Tirzepatide is an FDA-approved dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist developed by Eli Lilly for the treatment of type 2 diabetes (Mounjaro, approved 2022) and obesity (Zepbound, approved 2023). It is the first FDA-approved dual incretin receptor agonist, representing a major advancement beyond single GLP-1 agonists like semaglutide. By activating both GIP and GLP-1 receptors, tirzepatide produces superior weight loss and glycemic control compared to GLP-1 monotherapy. In clinical trials, tirzepatide achieved up to 22.5% body weight reduction in obese adults and HbA1c reductions of 2-2.5% in type 2 diabetes patients. Administered once weekly via subcutaneous injection, tirzepatide has become one of the most effective pharmacologic treatments for obesity ever approved. The dual agonism exploits complementary mechanisms: GLP-1 primarily drives appetite suppression and glucose control, while GIP enhances insulin sensitivity, modulates adipose tissue metabolism, and may amplify GLP-1's effects on satiety.
5 days
Subcutaneous injection
25
~4800 Da
Tirzepatide acts as a 'dual agonist' activating both GIP and GLP-1 receptors: (1) GLP-1 receptor agonism: Stimulates glucose-dependent insulin secretion from pancreatic beta cells (reducing hypoglycemia risk), suppresses glucagon release from alpha cells, slows gastric emptying to prolong satiety, and activates hypothalamic GLP-1 receptors to reduce appetite and food intake; (2) GIP receptor agonism: Potentiates glucose-dependent insulin secretion (synergizing with GLP-1 effect), improves insulin sensitivity in adipose tissue and muscle, modulates adipocyte function to favor fat utilization over storage, and may act centrally to enhance GLP-1's appetite-suppressing effects. Tirzepatide is described as an 'imbalanced' dual agonist—it has higher GIP receptor activity than GLP-1 activity, which distinguishes it from a 'balanced' co-agonist. The GIP component appears to enhance metabolic benefits beyond GLP-1 alone, explaining superior efficacy vs. GLP-1 monotherapy (semaglutide). Tirzepatide is engineered for once-weekly dosing through modifications including a C20 fatty acid side chain that binds to albumin, extending half-life and preventing DPP-4 degradation.
Tirzepatide is one of the most extensively studied obesity/diabetes medications. SURPASS program (8 Phase 3 trials) for type 2 diabetes enrolled >13,000 patients. SURMOUNT program (4 Phase 3 trials) for obesity enrolled >5,000 patients. FDA-approved based on robust efficacy and safety data. Ongoing cardiovascular outcomes trial (SURPASS-CVOT). Real-world evidence accumulating since 2022 Mounjaro approval and 2023 Zepbound approval. Tirzepatide represents a paradigm shift in obesity pharmacotherapy—first dual incretin agonist approved.
39-amino acid synthetic peptide with fatty acid side chain for albumin binding