Tirzepatide leads to significantly greater loss of weight and waist circumference compared with semaglutide among adults with obesity but without diabetes, according to new results from the SURMOUNT-5 phase 3b trial, published in The New England Journal of Medicine.

Louis J. Aronne, MD, et al., randomly assigned 751 patients (mean age 45 years) to receive the maximum tolerated dose of either tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly across 32 sites in the U.S. and Puerto Rico from April 2023 to November 2024. Eligible individuals had a BMI of ≥30 kg/m² (or ≥27 kg/m² plus one or more obesity-related complication) and no diabetes.

Results showed that at 72 weeks, the least-squares mean percent change in body weight was −20.2% for tirzepatide users vs. −13.7% for semaglutide users (p<0.001). This translated to an average weight loss of 22.8 kg with tirzepatide and 15.0 kg with semaglutide.

Notably, tirzepatide users were more likely than semaglutide users to achieve reductions of at least 10-25% in body weight.

As for waist circumference, findings revealed a least-squares mean change of −18.4 cm for participants taking tirzepatide vs. −13.0 cm for those on semaglutide (p<0.001).

Regarding safety, most adverse events were mild to moderately severe and occurred during dose escalation. Gastrointestinal adverse events causing discontinuation of treatment were observed more often with semaglutide (5.6%) vs. tirzepatide (2.7%).

Importantly, weight loss was approximately 6% lower in men than women in both treatment groups in the current trial, which included a higher percentage of men (35%) than most obesity trials. The trial authors believe this finding may explain why the weight loss was slightly lower in this trial compared with previous trials.

In an accompanying editorial comment, Frank L. Greenway, MD, suggests that the "differential weight loss" could be due to stimulation of the GLP-1 receptor mechanism of both drugs and that "the finding raises a question about the body constituents involved in weight loss and why these may vary according to sex."

Greenway writes that the trial "provides helpful guidance to physicians treating patients with obesity and points out differential mechanisms of weight loss between men and women."