Tirzepatide as Compared with Semaglutide for the Treatment of Obesity - Article Summary

Summary Author: Maximillian Brune

Brief Summary:

Tirzepatide and semaglutide are both part of a new generation of drugs for the treatment of obesity. Semaglutide is a long-acting glucagon-like peptide 1 (GLP-1) agonist, while tirzepatide is both a GLP-1 agonist and a glucose dependent insulinotropic polypeptide (GIP). Both medications are highly effective in producing clinically important weight reductions, with prior cohort studies showing significantly greater weight loss with tirzepatide than semaglutide. However, this clinical trial marks the first direct comparison of the efficacy and safety of the two in adults with obesity but without type 2 diabetes.

Study Design:

This was a phase 3b, multicenter, parallel-arm, open-label, randomized, controlled clinical trial that was conducted over a 72 week period in the United States and Puerto Rico. Participants were included if they were 18 years of age or older, had a BMI of 30 or higher (or ≥27 with at least one obesity-related complication), and reported at least one unsuccessful dietary effort for weight loss. Participants were randomly assigned in a 1:1 ratio to receive a weekly dose of either the maximum tolerated dose of tirzepatide (titrated up to 10 or 15mg) or the maximum tolerated dose of semaglutide (titrated up to 1.7 mg or 2.4mg). A total of 750 patients received at least one dose of their assigned treatment, and 80.2% completed the 72 weeks of treatment (81.6% in the tirzepatide group and 78.7% in the semaglutide group). The primary endpoint was the percent change in body weight over the 72 weeks, and the key secondary endpoints were a weight reduction of at least 10%, 15%, 20%, and 25% and a change in waist circumference.

Findings:

Change in body weight: The mean percent change in body weight was -20.2% with tirzepatide (95% CI, -21.4 to -19.1) and -13.7% with semaglutide (95% CI, -14.9 to -12.6). The estimated treatment difference was -6.5% (95% CI, -8.1 to -4.9; P<0.001), showing that the weight reduction was significantly greater with tirzepatide. In addition, more patients treated with tirzepatide had reductions in body weight of at least 10%, 15%, 20%, and 25% (P<0.001).

Change in waist circumference: The mean change in waist circumference was −18.4 cm with tirzepatide (95% CI, −19.6 to −17.2) and −13.0 cm with semaglutide (95% CI, −14.3 to −11.7). The estimated treatment difference was −5.4 cm (95% CI, −7.1 to −3.6; P<0.001), showing that tirzepatide was also more efficacious in reducing waist circumference compared to semaglutide.

Strengths and Limitations:

One of the strengths of this study is in the diversity of their participants as 19% reported their race as Black and 26% reported their ethnic group as Hispanic or Latino, which is representative

of the US population living with obesity. One of the key limitations of this trial was that it was not blinded. However, the findings of this trial were consistent with the findings of previous blinded trials which supports its generalizability.

Conclusions:

In this direct comparison trial, tirzepatide showed significantly greater weight reduction over a 72-week period than semaglutide, as well as significantly greater reduction in waist circumference. Tirzepatide demonstrated a mean body weight reduction of 20.2% while the mean body weight reduction was 13.7% for participants receiving semaglutide. Additionally, the safety profiles were similar and consistent with prior trials of these drugs; adverse effects mostly consisted of mild to moderate gastrointestinal symptoms. While greater magnitudes of weight reduction can potentially lead to significant improvements in cardiovascular risk factors in some patients, not all patients will require higher magnitudes of weight reduction. For many, the treatment of choice will likely depend on insurance coverage, out-of-pocket costs, and treatment goals.

Main Takeaway

While both drugs induce clinically significant weight loss, tirzepatide shows superior efficacy in weight reduction compared to semaglutide.

References:

Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. New England Journal of Medicine. Published online May 11, 2025. doi:10.1056/NEJMoa2416394