How does Mounjaro (tirzepatide) lower blood glucose levels?

From the Guidelines

Mounjaro (tirzepatide) lowers blood sugar by mimicking two hormones that regulate glucose levels in the body, specifically as a dual GIP and GLP-1 receptor agonist, as noted in the 2024 systematic review and network meta-analysis for the American College of Physicians 1.

Mechanism of Action

Mounjaro works in multiple ways to lower blood glucose levels:

• Stimulates insulin release from the pancreas in a glucose-dependent manner, meaning it only increases insulin when blood sugar is elevated
• Slows gastric emptying, which delays glucose absorption and reduces post-meal blood sugar spikes
• Suppresses glucagon secretion, a hormone that normally raises blood sugar
• Promotes satiety, leading to reduced food intake and potential weight loss, which further improves insulin sensitivity

Administration and Dosage

Mounjaro is typically administered as a once-weekly subcutaneous injection, with starting doses of 2.5 mg for the first 4 weeks, then gradually increasing to 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg based on blood sugar response and tolerability, as suggested by the 2024 standards of care in diabetes 1.

Side Effects

Common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, and constipation, which often improve over time, as reported in the 2024 systematic review and network meta-analysis for the American College of Physicians 1.

Clinical Considerations

When considering the use of Mounjaro, it is essential to weigh the benefits of improved glycemic control against potential side effects and consider individual patient factors, such as cardiovascular risk and renal function, as discussed in the 2024 standards of care in diabetes 1 and the 2024 systematic review and network meta-analysis for the American College of Physicians 1.

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. Tirzepatide lowers fasting and postprandial glucose concentration, decreases food intake, and reduces body weight in patients with type 2 diabetes mellitus. Tirzepatide reduces fasting and postprandial glucagon concentrations Tirzepatide delays gastric emptying. The delay is largest after the first dose and this effect diminishes over time. Tirzepatide slows post-meal glucose absorption, reducing postprandial glucose.

Mounjaro (tirzepatide) lowers blood glucose levels by:

• Enhancing first- and second-phase insulin secretion
• Reducing glucagon levels
• Delaying gastric emptying and slowing post-meal glucose absorption
• Increasing insulin sensitivity 2

From the Research

Mechanism of Action

• Mounjaro (tirzepatide) is a dual glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist, which helps to lower blood glucose levels 3, 4.
• The incretin effect, which is the greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, is markedly reduced or absent in type 2 diabetes, and tirzepatide helps to improve this effect 5.
• Tirzepatide reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists, such as semaglutide 4, 5.

Clinical Trials

• The SURPASS clinical trials have demonstrated that tirzepatide has potent glucose-lowering and weight-loss effects, with adverse effects comparable to GLP-1 receptor agonists 3, 4, 6, 7.
• In the SURPASS-4 trial, tirzepatide was compared to insulin glargine in adults with type 2 diabetes and high cardiovascular risk, and was found to have greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycemia 6.
• The SURPASS trials have also shown that tirzepatide is effective in reducing body weight, with a significant proportion of patients achieving a weight loss of more than 10% of their baseline body weight 4, 7.

Efficacy and Safety

• Tirzepatide has been shown to be safe and effective in treating type 2 diabetes, with most adverse events being gastrointestinal in nature 4, 6, 7.
• The medication has been found to have a low withdrawal rate in active treatment arms, and is likely to be recommended as a preferred option in the American Diabetes Association treatment algorithm for high glucose-lowering effects in patients with a compelling need for low hypoglycemia risk and weight loss 7.
• Tirzepatide has also been found to improve insulin sensitivity and insulin secretory responses, and to reduce prandial insulin and glucagon concentrations 4.