From the Guidelines
Tirzepatide works as a dual agonist that simultaneously activates both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, providing a synergistic effect on glycemic control and weight reduction. When tirzepatide binds to GLP-1 receptors in the pancreas, it stimulates insulin secretion in a glucose-dependent manner while suppressing glucagon release when blood glucose levels are elevated 1. Through GIP receptor activation, tirzepatide enhances this insulin response and may help preserve beta cell function. The medication also slows gastric emptying, which delays glucose absorption and contributes to reduced postprandial glucose excursions. Additionally, tirzepatide acts on the brain's appetite centers to increase satiety and reduce food intake, leading to weight loss 1. Some key points about tirzepatide's mechanism of action include:
- Dual GIP and GLP-1 receptor agonism
- Glucose-dependent insulin secretion
- Suppression of glucagon release
- Delayed gastric emptying
- Increased satiety and reduced food intake The synergistic effect of targeting both GIP and GLP-1 receptors appears to provide greater glycemic control and weight reduction than selective GLP-1 receptor agonists alone, as evidenced by studies showing tirzepatide's potent effects on both blood glucose management and weight reduction in patients with type 2 diabetes 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.
The mechanism of action (MOA) of Tirzepatide is as a dual GIP and GLP-1 receptor agonist. It works by:
- Enhancing first- and second-phase insulin secretion
- Reducing glucagon levels in a glucose-dependent manner
- Increasing insulin sensitivity
- Delaying gastric emptying, which slows post-meal glucose absorption and reduces postprandial glucose 2 2
From the Research
Mechanism of Action (MOA) of Tirzepatide
The mechanism of action of tirzepatide, a dual GIP and GLP-1 receptor agonist, involves the activation of 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.
- Insulin Secretion: Tirzepatide improves insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, a selective GLP-1 receptor agonist, and this is associated with lower prandial insulin and glucagon concentrations 3.
- Weight Loss: Tirzepatide causes greater weight loss than semaglutide, despite similar reductions in appetite, suggesting that GIPR agonism may contribute to weight loss through mechanisms other than reduced appetite 3.
- GIPR Agonism: GIPR agonism has been shown to mediate weight-independent insulin sensitization by tirzepatide in obese mice, improving insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT) 4.
- Glucose-Dependent Insulinotropic Polypeptide (GIP): GIP reduces food intake and body weight in rodents, but these effects have not been demonstrated in humans, and it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who are unresponsive to GIP 3.
Clinical Efficacy
Tirzepatide has been shown to be effective in reducing HbA1c and body weight in patients with type 2 diabetes, with a dose-dependent superiority in lowering HbA1c and reducing body weight compared to placebo, GLP-1 receptor agonists, and basal insulin regimens 5.
- HbA1c Reduction: Tirzepatide has been shown to reduce HbA1c by 1.24 to 2.58% in clinical trials, with a significant proportion of patients achieving an HbA1c of <5.7% 3.
- Body Weight Reduction: Tirzepatide has been shown to reduce body weight by 5.4-11.7 kg in clinical trials, with a significant proportion of patients losing more than 10% of their baseline body weight 3.
Safety Profile
Tirzepatide has been shown to have a similar safety profile to GLP-1 receptor agonists, with the most common adverse events being mild to moderate gastrointestinal events, including nausea, vomiting, diarrhea, and constipation 3, 5.
- Hypoglycemia: Tirzepatide has been shown to have a lower risk of hypoglycemia compared to basal insulin regimens 6, 5.
- Gastrointestinal Adverse Events: Tirzepatide has been shown to have a higher incidence of gastrointestinal adverse events, including nausea, vomiting, and diarrhea, compared to placebo, but similar to GLP-1 receptor agonists 5.