Tirzepatide

Tirzepatide is the first approved dual GIP/GLP-1 receptor co-agonist — a 39-amino acid synthetic peptide often termed a "twincretin" — that integrates the actions of two endogenous incretin hormones into a single molecule. Its structure is based on the native GIP peptide sequence with α-aminoisobutyric acid (Aib) substitutions at positions 2 and 13 to resist DPP-4 degradation, and a C20 eicosanedioic acid fatty diacid is covalently attached via a γGlu-(AEEA)2 linker at position 20 lysine, enabling once-weekly dosing with a half-life of approximately 5 days. Tirzepatide exhibits an "imbalanced" agonism profile — comparable affinity to native GIP at the GIPR but approximately 18–20× weaker affinity for GLP-1R than native GLP-1. This pharmacological difference produces unique metabolic synergy: co-activation of both receptors generates insulin responses and glucagonostatic effects that exceed either incretin alone. The SURPASS clinical trial program documented that tirzepatide reduces HbA1c and body weight to a significantly greater extent than selective GLP-1 agonists including semaglutide, with weight reductions of up to 22.5% in obese subjects at 15 mg weekly dosing. Beyond glycemic and weight effects, tirzepatide research has demonstrated improvements in insulin sensitivity, beta-cell function, lipid profiles, blood pressure, and markers of hepatic steatosis. The SURMOUNT-4 trial established durable weight loss maintenance with continued treatment. Active research areas include heart failure with preserved ejection fraction (HFpEF), sleep apnea, NASH, chronic kidney disease, and metabolic syndrome.