From the Guidelines
Tirzepatide has a dual receptor binding profile, activating both GIP and GLP-1 receptors, whereas semaglutide is a selective GLP-1 receptor agonist, which may contribute to the differences in their efficacy and metabolic benefits. The receptor sensitivities of tirzepatide and semaglutide differ significantly, with tirzepatide having a higher affinity for GIP receptors compared to GLP-1 receptors, approximately 5-fold less than that of endogenous GLP-1 for the GLP-1 receptor 1. Some key points to consider are:
- Tirzepatide's dual receptor activation is thought to provide complementary and potentially synergistic effects on glucose control and weight loss.
- Semaglutide, on the other hand, binds exclusively to GLP-1 receptors with high affinity and specificity, activating only the GLP-1 pathway.
- The dual receptor engagement of tirzepatide is believed to contribute to its greater efficacy in clinical trials, where it has demonstrated superior glycemic control and weight reduction compared to semaglutide at their respective therapeutic doses 1.
- A recent meta-analysis of RCTs reported that 15 mg weekly of tirzepatide was associated with greater weight loss compared with 2.4 mg weekly of subcutaneous semaglutide, with a mean difference of 5.1% 1. Overall, the difference in receptor pharmacology between tirzepatide and semaglutide may explain why tirzepatide offers enhanced metabolic benefits in patients with type 2 diabetes and obesity.
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.
The main difference in receptor sensitivities between tirzepatide and semaglutide is that:
- Tirzepatide is a dual GIP and GLP-1 receptor agonist, activating both receptors.
- Semaglutide is a GLP-1 receptor agonist, only activating the GLP-1 receptor. There is no direct comparison of the receptor sensitivities of tirzepatide and semaglutide in the provided drug labels 2 3.
From the Research
Receptor Sensitivities of Tirzepatide and Semaglutide
- Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, whereas semaglutide is a selective GLP-1 receptor agonist 4, 5.
- The dual action of tirzepatide on both GIP and GLP-1 receptors may contribute to its greater efficacy in reducing HbA1c and body weight compared to semaglutide 5, 6, 7.
Comparison of Efficacy
- Studies have shown that tirzepatide is noninferior and superior to semaglutide in reducing HbA1c levels and body weight in patients with type 2 diabetes 5, 6, 7.
- The mean difference in weight loss between tirzepatide and semaglutide was -4.84 kg, favoring tirzepatide 6.
- Tirzepatide also demonstrated a more pronounced effect on HbA1c and weight reduction compared to semaglutide in a network meta-analysis of randomized controlled trials 7.
Safety Profiles
- Both tirzepatide and semaglutide have similar safety profiles, with the most common adverse events being gastrointestinal in nature 5, 6, 7.
- The incidence of serious adverse events and severe hypoglycemia was similar between the two drugs 5, 7.
Potential Therapeutic Uses
- Tirzepatide and semaglutide may also have potential therapeutic benefits in patients with type 1 diabetes, double diabetes, and latent autoimmune diabetes in adults, although more research is needed to fully understand their effects in these populations 8.