In 2021, the U.S. Food and Drug Administration (FDA) approved the use of 2.4?mg subcutaneous semaglutide for the treatment of obesity. Semaglutide mimics endogenous GLP-1 and activates its receptor in a prolonged manner due to chemical modifications that extend its duration of action in the body, promoting greater insulin secretion, reduced glucagon levels, delayed gastric emptying, and appetite regulation without causing hypoglycemia. 

Tirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors. The synergistic effect of these two incretins promotes weight loss and improves glycemic control. Unlike GLP-1, GIP regulates glucagon levels during hypoglycemic episodes and supports fat metabolism. Consequently, in 2023, tirzepatide was approved by the FDA for chronic weight management at a maximum dose of 15 mg.

Trial

A total of 28 RCTs were included, comprising 34?367 participants, 39.6% of whom were women and with a mean age of 57.8?±?8.95?years. Tirzepatide demonstrated superiority over semaglutide in percentage weight reduction (mean difference [MD] 6.10%; 95% CI: 3.64, 8.57), absolute weight loss (MD 4.55?kg; 95% CI: 1.28, 7.83), BMI reduction (MD 1.71?kg/m2; 95% CI: 0.08, 3.34), and waist circumference reduction (MD 2.89?cm; 95% CI: 1.25, 4.53). Regarding glycemic parameters, tirzepatide was also more effective than semaglutide in reducing HbA1c (MD 0.33%; 95% CI: 0.20, 0.46) and fasting blood glucose (MD 10.39?mg/dL; 95% CI: 4.48, 16.29)^[1].

Results

Tirzepatide demonstrated greater effectiveness in reducing body weight compared to semaglutide and placebo, both in percentage and absolute kilograms, and also led to more pronounced reductions in BMI and waist circumference.

Beyond weight loss, tirzepatide was superior to semaglutide in improving glycemic parameters, achieving greater reductions in HbA1c and fasting blood glucose in individuals with overweight or obesity.

References

[1] Bernardi, J. C., Cavalcante, D. V. S., Huntermann, R., Molinari, M. E., Zanon, L. Z., Khater, J., Gomez, V. A., & Fischer-Bacca, C. O. (2026). Who Wins the Battle Against Obesity? A Network Meta-Analysis Comparing Tirzepatide and Semaglutide. Journal of Diabetes, 18 2. https://doi.org/10.1111/1753-0407.70192