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 capabilities. Tirzepatide (Mounjaro, Zepbound) is a dual GIP/GLP-1 receptor agonist that typically produces greater A1C reduction (2.0-2.4%) and weight loss (15-20% of body weight) compared to semaglutide (Ozempic, Wegovy), which is a GLP-1 receptor agonist that typically reduces A1C by 1.4-1.8% and weight by 10-15% 1. Some key points to consider when choosing between these medications include:

• Dosage: Tirzepatide is dosed weekly starting at 2.5mg and titrating up to a maximum of 15mg, while semaglutide starts at 0.25mg weekly and increases to a maximum of 2mg (for diabetes) or 2.4mg (for weight management).
• Side effects: Both medications have similar side effect profiles including nausea, vomiting, and diarrhea, which typically improve with time. Tirzepatide may cause more gastrointestinal side effects initially but offers potentially greater efficacy.
• Cost and insurance coverage: These factors vary significantly between these medications and may influence choice.
• Lifestyle modifications: Both medications should be used alongside lifestyle modifications for optimal results. It's also important to note that while semaglutide has been shown to reduce MACE in patients with type 2 diabetes and CVD, including underlying PAD 1, tirzepatide's effects on MACE are still being studied. However, based on the available evidence, tirzepatide is the preferred choice for patients with type 2 diabetes and weight management due to its superior efficacy.

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. 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.

The main difference between tirzepatide and semaglutide is that tirzepatide is a dual GIP and GLP-1 receptor agonist, while semaglutide is a GLP-1 receptor agonist only.

• Mechanism of action: Tirzepatide enhances first- and second-phase insulin secretion and reduces glucagon levels by activating both GIP and GLP-1 receptors, whereas semaglutide stimulates insulin secretion and lowers glucagon secretion by activating the GLP-1 receptor only.
• Pharmacodynamics: Both tirzepatide and semaglutide lower fasting and postprandial glucose concentrations and reduce body weight in patients with type 2 diabetes mellitus.
• Key differences: The dual mechanism of action of tirzepatide may provide additional benefits in terms of glucose control and weight loss compared to semaglutide 2, 3.

From the Research

Comparison of Tirzepatide and Semaglutide

• Tirzepatide is a dual GIP/GLP-1 receptor 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, is a well-established GLP-1 receptor agonist that 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 shown to be effective in reducing HbA1c by 1.24-2.58% and body weight by 5.4-11.7 kg in clinical trials 4
• Semaglutide has been shown to be effective in reducing HbA1c by 1.0-1.5% and body weight by 2.3-5.5 kg in clinical trials 7, 4
• Both tirzepatide and semaglutide have been associated with gastrointestinal adverse events, such as nausea, vomiting, and diarrhea, but the incidence of these events is higher with tirzepatide 4, 5, 6

Clinical Implications

• Tirzepatide may be a more effective treatment option for patients with type 2 diabetes who require greater improvements in glycemic control and body weight loss 4, 5
• Semaglutide may be a more suitable treatment option for patients who are at risk of gastrointestinal adverse events or who require a more established treatment with a longer safety profile 7, 4
• Further studies are needed to fully understand the clinical implications of tirzepatide and semaglutide in the treatment of type 2 diabetes 4, 5