum tolerated dose of tirzepatide (10 or 15 mg; n = 374) or semaglutide (1.7 or 2.4 mg; n = 376) once weekly for 72 weeks.
Most participants were women (64.7%) and White (76.1%), with a mean age of 44.7 years. All had at least one obesity-related condition and a history of at least one unsuccessful dietary effort to lose weight. Median self-reported obesity duration was 16 years.
At week 72, the mean percent change in weight was −20.2% (95% CI, −21.4 to −19.1) with tirzepatide and −13.7% (95% CI, −14.9 to −12.6) with semaglutide (P < .001), while waist circumference dropped by a mean of 18.4 cm with tirzepatide and 13.0 cm with semaglutide (P < .001).
Aronne noted the sex-based differences: Women vs men lost a mean of 18% vs 11% on semaglutide and 17.8% vs 11% on tirzepatide. “The waist circumference difference mirrors the weight-loss results [−15.7 cm and −20 cm in semaglutide and tirzepatide, respectively],” he said, pointing out that, “The 5.4 cm greater reduction in waist circumference with tirzepatide compared with semaglutide was statistically superior and clinically meaningful and has been shown to reduce blood pressure and other metabolic parameters — remembering that waist circumference is a surrogate for visceral fat.”
More participants on tirzepatide than on semaglutide achieved weight reduction targets of 10% (81.6 vs 60.5%),15% (64.6 vs 40.1%), 20% (48.4 vs 27.3%), and 25% (31.6 vs 16.1%).
Metabolic Parameters Showed Greater Improvement With Tirzepatide
At week 72, tirzepatide was associated with greater improvements in cardiometabolic parameters than semaglutide, including greater mean reductions in BMI, systolic and diastolic blood pressures, glycemia, fasting insulin, triglycerides, and very low–density lipoprotein cholesterol and a greater mean increase in high-density lipoprotein (HDL) cholesterol; mean reductions in non-HDL and low-density lipoprotein cholesterol were similar in both groups. There was also a greater improvement in cardiometabolic parameters with a greater weight reduction with both treatment groups.
“In general, the more weight someone loses then the better the metabolic parameters will be,” Aronne explained.
Safety Results
Gastrointestinal adverse events were the most common for both drugs and occurred primarily during dose escalation. These events were generally mild to moderate in severity. Treatment-emergent adverse events were reported in 76.7% of patients on tirzepatide and 79.0% of those on semaglutide. Serious adverse events occurred in 3.5% and 4.8% of patients, respectively.
“The side effects of these medicines keep getting reported, but if you look at the people who discontinue in the trial, then the rate was very low,” Aronne said. Discontinuation due to adverse events occurred in 6.1% of the tirzepatide group and 8.0% of the semaglutide group.
Clinical Use Most Dependent on Availability
Commenting on the findings for Medscape Medical News, David Horner, MD, of the University of Copenhagen in Copenhagen, Denmark, noted, “They’re both very good medications. 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.”
Horner, who has worked extensively in endocrinology and cardiovascular medicine in both the United Kingdom and Denmark, said clinical application will depend heavily on availability, country-specific guidelines, and healthcare system factors. “Much will depend on availability of the medication…and many clinical decisions will be based on that,” he added.
“There are around 150 medications currently in trial, and it is the golden age of these medicines. These two mechanisms in tirzepatide do seem to have an additive effect.”
Aronne and co-authors’ disclosures are available on the NEJM website. Horner reported having no conflicts of interest. The study was sponsored by Eli Lilly & Company.
