Summary: In a 72-week randomized clinical trial, tirzepatide (Zepbound) produced substantially greater weight loss than semaglutide (Wegovy) when both drugs were given at their highest approved doses to adults with obesity but without type 2 diabetes. Participants treated with tirzepatide lost an average of 20.2% of body weight (about 50 pounds), compared with an average loss of 13.7% (about 33 pounds) for those taking semaglutide. The trial also found larger reductions in waist circumference and higher rates of very large weight loss with tirzepatide.
- Greater efficacy: Mean weight loss ~20.2% with tirzepatide versus ~13.7% with semaglutide at week 72.
- Dual mechanism: Tirzepatide activates both GLP-1 and GIP pathways, which likely enhances appetite suppression and metabolic effects.
- Higher rates of major weight loss: 32% of tirzepatide-treated participants achieved ≥25% weight loss, compared with 16% for semaglutide.
Study overview
The phase 3b SURMOUNT-5 trial compared tirzepatide and semaglutide head-to-head over 72 weeks in 751 adults with obesity but without type 2 diabetes. Conducted at multiple centers and led by investigators at Weill Cornell Medicine among other institutions, the open-label study randomized participants to the maximum tolerated weekly dose of either tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg). All participants received standardized counseling on diet and exercise.
Efficacy and clinical findings
At week 72, the least-squares mean percent change in body 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 < 0.001). Waist circumference fell by a mean of 18.4 cm with tirzepatide versus 13.0 cm with semaglutide (P < 0.001). Participants on tirzepatide were significantly more likely to reach categorical weight-loss milestones (≥10%, ≥15%, ≥20%, and ≥25%) than those on semaglutide, including a twofold higher proportion achieving ≥25% weight loss (32% vs. 16%).
Safety and tolerability
Both medications produced similar side-effect profiles, predominantly gastrointestinal and mostly mild to moderate in severity, occurring primarily during dose escalation. Approximately 44% of participants in each group reported nausea, and about 25% reported abdominal pain. No unexpected safety signals emerged in this 72-week comparison, though long-term outcomes and effects on cardiovascular events are still under investigation.
Why tirzepatide may be more effective
Tirzepatide is a dual agonist that mimics both glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), whereas semaglutide is a selective GLP-1 receptor agonist. Activating both GLP-1 and GIP receptors appears to enhance appetite suppression, improve glucose handling, and influence fat-cell metabolism, which likely explains the greater average and categorical weight loss seen with tirzepatide in this trial. As Dr. Louis Aronne and colleagues note, targeting multiple regulatory pathways of energy balance may yield additive benefits.
Trial design and limitations
SURMOUNT-5 was an open-label, randomized, controlled trial, which enabled direct comparison of the two agents but did not blind participants or investigators because the drugs were administered via clearly labeled auto-injector devices. The sponsor of the trial was Eli Lilly, the manufacturer of tirzepatide. All participants received concurrent lifestyle counseling, and the trial included a diverse set of clinical sites across the United States and Puerto Rico.
Next-generation therapies and future directions
Investigators are already testing next-generation multi-agonist compounds designed to act on three hormonal pathways (for example, GLP-1, GIP and glucagon). Early agents in development—such as retatrutide—aim to further increase weight-loss efficacy and potentially help people who do not respond adequately to current treatments. Ongoing and future trials will also evaluate whether these therapies reduce cardiovascular risk and provide durable long-term benefits.
Conflicts of interest
Dr. Louis Aronne, the principal investigator of SURMOUNT-5, has served as a paid consultant and advisory-board member for Eli Lilly (manufacturer of Zepbound/tirzepatide) and for Novo Nordisk (manufacturer of Wegovy/semaglutide). The trial was funded by Eli Lilly.
About this research
Author: Krystle Lopez
Source: Weill Cornell University
Contact: Krystle Lopez – Weill Cornell University
Image credit: Neuroscience News
Original research: “Tirzepatide as Compared with Semaglutide for the Treatment of Obesity” by Louis Aronne et al., published in the New England Journal of Medicine. (SURMOUNT-5; ClinicalTrials.gov number NCT05822830.)
Abstract
Background
Tirzepatide and semaglutide are effective pharmacologic approaches to weight loss. Direct comparative data on their relative efficacy and safety in adults with obesity but without type 2 diabetes were previously lacking.
Methods
In this phase 3b, open-label, randomized trial, 751 adults with obesity but without diabetes were assigned 1:1 to weekly subcutaneous tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) at maximum tolerated doses for 72 weeks. The primary endpoint was percent change in body weight from baseline to week 72. Key secondary endpoints included categorical weight-loss thresholds (≥10%, ≥15%, ≥20%, ≥25%) and change in waist circumference.
Results
Tirzepatide produced a mean −20.2% weight change versus −13.7% with semaglutide (P < 0.001). Waist circumference decreased more with tirzepatide (−18.4 cm vs. −13.0 cm; P < 0.001). Gastrointestinal adverse events were the most common side effects in both groups, generally mild to moderate and concentrated during dose escalation.
Conclusions
Among adults with obesity but without diabetes, tirzepatide was superior to semaglutide in reducing body weight and waist circumference after 72 weeks when both agents were used at their highest tolerated weekly doses.
Funding: Funded by Eli Lilly.