What is the mechanism of action of tirzepatide (a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist)?

From the Guidelines

Tirzepatide works by mimicking two hormones in the body to help control blood sugar and promote weight loss, as a dual GIP and GLP-1 receptor agonist administered as a once-weekly injection. When injected, tirzepatide binds to GIP and GLP-1 receptors in the pancreas, stimulating insulin release when blood sugar levels are high while suppressing glucagon, a hormone that raises blood sugar 1. It also slows gastric emptying, making you feel full longer after eating, and acts on the brain to reduce appetite and food intake. The medication is typically started at a low dose (2.5 mg weekly) and gradually increased to minimize side effects like nausea and vomiting. The therapeutic dose ranges from 5 mg to 15 mg weekly, depending on the condition being treated and individual response. This dual-action mechanism makes tirzepatide particularly effective for both type 2 diabetes management and weight loss, as it addresses multiple aspects of metabolic regulation simultaneously.

Some key points to consider about tirzepatide include:

• It is a dual GIP and GLP-1 receptor agonist, which means it has a unique mechanism of action compared to other diabetes and weight loss medications 1.
• Tirzepatide has been shown to be effective in promoting weight loss, with a mean weight loss of 20.9% at 72-week follow-up in one study 1.
• The medication is administered via a once-weekly injection, which may be more convenient for some patients compared to daily or twice-daily medications.
• Tirzepatide has been associated with a range of benefits, including improved glycemic control, weight loss, and reduced risk of major adverse cardiovascular events, although the evidence for these benefits is still emerging and not all studies have found significant effects 1.

Overall, tirzepatide is a promising new medication for the treatment of type 2 diabetes and obesity, with a unique mechanism of action and a range of potential benefits. However, as with any medication, it is essential to carefully consider the potential risks and benefits and to monitor patients closely for any adverse effects.

From the FDA Drug Label

Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It is an amino-acid sequence including a C20 fatty diacid that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1 Tirzepatide enhances first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner.

Tirzapetide works by selectively binding to and activating both the GIP and GLP-1 receptors. This leads to:

• Enhanced first- and second-phase insulin secretion
• Reduced glucagon levels, both in a glucose-dependent manner 2

From the Research

Mechanism of Action

• Tirzepatide is a dual GIP/GLP-1 receptor co-agonist, which means it activates both the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors 3, 4, 5, 6, 7.
• The activation of these receptors leads to an increase in insulin secretion and a decrease in glucagon secretion, resulting in improved glycemic control 3, 5, 6.
• Tirzepatide also has an effect on food intake and body weight, with studies showing that it can reduce appetite and lead to significant weight loss 3, 4, 6, 7.

Pharmacokinetics

• Tirzepatide is administered via weekly subcutaneous injections, and its acylation technology allows it to bind to albumin, making it possible to dose the drug once a week 6.
• The drug has been shown to have a dose-dependent effect on glycemic and lipid control, as well as body weight, in patients with type 2 diabetes mellitus (T2DM) 6.

Clinical Trials

• The SURPASS phase III clinical trials, which include five global trials and the global SURPASS-CVOT trial, have been conducted to evaluate the safety and efficacy of tirzepatide in patients with T2D 7.
• The results of these trials have shown that tirzepatide is effective in reducing HbA1c and body weight, and has a favorable safety profile compared to other GLP-1 receptor agonists 3, 4, 6, 7.

Potential Benefits

• Tirzepatide has the potential to provide improved glycemic control, weight loss, and cardiovascular benefits for patients with T2D 3, 4, 6, 7.
• The drug's dual mechanism of action, targeting both GIP and GLP-1 receptors, may provide a more comprehensive approach to treating T2D and related comorbidities 5, 6, 7.