What is the mechanism of action of Mounjaro (tirzepatide)?

From the Guidelines

Tirzepatide (Mounjaro) works through a dual mechanism of action as both a GIP (glucose-dependent insulinotropic polypeptide) receptor agonist and a GLP-1 (glucagon-like peptide-1) receptor agonist, as reported in a recent review on obesity management in adults 1. The medication's dual-hormone agonistic activity allows it to stimulate insulin secretion in a glucose-dependent manner, slow gastric emptying, decrease glucagon secretion, and increase satiety, leading to reduced postprandial glucose spikes and weight loss. Some key points about the mechanism of action of tirzepatide include:

• Dual receptor activation: tirzepatide binds to and activates both GIP and GLP-1 receptors on pancreatic beta cells, stimulating insulin secretion in a glucose-dependent manner 1.
• Glucose-dependent insulin secretion: insulin is only released when blood glucose levels are elevated, reducing the risk of hypoglycemia.
• Delayed gastric emptying: tirzepatide slows gastric emptying, delaying glucose absorption and contributing to reduced postprandial glucose spikes.
• Decreased glucagon secretion: tirzepatide decreases glucagon secretion from pancreatic alpha cells when glucose levels are elevated, further helping to lower blood glucose.
• Appetite regulation: the medication acts on the brain to increase satiety and reduce hunger, leading to decreased food intake and weight loss, as demonstrated in a recent meta-analysis of RCTs that included 12,371 adults with overweight or obesity without diabetes 1. The combination of these effects makes tirzepatide particularly effective for managing type 2 diabetes and promoting weight loss, with a recent study showing that 15 mg weekly of tirzepatide was associated with greater weight loss compared with other medications 1.

From the Research

Mechanism of Action of Mounjaro (Tirzepatide)

The mechanism of action of Mounjaro (tirzepatide) involves its role as a dual incretin agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors 2, 3, 4, 5.

• Key Components:
  • Tirzepatide is engineered to activate both GIP and GLP-1 receptors, which are key mediators of insulin secretion and are also expressed in regions of the brain that regulate food intake 3.
  • The activation of these receptors leads to improved glycaemic control and body weight reduction 2, 3, 4, 5.
• Physiological Effects:
  • The dual action on GIP and GLP-1 receptors results in enhanced insulin secretion and sensitivity, as well as reduced glucagon levels, leading to improved glycaemic control 3, 4.
  • Tirzepatide also affects appetite regulation and energy metabolism, contributing to its weight-loss effects 3, 5.
• Pharmacological Profile:
  • Tirzepatide is a synthetic linear peptide with acylation technology that allows it to bind to albumin, enabling once-weekly subcutaneous dosing 4, 5.
  • Its pharmacokinetic profile supports its use as a once-weekly injection for the treatment of type 2 diabetes mellitus (T2DM) 4.
• Clinical Implications:
  • The unique mechanism of action of tirzepatide offers a promising approach for the treatment of T2DM and related cardiometabolic disorders, with significant improvements in glycaemic control, weight loss, and lipid metabolism 2, 3, 4, 5.
  • Further research is needed to fully understand the contribution of GIP receptor activation to the clinical effects of tirzepatide and to explore its potential in other therapeutic areas 6.