How does tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist) work to regulate blood sugar levels in patients with type 2 diabetes?

From the Guidelines

Tirzepatide effectively regulates blood sugar in type 2 diabetes by simultaneously activating both GLP-1 and GIP receptors, providing a dual-action mechanism that stimulates insulin secretion, suppresses glucagon release, slows gastric emptying, and increases satiety, leading to reduced food intake and weight loss. This medication works through several key mechanisms:

• Stimulating insulin secretion from pancreatic beta cells when glucose levels are elevated
• Suppressing glucagon release from alpha cells to prevent excess glucose production by the liver
• Slowing gastric emptying to reduce post-meal glucose spikes
• Increasing satiety, leading to reduced food intake and weight loss, as noted in studies such as 1 and 1. The standard dosing begins at 2.5 mg once weekly by subcutaneous injection for 4 weeks, then increases to 5 mg weekly, with potential further increases to 10 mg and 15 mg weekly as needed based on glycemic response and tolerability, as outlined in guidelines like those found in 1. Common side effects include nausea, vomiting, and diarrhea, which typically improve over time, as discussed in 1 and 1. Tirzepatide's effectiveness stems from its unique structure as a single molecule that targets both incretin hormone pathways, providing more robust glycemic control than medications that target only one pathway, as highlighted in 1 and 1. This dual receptor activation creates synergistic effects that enhance insulin secretion while reducing glucagon levels, addressing multiple aspects of the metabolic dysfunction present in type 2 diabetes, making it a preferred agent for managing type 2 diabetes, especially in patients with established or high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, as recommended in 1 and 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 works by:

• Activating GLP-1 and GIP receptors: This helps to increase insulin secretion and decrease glucagon levels in a glucose-dependent manner.
• Enhancing first- and second-phase insulin secretion: This means that tirzepatide helps the body to release more insulin when blood sugar levels are high.
• Reducing glucagon levels: Glucagon is a hormone that raises blood sugar levels, so reducing its levels helps to lower blood sugar.
• Delaying gastric emptying: This slows down the absorption of glucose from food, which helps to reduce postprandial (after meal) glucose spikes.
• Increasing insulin sensitivity: This means that the body's cells are more responsive to insulin, which helps to lower blood sugar levels.

Overall, tirzepatide helps to regulate blood sugar levels in patients with type 2 diabetes by increasing insulin secretion, decreasing glucagon levels, and slowing down glucose absorption. 2

From the Research

How Tirzepatide Works

Tirzepatide is a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist that works to regulate blood sugar levels in patients with type 2 diabetes.

• It is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake 3.
• The activation of these receptors leads to an increase in insulin secretion and a decrease in glucagon secretion, resulting in improved glycemic control 4.
• Tirzepatide also reduces food intake and delays gastric emptying, which contributes to its weight-loss effects 4.
• Additionally, tirzepatide has been shown to improve insulin sensitivity and reduce body weight, which are important factors in the management of type 2 diabetes 3, 5.

Mechanism of Action

The exact mechanism of action of tirzepatide is not fully understood, but it is thought to involve the activation of both GLP-1 and GIP receptors.

• Some studies suggest that tirzepatide may have a biased GLP-1 receptor activation profile and GIP receptor downregulation 6.
• Further research is needed to fully understand the mechanism of action of tirzepatide and its effects on glucose metabolism and weight loss 6, 7.

Clinical Effects

Tirzepatide has been shown to have significant clinical effects in patients with type 2 diabetes, including:

• Improved glycemic control, with reductions in HbA1c of up to 2.58% 3.
• Significant weight loss, with up to 11.7 kg of weight lost in clinical trials 3.
• Improved insulin sensitivity and reduced body weight 3, 5.
• Reduced risk of cardiovascular events, although further research is needed to confirm this effect 3, 5.