GLP-1s
Jen Hand
A head-to-head battle between two highly effective weight loss drugs revealed a clear winner, according to a study published in NEJM on May 11, 2025.
Participants in the SURMOUNT-5 trial treated with tirzepatide achieved an average weight reduction of 20.2% compared to 13.7% for those treated with semaglutide—a 47% greater relative weight loss. Study findings also showed participants on tirzepatide had a higher average waist circumference reduction (7.2 in) compared to those on semaglutide (5.1 in).
The article’s authors acknowledged that clinically meaningful weight reductions occur with both medications, as shown in prior studies.
“Both treatments decrease appetite and regulate food-related behaviors, presumably through expression of their respective receptor targets in subcortical regions of the brain that regulate food intake,” said the researchers. “The patterns of central expression of GIP receptors do not fully overlap with those of GLP-1 receptors, and this variation is hypothesized to contribute to the higher weight reduction that has been noted with the dual agonism of GIP and GLP-1 receptors than with agonism of either receptor alone in preclinical models.”
Tirzepatide is a GIP and GLP-1 receptor agonist, and semaglutide is a GLP-1 receptor agonist.
“The SURMOUNT-5 head-to-head results demonstrated tirzepatide led to greater weight reduction compared to semaglutide, providing further evidence to support tirzepatide as an effective option for obesity management,” said Louis J. Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine and principal investigator of SURMOUNT-5, in a press release.
Study design
SURMOUNT-5 was designed to evaluate the efficacy and safety of the maximum tolerated doses of tirzepatide and semaglutide. The multicenter randomized trial was conducted across 32 sites in the United States and Puerto Rico over a 72-week period that ended in November 2024. It included participants who were 18 years or older, had a BMI of 30 or higher, or a BMI of 27 or higher and at least one prespecified obesity-related complication. They also needed to have reported at least one unsuccessful dietary effort for weight loss.
The trial excluded people with diabetes, individuals with previous or planned surgical treatment for obesity, anyone treated with weight loss medication or a GLP-1 agonist within 90 days before screening, or those who had a change in body weight of more than 11 pounds within 90 days before screening.
A total of 750 participants were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg) once a week subcutaneously for the trial’s duration. All patients were counseled on nutrition and physical activity.
Study participants who took tirzepatide lost an average of 50.3 pounds, and patients on semaglutide lost an average of 33.1 pounds. Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%, the key secondary end point targets. Results showed nearly 50% of people taking tirzepatide reaching at least 20% weight loss versus 27.3% of those on semaglutide.
Building the evidence
With both treatments in the trial, as weight loss increased, “greater improvements occurred in cardiometabolic risk factors including BP, glycemia, and lipid levels,” study authors said. They noted that their findings were consistent with previous reports.
The safety profiles of both drugs were consistent with prior trials as well. The authors said any GI adverse events were predominately mild to moderate in severity and happened mostly during dose escalation. Treatment discontinuation occurred more often with semaglutide than with tirzepatide. Researchers found the tirzepatide group had more injection-site reactions than the semaglutide group as well.
One strength of the trial was the diversity of the participants, “with 19% reporting their race as Black and 26% reporting their ethnic group as Hispanic or Latino, which is representative of the populations living with obesity,” said the study authors.
One limitation was that the trial was not blinded, but the consistency of results with those from previous blinded trials “supports their generalizability,” wrote the researchers.
“Thanks to the latest advancements in obesity management medications, more physicians and patients are witnessing significant weight reduction beyond what they have seen before,” Aronne said in the press release.
He recognizes this period as a “golden age” for weight loss drug development, likening it to BP medications in the 1980s and statins in the 1990s.
“It’s taken a number of years, but we are now in the next phase,” he said. ■