Tirzepatide beats semaglutide for weight loss in first randomized head-to-head obesity trial

In the first randomized head-to-head trial of the two leading obesity drugs, tirzepatide produced more weight loss than semaglutide over 72 weeks, according to results published May 11, 2025, in The New England Journal of Medicine ^[1][3].

The trial, called SURMOUNT-5, enrolled 751 adults with obesity who did not have type 2 diabetes. Participants were assigned at random, in equal numbers, to weekly injections of tirzepatide at the highest dose they could tolerate (10 mg or 15 mg) or semaglutide at the highest dose they could tolerate (1.7 mg or 2.4 mg), for 72 weeks ^[1]. The study was open-label, meaning participants and their doctors knew which drug was given ^[1]. The average age was 44.7 years, and 64.7% of participants were women ^[4]. Eli Lilly, which makes tirzepatide, funded the trial ^[1][3].

At week 72, average weight fell 20.2% with tirzepatide and 13.7% with semaglutide, a difference of 6.5 percentage points (95% CI, -8.1 to -4.9; P<.001). Waist circumference fell 18.4 cm with tirzepatide and 13.0 cm with semaglutide, a difference of 5.4 cm (95% CI, -7.1 to -3.6; P<.001) ^[1][4].

More people on tirzepatide reached each weight-loss threshold: at least 10% loss, 81.6% versus 60.5%; at least 15%, 64.6% versus 40.1%; at least 20%, 48.4% versus 27.3%; and at least 25%, 31.6% versus 16.1% ^[4]. Both groups also had improvements in systolic and diastolic blood pressure, HbA1c, fasting glucose and lipid levels ^[4].

Side effects were similar overall. Adverse events were reported by 76.7% of people on tirzepatide and 79% of those on semaglutide. Gastrointestinal problems were the most common in both groups, were mostly mild to moderate, and occurred mainly during dose escalation. Serious adverse events were reported by 4.8% on tirzepatide and 3.5% on semaglutide. There was one confirmed case of pancreatitis, in the semaglutide group. No deaths, major cardiovascular events, medullary thyroid cancer or pancreatic cancer were reported ^[4]. The journal's abstract states the same pattern: gastrointestinal events were most common in both groups, mostly mild to moderate and primarily during dose escalation ^[1].

Tirzepatide activates two metabolic receptors, GIP and GLP-1, while semaglutide activates GLP-1 alone. The researchers wrote that this dual activity "may contribute to the greater weight reduction" seen with tirzepatide ^[4]. In the United States, tirzepatide is sold as Zepbound for obesity, and semaglutide is sold as Wegovy ^[4].

Why it matters for patients

The trial reports group averages from a single 72-week study, not a prediction of what any one person will experience. Sangeeta Kashyap, MD, of NewYork-Presbyterian/Weill Cornell Medical Center, wrote in a commentary that the results position tirzepatide as a potential game changer, and added that for patients who succeed with tirzepatide, switching to semaglutide for weight-loss maintenance is not an option and will likely lead to weight regain ^[4]. That is her assessment; the trial did not test switching between the drugs.

Coverage may shape the choice more than the trial data. Katherine H. Saunders, MD, an obesity medicine physician at Weill Cornell Medicine, told Healio that obesity drug decisions are often driven by insurance coverage, and that some patients do not respond to or cannot tolerate one of the medications, so having multiple options matters ^[4].

That tension is already visible: CVS Health announced on May 1 that semaglutide would become the preferred GLP-1 medication for obesity treatment under CVS Caremark starting July 1, a change Saunders said could limit access to tirzepatide for many patients ^[4].

The trial did not report costs, and it did not compare the drugs in people with type 2 diabetes ^[1][4].

What happens next

• July 1, 2025: the CVS Caremark preferred-status change for semaglutide is scheduled to take effect ^[4].
• July 3, 2025: the results appear in the print issue of The New England Journal of Medicine ^[3].
• Oct. 23, 2025: correspondence about the trial, including a reply from lead author Louis J. Aronne, MD, is published in the journal ^[1].
• The trial is registered as NCT05822830 on ClinicalTrials.gov ^[2].