Dual GLP-1/GIP receptor agonists (e.g., tirzepatide) and multi-agonists (e.g., retatrutide) produce superior weight loss compared to single GLP-1 receptor agonists by synergistically enhancing anorectic effects in the CNS and reducing emetogenic side effects.

Tirzepatide, a new molecule recently approved by the FDA for the treatment of obesity, is a dual receptor agonist acting on the previously mentioned GLP-1 receptors and glucose-dependent insulinotropic peptide (GIP) receptors. It turned out to be more effective in reducing HbA1c levels and, above all, in reducing body weight compared to GLP-1R agonists... In animal models, it interacts synergistically with GLP-1, enhancing the anorectic effect in the CNS. Additionally, an increased expression of POMC was also demonstrated [73]. Activation of the GIP receptor in the hindbrain has another positive effect, which is the reduction in the emetogenic effect listed as one of the most common side effects of GLP-1RAs.