How do GLP-1 agonists like Semaglutide and Tirzepatide promote weight loss?

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide, and dual GLP-1/GIP receptor agonists such as tirzepatide, promote weight loss primarily by reducing appetite and caloric intake through central and peripheral mechanisms. These agents mimic the action of endogenous GLP-1, a gut hormone released after food intake, which acts on GLP-1 receptors in the hypothalamus and other brain regions to increase satiety and decrease hunger, leading to a significant reduction in food intake. Semaglutide also delays gastric emptying, further enhancing postprandial fullness and reducing overall caloric consumption.[1][3-4]

Tirzepatide, in addition to GLP-1 receptor agonism, activates the glucose-dependent insulinotropic polypeptide (GIP) receptor. GIP receptor activation is hypothesized to further suppress appetite via central pathways and may also directly influence adipocyte metabolism, potentially enhancing lipolysis and improving energy balance. The dual agonism of tirzepatide is thought to explain its greater weight loss efficacy compared to GLP-1 RA monotherapy.[1-2][4][6]

The American College of Cardiology and the American Diabetes Association both state that these medications are among the most effective pharmacologic options for obesity, with semaglutide 2.4 mg and tirzepatide 10–15 mg once weekly producing mean weight reductions of 13–19% in randomized controlled trials.[1][7] The American Gastroenterological Association also highlights the pleiotropic metabolic effects of GLP-1 RAs, including appetite suppression, delayed gastric emptying, and improved glycemic control.[3] Gastrointestinal adverse effects are common but typically mild and transient, especially during dose escalation.[8]

1.2025 Concise Clinical Guidance: An ACC Expert Consensus Statement on Medical Weight Management for Optimization of Cardiovascular Health: A Report of the American College of Cardiology Solution Set Oversight Committee.

Gilbert O, Gulati M, Gluckman TJ, et al.

Journal of the American College of Cardiology. 2025;:S0735-1097(25)06504-0. doi:10.1016/j.jacc.2025.05.024.

Practice Guideline

Leading Journal

New Research

2.Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.

Aronne LJ, Horn DB, le Roux CW, et al.

The New England Journal of Medicine. 2025;. doi:10.1056/NEJMoa2416394.

Leading Journal

New Research

3.AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.