Tirzepatide tops semaglutide for weight loss in 72-week head-to-head trial

Adults with obesity lost more weight on tirzepatide than on semaglutide over 72 weeks, with an average change of −20.2% of body weight on tirzepatide and −13.7% on semaglutide ^[1].

The findings come from SURMOUNT-5, published in the New England Journal of Medicine ^[1]. The trial assigned 751 participants, in equal numbers, to the highest dose they could tolerate of either tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg), injected once weekly for 72 weeks ^[1]. Enrollment took place at 32 sites in the United States and Puerto Rico from April 2023 through November 2024 ^[2]. To qualify, participants needed a body mass index of at least 30, or at least 27 along with one or more obesity-related complications, and none had diabetes ^[2]. Their average age was 45, and 35% were men ^[2]. Everyone involved knew which drug was being given, because the trial was open-label ^[1].

The tirzepatide result carried a 95% confidence interval of −21.4% to −19.1%, and the semaglutide result of −14.9% to −12.6%, a gap the authors reported as significant (P<0.001) ^[1]. In kilograms, that averaged 22.8 kg lost on tirzepatide and 15.0 kg on semaglutide ^[2]. Waist circumference shrank by a least-squares mean of 18.4 cm and 13.0 cm respectively (P<0.001) ^[1]. More people on tirzepatide reached each threshold the trial measured, from at least 10% weight loss up through 25% ^[1]. At the highest cutoff reported, 19.7% of the tirzepatide group and 6.9% of the semaglutide group lost at least 30% of their body weight ^[1].

Stomach and intestinal problems were the most frequently reported side effects in both groups; most were mild or moderate and appeared mainly while doses were being raised ^[1]. Dropouts caused by those gastrointestinal effects were more common on semaglutide, at 5.6%, than on tirzepatide, at 2.7% ^[2].

Men in the trial lost roughly 6% less weight than women in both treatment groups ^[2]. The authors point to the trial's relatively high share of male participants, 35%, as a possible reason its overall weight loss came in somewhat below earlier studies of the same drugs ^[2]. In an editorial published alongside the paper, Frank L. Greenway, MD, wrote that the trial "provides helpful guidance to physicians treating patients with obesity and points out differential mechanisms of weight loss between men and women" ^[2]. Eli Lilly, which sells tirzepatide, funded the research, and several of its employees are listed among the authors ^[1]. The paper appeared online on May 11, 2025, and in the July 3, 2025 issue of the journal ^[1].

Why it matters for patients

Choosing between these two medicines has largely meant comparing results from separate studies that enrolled different people. SURMOUNT-5 puts both drugs into a single study with one dosing schedule and one main measurement, which offers a more direct comparison ^[1]. The paper describes both as highly effective medications for obesity management ^[1].

The results are group averages, not predictions for any one person. The trial enrolled people with obesity and without type 2 diabetes, so its numbers may not describe people who have diabetes ^[1]. Because the trial was open-label, participants knew which treatment they were getting, a design that can influence how side effects are reported ^[1].

These reports do not address price or insurance coverage, so it has not been reported whether either drug is easier to obtain or afford. It also has not been reported whether the gap between the two drugs continues past 72 weeks, or what happens to weight after treatment stops. The trial is registered on ClinicalTrials.gov as NCT05822830 ^[1].