What is the comparison between Tirzepatide (Dual Glucagon-Like Peptide-1 (GLP-1) and Glucagon Receptor Agonist) and Semaglutide (Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist)?

From the Guidelines

Tirzepatide is generally considered superior to semaglutide for type 2 diabetes and weight management due to its greater A1C reduction and weight loss benefits, despite potential increased gastrointestinal side effects. When comparing tirzepatide and semaglutide, several key points should be considered:

• Tirzepatide is a dual GIP/GLP-1 receptor agonist, whereas semaglutide is a GLP-1 receptor agonist.
• The dosing regimens differ, with tirzepatide starting at 2.5mg and titrating up to 15mg weekly, and semaglutide starting at 0.25mg and increasing to a maximum of 2mg weekly for diabetes or 2.4mg for weight management.
• Both medications have similar side effect profiles, including nausea, vomiting, and diarrhea, which typically improve over time 1.
• The choice between these medications may be influenced by cost and insurance coverage, which can vary significantly.
• Patients should start with the lowest dose and gradually increase to minimize side effects, and can take the medication with or without food, storing it in the refrigerator until first use.
• It is essential to consider the potential benefits and risks of each medication, including the reduction of major adverse cardiovascular events (MACE) and the improvement of glycemic control and weight loss, as reported in recent studies 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 Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1.

Comparison of Mechanism of Action:

• Tirzepatide is a dual GIP and GLP-1 receptor agonist, while semaglutide is a GLP-1 receptor agonist only.
• Both drugs enhance insulin secretion and reduce glucagon levels in a glucose-dependent manner.
• Tirzepatide also delays gastric emptying, which slows post-meal glucose absorption and reduces postprandial glucose.

Key Differences:

• Tirzepatide has a dual mechanism of action, targeting both GIP and GLP-1 receptors, while semaglutide only targets the GLP-1 receptor.
• The pharmacokinetics of tirzepatide and semaglutide are similar, with both drugs having a long half-life enabling once-weekly dosing 2, 3.

From the Research

Comparison of Tirzepatide and Semaglutide

• Tirzepatide is a dual GIP/GLP-1 receptor co-agonist, while semaglutide is a selective GLP-1 receptor agonist 4
• Tirzepatide has been shown to be more effective in reducing HbA1c and body weight compared to semaglutide in clinical trials 4, 5
• In the SURPASS-1 trial, tirzepatide monotherapy resulted in significant improvements in glycemic control and body weight loss, with a dose-dependent effect 6
• Semaglutide, on the other hand, has been shown to be effective in reducing HbA1c and body weight, but to a lesser extent compared to tirzepatide 7, 4

Efficacy and Safety

• Tirzepatide has been associated with a higher incidence of gastrointestinal adverse events, such as nausea, vomiting, and diarrhea, compared to semaglutide 4, 5, 6
• However, tirzepatide has not been shown to increase the risk of hypoglycemia, which is a common adverse event associated with other glucose-lowering therapies 4, 5, 6
• Semaglutide has been shown to be safe and effective in reducing the risk of major cardiovascular events, such as myocardial infarction and stroke, in patients with type 2 diabetes 7, 8

Clinical Implications

• Tirzepatide may be a useful treatment option for patients with type 2 diabetes who require improved glycemic control and weight loss, particularly those who have not responded to other therapies 4, 5, 6
• Semaglutide may be a suitable option for patients with type 2 diabetes who are at high risk of cardiovascular events, or those who require a treatment with a established cardiovascular benefit 7, 8
• Further research is needed to fully understand the clinical implications of tirzepatide and semaglutide, and to determine their optimal use in clinical practice 4, 5